WO2024178386A1 - Methods of treating endosomal trafficking diseases - Google Patents

Abstract

S0RL1 encodes the retromer-associated receptor SORL1 that functions in endosomal recycling. Rare variants in SORL1 have been associated with Alzheimer's disease (AD) and rare pathogenic variants are estimated to occur in up to 2.75% of early onset AD patients and in 1.5% of unrelated late onset AD patients. While truncation mutations are observed almost exclusively in AD patients, it is currently unknown which among the hundreds of rare missense variants identified in SORL1, are pathogenic. This question is addressed by relying on SORLl's distinct molecular architecture. First, a structure-guided sequence alignment was completed for all the protein domains. Next, proteins that contain domains homologous to those of SORL1 were identified, which include pathogenic variants for monogenic diseases. The analogous domain positions of these variants in the SORL1 protein sequence were identified and showed that variants in these positions similarly impair SORL1, and lead to AD. Together, the findings represent a comprehensive compendium on SORL1 protein variation and functional effects, which allowed for the prioritization of SORL1 genetic variants into high or moderate priority mutations. This compendium may be used by clinical geneticists for assessing variants they identify in patients, allowing further development of diagnostic procedures and patient counseling strategies. Ultimately, this compendium will inform investigations into the molecular mechanisms of endosomal recycling which will support the development of therapeutic treatment strategies for SORL1 variant-carrying patients.

Description

METHODS OF TREATING ENDOSOMAL TRAFFICKING DISEASES [0001] This application claims priority under 35 U.S.C. § 119(e) of U.S. Provisional Application, U.S.S.N.63/448,227 filed February 24, 2023, which is incorporated herein by reference. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING [0002] The contents of the electronic sequence listing (R085670007WO00-SEQ- CHB.xml; Size: 537,516 bytes; and Date of Creation: February 22, 2024) is herein incorporated by reference in its entirety. BACKGROUND [0003] Neurodegenerative diseases, such as Alzheimer’s disease, affect millions of people across the world each year. Alzheimer’s disease causes memory loss, decreased cognition, and death. Regulation of endosomal trafficking in the brain appears to play a role in the development of neurodegenerative diseases, such as Alzheimer’s disease. In humans, SORL1 is important for the regulation of endosomal trafficking. SORL1 is a member of the VPS10p- domain receptor family of type 1 sorting receptors and specifically functions to transport proteins from the membrane to endosomes and eventually to the lysosome. A number of loss- of-function mutations in SORL1 have been associated with both early-onset and late-onset Alzheimer’s disease. Other mutations in SORL1 associated with Alzheimer’s disease are known to reduce SORL1 expression levels. SORL1 regulates release of amyloid precursor protein (APP) from endosomes, thereby impacting processing of APP into amyloidogenic forms. Additionally, SORL1 interacts with the retromer complex which regulates trafficking of cargo out of endosomes. Importantly, studies indicate that dysregulation of retromer subunits is associated with amyloidogenesis and Alzheimer’s disease. Therefore, modulating SORL1- and retromer-dependent pathways is a potential therapeutic approach for the treatment of neurodegenerative diseases, such as Alzheimer’s disease. SUMMARY [0004] SORL1 encodes a retromer-associated receptor that functions in endosomal recycling. Rare variants in SORL1 have been associated with Alzheimer’s disease (AD), and rare pathogenic variants are estimated to occur in up to 2.75% of early onset AD patients and in exclusively in AD patients, it is currently unknown which among the hundreds of rare missense variants identified in SORL1, are pathogenic. Using the methods, compositions, and systems described herein, this question is addressed by relying on SORL1’s distinct molecular architecture. [0005] The disclosure relates, at least in part, to mutations that affect SORL1 structures that are involved in cellular processes including, but not limited to, endosomal trafficking. SORL1 mutations described herein include those that disrupt and/or reduce the function of SORL1 in endosomal trafficking pathways which are implicated in cellular changes associated with neurological diseases, such as a protein aggregation (e.g., aggregation of amyloid and/or tau proteins), oxidative stress, altered cell-cell signaling in the central nervous system, neuroinflammation, cytotoxicity, and other abnormalities. Therapeutic agents of the disclosure can be administered to a subject characterized as having or suspected of having a SORL1/SORL1 mutation described herein and used to, for example, modulate endosomal trafficking in nervous system tissue cells, such as by altering the levels and/or activity of endosomal trafficking pathway factors (e.g., regulators and/or cargos), genetically edit SORL1 sequences comprising disease-associated mutations, and/or reduce the expression of SORL1 mutants comprising disease-associated mutations. [0006] Accordingly, aspects of the present disclosure relate to methods for treating a neurological disease in a cell, biological sample, or subject comprising a SORL1 gene comprising a disease-associated mutation described herein. [0007] Other aspects of the present disclosure relate to methods of treating a neurological disease in a cell, biological sample, or subject comprising obtaining a query SORL1 gene sequence from the cell, biological sample, or subject; identifying the presence of a disease- associated mutation in the query SORL1 gene sequence; and administering to the cell, biological sample, or subject an agent that modulates endosomal trafficking. [0008] Other aspects of the present disclosure relate to methods for modulating endosomal trafficking in a cell, biological sample, or subject comprising obtaining a query SORL1 gene sequence from the cell, biological sample, or subject; identifying the presence of a disease- associated mutation in the query SORL1 gene sequence; and administering to the cell, biological sample, or subject an agent that modulates endosomal trafficking. [0009] Other aspects of the present disclosure relate to methods of identifying a subject for treatment comprising obtaining a query SORL1 gene sequence from the cell, biological sample, or subject; identifying the presence of a disease-associated mutation in the query SORL1 gene sequence; and administering to the subject an agent that modulates endosomal trafficking. In some embodiments, the step of identifying the presence of the disease- associated mutation in the query SORL1 gene sequence comprises aligning the query SORL1 gene sequence against a reference SORL1 gene sequence comprising the disease-associated mutation. [0010] In some embodiments, the disease-associated mutation in the SORL1 gene occurs in the VPS10p domain, the 10CC domain, the YWTD domain, the EGF domain, the CR domain, the FnIII domain, the transmembrane-domain, or the cytoplasmic tail domain. In some embodiments, the disease-associated mutation is a pathogenic mutation as set forth in Table 13. [0011] In some embodiments, the disease-associated mutation is a mutation implicated in a neurological disease. In some embodiments, the neurological disease is a neurodegenerative disease, optionally wherein the neurodegenerative disease is selected from the group consisting of Parkinson’s Disease, Dementia, Pick’s Disease, Lewy Body Dementia, Huntington’s Disease, Alzheimer’s disease, Early-Onset Alzheimer’s disease, Late-Onset Alzheimer’s disease, and Familial Alzheimer’s disease. [0012] In some embodiments, administering the agent comprises administering a small molecule, a biologic (e.g., protein, peptide, polynucleotide), a gene therapy, a gene-editing therapy, or any combination thereof. In some embodiments, the small molecule therapy comprises administration of an aminoguanidine hydrazone. In some embodiments, the small molecule therapy comprises administration of a retromer chaperone. In some embodiments, the gene therapy comprises administration of an engineered nucleic acid or a transgene encoding a retromer protein VPS35, VPS26a, or VPS26b. In some embodiments, the gene therapy comprises administration of an antisense oligonucleotide (ASO) comprising sequence complementarity to a SORL1 mRNA transcript comprising the disease-associated mutation. In some embodiments, the ASO is an exon-skipper. In some embodiments, the gene therapy comprises administration of an engineered nucleic acid encoding a SORL1 variant. In some embodiments, the SORL1 variant is provided in a transgene flanked by adeno-associated virus (AAV) inverted terminal repeats (ITRs) or long terminal repeats (LTRs). In some embodiments, the vector comprises a polynucleotide that is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% sequence identical to any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43-59. In some embodiments, the vector comprises the polynucleotide sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 29- 32, 35-37, or 43-59. In some embodiments, the vector is a lentivirus. In some embodiments, the vector is a recombinant adeno-associated virus. In some embodiments, the gene-editing therapy comprises a nuclease and a guide RNA (gRNA) comprising a sequence that is complementary to a region of SORL1. In some embodiments, the gene-editing therapy corrects a disease-associated mutation in SORL1. [0013] In some embodiments, administration of a therapeutic agent increases SORL1 activity in the cell, biological sample, or subject. In some embodiments, administration of a therapeutic agent increases sAPPα in the cell, biological sample, or subject. In some embodiments, administration of a therapeutic agent decreases Aβ30, Aβ40, and/or Aβ42 in the cell, biological sample, or subject. In some embodiments, administration of a therapeutic agent increases VPS35 activity in the cell, biological sample, or subject. [0014] Other aspects of the present disclosure relate to methods for identifying mutation(s) in SORL1 that are associated with abnormal endosomal trafficking comprising aligning a clustered domain or repeat sequence within a query SORL1 gene sequence against a reference sequence corresponding to a disease-associated gene variant and identifying mutations in the query SORL1 gene sequence that align with a disease-associated domain position in the reference sequence, wherein the disease-associated domain position comprises homology to one or more cluster domains or repeat sequences of the query SORL1 gene sequence. [0015] In some embodiments, the cluster domain or repeat sequence corresponds to the VPS10p domain, the 10CC domain, the YWTD motif, the EGF domain, the CR domain, the FnIII-domain, the transmembrane domain, or cytoplasmic tail domain. [0016] In some embodiments, the query SORL1 gene sequence is obtained from a cell, biological sample, or subject. [0017] In some embodiments, the subject or the cell or biological sample are derived from a subject who is characterized as suspected of having, diagnosed with, or at risk of developing a neurological disease. In some embodiments, the neurological disease is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is selected from the group consisting of Parkinson’s Disease, Dementia, Pick’s Disease, Lewy Body Dementia, Huntington’s Disease, Alzheimer’s disease, Early-Onset Alzheimer’s disease, Late-Onset Alzheimer’s disease, and Familial Alzheimer’s disease. [0018] In some embodiments, the method further comprises assaying the endosomal trafficking activity of SORL1 in the biological sample. [0019] In some embodiments, the method further comprises assaying the activity or protein level of sAPPα, Aβ30, Aβ40, Aβ42, and/or VPS35 in the biological sample. [0020] Other aspects of the disclosure relate to an agent or a plurality thereof for use in a method of comprising administering the agent or the plurality thereof to the subject, wherein the agent comprises a small molecule therapy, a biologic, a gene therapy, or a gene-editing therapy and the plurality thereof comprises any combination of the small molecule therapy, the gene therapy or the gene-editing therapy, wherein the subject is characterized as having or is suspected of having a disease-associated mutation in SORL1 which is encoded by a SORL1 gene sequence. [0021] Other aspects of the disclosure relate to use of an agent or a plurality thereof in the manufacture of a medicament for the treatment of a subject characterized as having or suspected of having a disease-associated mutation in SORL1 which is encoded by a SORL1 gene sequence, wherein the agent comprises a small molecule therapy, a biologic, a gene therapy, or a gene-editing therapy and the plurality thereof comprises any combination of the small molecule therapy, the biologic, the gene therapy or the gene-editing therapy. [0022] The summary above is meant to illustrate, in a non-limiting manner, some of the embodiments, advantages, features, and uses of the technology disclosed herein. Other embodiments, advantages, features, and uses of the technology disclosed herein will be apparent from the Detailed Description, the Drawings, the Examples, and the Claims. BRIEF DESCRIPTION OF DRAWINGS [0023] FIGs.1A-1C show the VPS10p-domain. FIG.1A shows the VPS10p-domain folds into a 10-bladed β-propeller (PDB: 3WSX 5) presented from the top (left) and from the side (right), with the 10CC-domains located at the bottom of the folded propeller. Each blade is shaded according to the code from Kitago, Y. et al. Structural basis for amyloidogenic peptide recognition by SORL1. Nat. Struct. Mol. Biol.22, 199-206, doi:10.1038/nsmb.2954 (2015). FIG.1B shows amino acids 205-246 corresponding to β3 are presented by their one- letter-code (SEQ ID NO: 194). The parallel rectangular backgrounds behind the amino acids indicate the four A-D anti-parallel strands. Asp-box residues are presented on a light grey background towards the bottom of the folded domain in the C-D loop. Sheet topology is indicated below. FIG.1C shows residues 1-753 in SORL1 comprise a signal peptide (SP; residues 1-28), a pro-peptide (ProP; residues 29-81), 10 repeats forming the VPS10p-domain (residues 82-617), and two parts with conserved cysteines (CCa/b; residues 618-753) (SEQ ID NO: 195). Numbering of the sequence follows Uniprot entry Q92673 from as originally described by ref 10. The 10 repeats are aligned based on the identified four β-strands within each repeat (grey; A-D), with positions of conserved hydrophobic amino acids in strands A-C as well as amino acids of the Asp-box motifs (SXDXGXTW) (SEQ ID NO: 134) shown in bold. Horizontal lines indicate the locations of the five disulfides that bridge the 10 cysteines in CCa and CCb. [0024] FIGs.2A-2E show the YWTD-domain. FIG.2A shows the YWTD-domain of LDLR folds into a 6-bladed β-propeller (PDB: 1IJQ 15), likely reflecting a similar structure for the YWTD-domain of SORL1. The propeller is shown from the top (left) and from the side (right). The EGF-domain of LDLR is shown in light grey at the bottom of the propeller. FIG. 2B shows schematics of the fifth β-sheet (β5) of the β-propeller (gray circle), depicting residues 921-960 by their one-letter-code with indication of the four A-D anti-parallel strands in grey background (SEQ ID NO: 196). The YWTD-motif in strand B together with some of the few additionally conserved residues of each repeat are presented with grey circles and bold letters. Blade topology is shown below. FIG.2C shows the alignment of the SORL1 sequence (SEQ ID NO: 113) spanning residues 754-1013 and corresponding to an YWTD- domain was done based on the YWTD-motif and the presence of the predicted four β-strands of each repeat (grey background). Lower case letters or capital letters indicate positions occupied by similar or identical residues in each repeat, respectively. Residues R879, W905, N924, Y964, and W979 forming the SBiN-motif are shown in white letters on a black background. FIG.2D shows histograms showing the number of pathogenic variants that occur for each YWTD-domain position as listed in FIG.2D. FIG.2E shows logo representation of the domain sequence conservation: the larger the letter the higher the conservation across YWTD-domain sequences. [0025] FIGs.3A-3B show the EGF-domain. FIG.3A shows schematics of the EGF-domain of SORL1 (grey circle), depicting residues 1014-1074 by their one-letter-code with indication of the three speculated disulfides, and the possible long loop including the extra pair of cysteines (the fourth and fifth Cys out of the eight, (residues 1040 and 1041 which are indicated by light grey and separated by an arginine residue)) (SEQ ID NO: 114). FIG.3B shows an alignment of SORL1 residues 1014-1074 (SEQ ID NO: 114) with sequences of EGF-domains located at the C-terminal of β-propellers of members from the LDLR family (as presented in FIG.10). From top to bottom, SEQ ID NOs of EGF-domain sequences are 172-174 and 160-171). All cysteines are shown in dark grey and indicated by connecting lines above and below the figure which indicate disulfide bridges, and residues at positions with strong (capital letters) or weak (lower case letters) conservation are shown below the alignment. On the top of the SORL1 sequence is indicated the Cys connectivity for the eight Cys residues located within integrin-type EGF-domains (as shown in FIG.3B). [0026] FIGs.4A-4E show CR-domains. FIG.4A shows the structure of CR7 from LRP1 (PDB: 1J8E) 76 with two short strands (dark grey anti-parallel strands indicated by arrow to the left of the calcium ion as shown in the left side panel) and a short α-helix (dark grey ribbon located in the top right hand corner of the left side panel). Close-up of the octahedral coordination of a Ca²⁺ ion (grey ball contacted with dashed lines) by side chain carboxylates of D37, D41, D47, and E48 as well as backbone carbonyls from residues at position 34 and 39 (numbering according to sequence position in FIG.4C). FIG.4B shows a schematic of the residues 1075-1114 of CR1 of SORL1 (SEQ ID NO: 197) with conserved residues on a dark grey background: cysteines (C15, C23, C29, C36, C42, C55), Ca²⁺ coordination via side chain carboxylates (D37, D41, D44, D47), and other highly conserved positions (Y21, G, I30, D44, S). FIG.4C shows alignments of the eleven CR-domains of SORL1 (residues 1075-1550) (SEQ ID NO: 115). Conserved residues including six cysteines, two hydrophobic amino acids at positions 21 and 30, and 5 acidic residues and a Ser are all indicated below the alignment. Light grey and black arrows on top of the alignment indicate positions involved in calcium chelation via side chain or backbone carbonyls, respectively. Horizontal lines indicate the locations of the three invariable disulfides. FIG.4D shows histograms showing the number of pathogenic variants that occur for each CR-domain position as listed in Table 10. FIG.4E shows logo representation of the domain sequence conservation: the larger the letter the higher the conservation across CR-domain sequences. [0027] FIGs.5A-5F show FnIII domains. FIG.5A shows the structure of the second SORL1 FnIII-domain (PDB: 2DM4), showing the two-bladed sandwich conformation representative for FnIII-domain structures in general. The BC-, C’E- and FG-loops together with the N- terminal residues (boxed) correspond to the antigen binding part of the similarly folded IgG- domains. FIG.5B shows the structure of the FnIII-domain showing how the alternating hydrophobic residues contribute to a compact core of the domain (light grey side chains – identified in panel c), forming hydrophobic interactions between their side chains that keep the two sheets tightly together. The side chain of the four conserved residues at positions 25 (Trp), 41 (Tyr), 77 (Leu), and 83 (Tyr) are indicated by dark grey. The two structures represent a 180 degree turn seeing into the sandwich from opposite sites. FIG.5C show residues 1932-2024 of the fifth FnIII-domain (SEQ ID NO: 198) presented according to the characteristic anti-parallel strand topology A-B-E-C’-C-F-G. The two β-sheets are indicated by light grey (A, B, E strands) and dark grey (C’, C, F, and G strands) background for their strands, respectively. The alternating residues that contribute to the hydrophobic domain interior are indicated by light grey circles, amino acids that are part of the BC-, C’E-, and FG-loops are on grey background, and the four most conserved residues W25, Y41, L77, and Y83 are presented on dark grey circles. Sheet topology is indicated below. FIG.5D shows the SORL1 sequence of residues 1551-2121 (SEQ ID NO: 116) represents six FnIII-domains. Alignment of the FnIII-domain sequences was done according to the β-strand secondary structure diagram shown in FIG.5C. The limited number of positions with conserved amino acids and the identified alternating hydrophobic residues (Φ) are presented below the alignment. Residues in top loop regions are included in the broken line boxes. The alignment was specifically designed to allow the conserved consensus motif for N-glycosylation (NXT, black background) to be located in the C’E-loop when possible. FIG.5E shows histograms showing the number of pathogenic variants that occur for each FnIII-domain position as listed in Table 12. FIG.5F shows logo representation of the domain sequence conservation: the larger the letter the higher the conservation across FnIII-domain sequences. [0028] FIGs.6A-6C show transmembrane and cytoplasmic domains. FIG.6A shows the cytosolic tail of SORL1 (SEQ ID NO: 23) contains different motifs that recognize molecular adaptors responsible of the intracellular localization of the receptor, including sites for binding to Retromer (motif: FANSHY) (SEQ ID NO: 135), PACS1 and AP1/AP2 (acidic motif: DDLGEDDED) (SEQ ID NO: 136), and GGA (motif: DDVPMVIA) (SEQ ID NO: 137). FIG.6B shows a schematic of the intracellular trafficking pathways in which different adaptor proteins determine if SORL1 goes into the secretory, endocytic, endosome delivery, or endosome recycling pathways. FIG.6C shows an alignment of the human SORL1 residues 2122-2214 (SEQ ID NO: 199) with the corresponding regions of SORL1 from different species, including mammals, fish, and insects (from top to bottom, SEQ ID NOs: 200-213). Residues 2138-2160 correspond to the transmembrane segment forming an α- helical structure. The three motifs in the cytoplasmic tail known to interact with adaptor proteins are shown below the alignment in bold letters (from left to right, SEQ ID NOs: 135- 137). [0029] FIG.7 shows a phylogenetic tree for SORL1. [0030] FIGs.8A-8D show the conformational space for SORL1. [0031] FIG.9 shows a diagram with 2,214 amino acids of human SORL1 (SEQ ID NO: 33). Diagram representing the entire 2,214 amino acid sequence as ball presentations. The foldings of individual domains are represented with the shading as in the figures that display these domains. Scissors at positions 28 and 81 indicate positions for cleavage by signal peptidase and Furin just after the signal- and the pro-peptides, respectively. A similar diagram will be made available at the alzforum.org as an interactive resource to provide detailed information on all known SORL1 variants. [0032] FIG.10 shows the SORL1 modular receptor and homologous proteins. Schematic representation of the structural elements of SORL1 and members of the mammalian LDLR- and VPS10p receptor families. Clustered copies of FnIII-domains close to the membrane is present in a large number of unrelated proteins with diverse function (only a small subset included), thus not enabling assignment to any class of unique proteins like the other two receptor families. Some of the diseases the homologous proteins can cause when hit by pathogenic variants are listed below individual proteins. [0033] FIG.11 shows SORL1 sequence alignments (SEQ ID NO: 33). Alignments of the different SORL1 domains are presented in more details with indications of b-strand secondary structure in the respective as described in Example 1. Amino acid positions that are conserved and/or identified to frequently contain disease-causing mutations in proteins containing homologous domains and thus likely to provide a high risk of disease when mutated is shown in white letters on a black background. Positions suggested to provide a moderate increased risk for development of AD on a grey background. [0034] FIGs.12A-12F show the FnIII domain alignment. The alignment follows the SORL1 alignment at the type and pathogenic variants are highlighted (red). From top to bottom, FIG: 12A shows SEQ ID NOs: 116 (SORLA) and 214 (Usherin); FIG.12B shows SEQ ID NOs: 215-219 ( L1CAM, INSR, IGF1R, Fibronectin, and DCC, respectively); FIG.12C shows SEQ ID NOs: 220-227 (Leptin receptor, Prolactin receptor, CRLF1, Integrin beta4, ROBO3, ROBO4, Tenascin, and TenascinX, respectively); FIG.12D shows SEQ ID NOs: 228-232 (SPEG, COL6A3, IL2RG, CDON, and COL12A1, respectively); FIG.12E shows SEQ ID NOs: 233-242 (EPHB4, IL31RA, IL21R, IL11RA, IL12RB, Interferon gamma receptor2, Nephrin, IL7R, Anosmin-1, and MYBPC3, respectively); and FIG.12F shows SEQ ID NOs: 243-249 (SPEG, Thrombopoietinreceptor, OSMR, GHR, CSF3R, CSF2R, and Tie2/TEK, respectively). [0035] FIGs.13A-13L show sequences of SORL1 alignments. From top to bottom in FIGs. 13A-13L, SEQ ID NOs: 33 and 250-288). [0036] FIG.14 shows results obtained from western blot analyses of SORL1 mini-receptor expression and SORL1 mini-receptor-dependent modulation of endosomal recycling pathway activity in cells comprising wild-type SORL1 or mutant SORL1. [0037] FIG.15 shows results obtained from eGluc-SORLA reporter assay analyses of SORL1 mini-receptor expression and SORL1 mini-receptor-dependent modulation of endosomal recycling pathway activity in cells comprising wild-type SORL1 or mutant SORL1. [0038] FIG.16 shows results obtained from flow cytometry analyses of SORL1 mini- receptor expression and SORL1 mini-receptor-dependent modulation of endosomal recycling pathway activity in cells comprising wild-type SORL1 or mutant SORL1. DETAILED DESCRIPTION [0039] Aspects of the present disclosure relate to methods that are based on analyses of SORL1 structure to guide treatment and identification of disease in cells, biological samples, and subjects related to endosomal trafficking. Exemplary characteristics of abnormal endosomal trafficking that may be exhibited in diseased cells, biological samples, or subjects include, but are not limited to, mutated SORL1, dysregulated SORL1 levels and/or function, dysregulated VPS35 levels and/or function, dysregulated VPS26a levels and/or function, dysregulated VPS26b levels and/or function, dysregulated sAPPα levels and/or function, dysregulated sAPPβ levels and/or function, dysregulated APP levels and/or function, dysregulated AMPA receptor levels and/or function, dysregulated Aβ30 levels and/or function, dysregulated Aβ40 levels and/or function, and dysregulated Aβ42 levels and/or function. In some embodiments, said methods may be used to guide identification and treatment of neurological diseases (e.g., neurodegenerative diseases, such as Parkinson’s Disease, Dementia, Pick’s Disease, Lewy Body Dementia, Huntington’s Disease, Alzheimer’s disease, Early-Onset Alzheimer’s disease, Late-Onset Alzheimer’s disease, Sporadic late-onset Alzheimer’s disease, SORL1-positive Alzheimer’s disease, APOE4- positive Alzheimer’s disease, Familial Alzheimer’s disease, frontotemporal disorders associated with neurodegeneration, Niemann Pick Type I, Neuronal Ceroid Lipofuscinosis, Hereditary Spastic Paraparesis, Amyotrophic Lateral Sclerosis, and tauopathies, such as progressive supranuclear palsy, and Steele-Richardson-Olszewski Syndrome). Other aspects of the disclosure relate to therapeutic agents, compositions and methods of administering therapeutic agents for modulating the levels and/or activity of a protein (e.g., SORL1, sAPPα, sAPPβ, tau, phosphorylated-tau, APP, AMPA receptor, Aβ30, Aβ40, Aβ42, VPS26a, VPS26b, and/or VPS35) involved in endosomal trafficking alterations (e.g., disruptions and/or decreases in endosomal trafficking) that are associated with a neurological disease in a cell, biological sample, or subject. This disclosure also relates to therapeutic agents, compositions and methods of administering therapeutic agents to a subject after identifying the presence of a SORL1 mutation, for example, a pathogenic SORL1 mutation in the subject. Moreover, the methods described herein may be used to identify new SORL1 mutations and provide new clinical insights into SORL1 mutations as they relate to neurological and other diseases, including diseases characterized by abnormal endosomal trafficking and neurodegenerative diseases (e.g., Alzheimer’s disease). Definitions [0040] In order for the present invention to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the specification. [0041] The term “AAV” is an abbreviation for adeno-associated virus and may be used to refer to the virus itself or derivatives thereof. The term covers all subtypes and both naturally occurring and recombinant forms, unless otherwise indicated. The abbreviation “rAAV” refers to recombinant adeno-associated virus, also referred to as a recombinant AAV vector (or “rAAV vector”), which refers to AAV comprising a polynucleotide sequence not of AAV origin (e.g., a transgene comprising the SORL1 variants described herein). [0042] The term “AAV virus”, “AAV viral particle”, “rAAV particle”, or “rAAV vector particle” refers to a viral particle comprising at least one AAV capsid protein and an encapsidated polynucleotide. In some embodiments, an rAAV vector may be packaged into a capsid protein and administered to a subject and/or delivered to a selected target cell. [0043] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject. Administration also encompasses contacting cells with therapeutic agents described herein and can be performed in vitro or in vivo. [0044] The terms “antisense oligonucleotide” or “ASO” refers to a single stranded nucleic acid that has sequence complementarity to a target sequence and is specifically hybridizable with a nucleic acid having the target sequence. An antisense nucleic acid is specifically hybridizable when binding of the antisense nucleic acid to the target nucleic acid is sufficient to produce complementary base pairing between the antisense nucleic acid and the target nucleic acid, and there is a sufficient degree of complementarity to reduce or avoid non-specific binding of the antisense nucleic acid to non-target nucleic acid under conditions in which specific binding is desired, e.g., under physiological conditions in the case of in vivo assays or therapeutic treatment, and in the case of in vitro assays, under conditions in which the assays are performed. ASOs may comprise natural nucleotides, chemically modified nucleotides, or a combination thereof. Moreover, ASOs may comprise deoxyribonucleotides, ribonucleotides, or a combination thereof. The function of ASOs is versatile such that ASOs may be used to upregulate, downregulate, or modulate the splicing of a gene. Accordingly, ASOs may exert an effect in a cell through a variety of mechanisms. ASOs may bind the 5ʹ- or 3′-untranslated regions (UTR) of an RNA. ASOs may also bind to the 3′-UTR of an RNA along with a trans-regulator in order mediate RNaseH decay. ASOs may bind an intron of an RNA. ASOs may bind to a splice boundary (e.g., a splice junction) between an exon and intron of an RNA thereby inducing exon skipping. An ASO may be a “gapmer” that binds to an exon (e.g., protein coding region) of an RNA and mediates RNaseH decay. ASOs may result in translation of a truncated protein that has a dominant negative effect on the wild- type, full-length protein. In some embodiments, an ASO is designed in order to selectively bind mRNAs corresponding to a SORL1 gene sequence comprising a disease-associated mutation. [0045] The terms “bind” and “binds,” as used herein, are intended to mean, unless indicated otherwise, the ability of a protein or molecule to form a chemical bond or attractive interaction with another protein or molecule, which results in proximity of the two proteins or molecules as determined by common methods known in the art. Methods of assessing binding will be apparent to those of ordinary skill in the art. Non-limiting examples of techniques for assessing the binding of two proteins include Förster Resonance Energy Transfer (FRET), mass spectrometry, chemical cross-linking experiments, co- immunoprecipitation, tandem affinity purification, electrophoretic mobility shift (EMSA) assays, enzyme-linked immunosorbent assay (ELISA), yeast two-hyrbid, or any combination and/or derivation thereof. Such methods and others can be used to assess binding affinity of SORL1 variants to retromer complex subunits. [0046] The term “biologic” refers to an agent that has been produced and purified from a biological system or comprises a biological system. Examples of biologics that can be used as therapeutic agents include, without limitation, nucleic acids (e.g., nucleic acids, such as inhibitory nucleic acids, guide RNAs, engineered nucleic acids encoding a SORL1 mini- receptor and/or a retromer complex subunit), recombinant viruses (e.g., recombinant AAVs and recombinant lentiviruses), peptides (e.g., inhibitory peptides or activating peptides, such as those involved in neuronal signaling), proteins (e.g., Cas molecules, a SORL1 mini- receptor, antibodies, and antigen-binding fragments), cells (e.g., nervous system cells, immune cells, stem cells, and progenitor cells), and tissues (e.g., tissues comprising genetically engineered cells and/or tissue comprised in samples that are obtained from a donor subject, such as those that can be used for engraftment). [0047] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue, such as those comprising living neural cells); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include brain tissues, blood, skin, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample. In some embodiments, a biological sample may be derived from a human subject, cultured in vitro, contacted with a therapeutic agent or composition described herein and then introduced into either the same human subject or a different human subject. In some embodiments, a biological sample comprises stem cells (e.g., neural stem cells) or central nervous system (CNS) cells derived from a human subject. In some embodiments, a biological sample comprises tissue from the cerebral cortex or hippocampus. When a biological sample comprises a mutation (e.g., a mutation in the endogenous SORL1 gene) the biological sample may be referred to as a mutant biological sample. [0048] The term “coding sequence” refers to a nucleic acid sequence encoding a peptide, polypeptide, or protein. [0049] The term “composition” refers to a solution of more than one dissolved chemical or biochemical component. The terms “composition” and “formulation” are used interchangeably herein. [0050] A sequence “complementary” to a portion of an DNA or RNA, refers to a sequence having sufficient complementarity to be able to hybridize with the DNA or RNA, forming a stable duplex; in the case of double-stranded antisense nucleic acids, a single strand of the duplex DNA may thus be tested. The ability to hybridize will depend on both the degree of complementarity and the length of the antisense nucleic acid. Generally, the longer the hybridizing nucleic acid, the more base mismatches with a DNA or RNA it may contain and still form a stable duplex. One skilled in the art can ascertain a tolerable degree of mismatch by use of standard procedures to determine the melting point of the hybridized complex. [0051] “Development” or “progression” of a disease, disorder, or condition means initial manifestations and/or ensuing progression of the disease, disorder, or condition. Development of the disease, disorder, or condition can be detectable and assessed using standard clinical techniques as well known in the art. However, development also refers to progression that may be undetectable. For the purpose of this disclosure, development or progression refers to the biological course of the symptoms. [0052] A “dimer” refers to a protein complex (e.g., one comprising SORL1 variants) comprising two polypeptides that are stably associated to each other via non-covalent or covalent interactions or a combination thereof. Dimers may be “heterodimers” comprised of two polypeptides with different amino acid sequences. Dimers may also be “homodimers” comprising two polypeptides (e.g., two SORL1 variants) with the same amino acid sequence and three-dimensional structure. Those skilled in the art will recognize that dimers may form through a variety of mechanisms. In some embodiments, dimers may form spontaneously in an experimental, cell-free environment (e.g., a 96-well plate, a test tube, a microtube, etc.) or in a cell via the biochemical affinity that each subunit of the dimer shares for each other. In some embodiments, dimers may form via chemical treatment (e.g., via a chemical cross- linking procedure). [0053] A “disease-associated mutation” refers to a deviation in the sequence of DNA, as well as the transcribed mRNA and protein products encoded by said DNA, that is causative of a disease symptom and/or state in a subject, wherein the deviation in the sequence is relative to a wild-type or non-disease-associated version of the gene or gene product. Examples of wild-type SORL1/SORL1 are provided as SEQ ID NOs: 33 and 60-120 and in Table 1. Examples of disease-associated mutations in SORL1 are provided in Tables 8, 10, 12, and 13. A disease symptom caused by a disease-associated mutation in SORL1/SORL1 can include a symptom exhibited in subjects having a neurological disease described herein. A disease state caused by a disease-associated mutation in SORL1/SORL1 can include one or more cellular changes associated with a neurological disease described herein (e.g., dysregulation of one or more endosomal trafficking regulators and/or cargos that interact with SORL1 geneticaly or interact with SORL1 physically) and also physiological effects associated with such changes (e.g., neuroinflammation, aggregation of amyloid and/or tau proteins, degeneration and/or death of neuronal tissue cells, reductions in cognition, memory, motor function, and other effects, such as mood changes and/or pain associated with neurological diseases). Those of ordinary skill in the art will understand that various types of mutations can occur in a gene (e.g., SORL1) that result in increased risk of disease. For example, disease-associated mutations include non-conservative mutations (i.e., an amino acid substitution for another residue with different biochemical properties), insertions, and deletions. Examples of non-conservative mutations include substitution of a hydrophobic amino acid for a hydrophilic amino acid or a negatively charged amino acid for a positively charged amino acid. Insertions include the addition of one or more residues into a protein. Deletions include the removal of one or more residues in a protein. Those of ordinary skill in the art will also understand that insertions and deletions include deletions of non-consecutive and consecutive amino acids and any combination thereof. Moreover, those of ordinary skill in the art will realize that disease-associated mutations are not limited to non-synonymous mutations (i.e., those that result in an amino acid change) but also include, in some instances, synonymous mutations (i.e., those that result in a change in the DNA sequence but do not change the amino acid sequence of the encoded protein). A “subject characterized as having or suspected of having a disease-associated mutation in SORL1/SORL1” can be a subject exhibiting one or more signs and symptoms of a neurological disease including, but not limited to memory deficit (e.g., short term memory loss), confusion, deficiencies of executive functions (e.g., attention, planning, flexibility, abstract thinking, etc.), loss of speech, and/or degeneration or loss of motor skills. In some embodiments, a subject having or suspected of having a disease-associated mutation in SORL1/SORL1may be a subject exhibiting one or more signs and/or one or more symptoms associated with a neurodegenerative disease, such as Alzheimer’s disease (AD). In some embodiments, a subject characterized as having or suspected of having a disease-associated mutation in SORL1/SORL1 comprises accumulated of β-amyloid (Aβ) peptides and/or hyper-phosphorylated tau protein in the brain tissue. In some embodiments, a subject characterized as having or suspected of having a disease- associated mutation in SORL1/SORL1 can be a subject who has been evaluated, being evaluated, or meets one or more clinical indicators that would result in the evaluation of a biomarkers associated with Alzheimer’s disease (e.g., biomarkers assessed by amyloid PET or Tau PET and/or by analyzing a biological sample obtained from the subject, such as analyses of amyloid, tau, or both performed on cerebrospinal fluid or plasma). A subject characterized as having or suspected of having a disease-associated mutation in SORL1/SORL1 subject can also be one who is diagnosed as having a neurological disease (e.g., a neurodegenerative disease) by a medical professional. For example, a subject characterized as having Alzheimer’s disease can be subject who was diagnosed according to the NINCDS-ADRDA Alzheimer's Criteria, as described by McKhann et al. (1984) "Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease". Neurology.34 (7): 939–44. Therapeutic agents and methods of the disclosure can be used to treat subjects that are heterozygous for a disease-associated mutation in SORL1 or homozygous for a disease-associated mutation in SORL1. In some embodiments, a subject having a disease-associated mutation in SORL1 is heterozygous for the disease-associated mutation. In some embodiments, a subject having a disease-associated mutation in SORL1 is homozygous for the disease-associated mutation. [0054] “Disease risk” refers to the potential of a subject or patient to develop a disease or disorder described herein. As used herein, disease risk as a result of a mutation in SORL1 is dependent on two criteria: 1) the conservation of the amino acid across internally repeated sequences, and 2) the occurrence of disease-associated variants at the same domain position in domains from homologous proteins. If both criteria are positive, there is a high risk associated with mutations at that position. If only one of the above criteria is positive, and the other not conclusive, a high priority is still assigned. If the position is only partly conserved, or has been assigned a functional role for the protein domain in general, but the two criteria do not provide full support for a high-risk position, a moderate risk for such positions is assigned. [0055] An “effective amount” of an agent described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on factors such as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health, or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. [0056] As used herein, an “engineered nucleic acid” sequence may encompass a DNA or RNA sequence. As used herein, the term “engineered” means artificially produced. As such, with respect to nucleic acids, the term “engineered” may also mean: (i) amplified in vitro by, for example, polymerase chain reaction (PCR); (ii) recombinantly produced by cloning; or (iii) synthesized by, for example, chemical synthesis. An engineered nucleic acid is one which has been manipulated by recombinant DNA techniques well known in the art. Thus, a nucleotide sequence contained in a vector in which 5' and 3' restriction sites are known, or for which polymerase chain reaction (PCR) primer sequences may be designed, is considered engineered. However, a nucleic acid sequence existing in its native state in its natural host is not. An engineered nucleic acid may be substantially purified but need not be. Accordingly, nucleic acids may be considered engineered when a non-naturally occurring gene sequence has been generated in a laboratory setting. Such non-naturally occurring gene sequences comprise, in general, select components derived from one or more sources of genetic information to yield a nucleic acid encoding a protein with unique functions not found in nature. Importantly, the term engineered nucleic acid may be used to describe a sequence encoding an ASO, components of a ribonucleoprotein complex that is capable of gene editing, or a coding sequence corresponding to a SORL1 variant. As such, engineered nucleic acids comprising components of a ribonucleoprotein complex that is capable of gene editing, or a SORL1 variant may be considered structural components of transgenes, vectors, recombinant viral genomes and lentiviruses, recombinant adeno-associated viruses, compositions, and kits thereof described herein. Furthermore, it should be appreciated that reference to an engineered nucleic acid comprising an ASO, components of a ribonucleoprotein complex that is capable of gene editing, or a SORL1 variant should not be considered limiting such that any nucleic acid modified to encode, among other things, an ASO, components of a ribonucleoprotein complex that is capable of gene editing, or a SORL1 variant (e.g., transgenes, vectors like lentiviral and rAAV vectors, and recombinant viral genomes) as described herein is a type of engineered nucleic acid. [0057] “An experimental/research animal,” as used herein, refers to pets and other domestic animals. Non-limiting examples of experimental/research animals include dogs and cats; livestock, such as horses, cattle, pigs, sheep, goats, and chickens; and other animals, such as mice, rats, guinea pigs, and hamsters. [0058] The term “gene” refers to a nucleic acid fragment that expresses a protein, including regulatory sequences preceding (5′ non-coding sequences) and following (3′ non- coding sequences) the coding sequence. “Native gene” refers to a gene as found in nature with its own regulatory sequences. [0059] The term “gene-editing therapy” refers to administration of a therapeutics agent(s) that is able to introduce changes into the DNA contained within a host cell. The components of gene editing systems that may be used as a therapeutic agent as described herein are well known in the art. In some embodiments, the gene-editing therapy utilizes a nuclease, such as a TALEN or a zinc-finger nuclease. In some embodiments, the gene-editing therapy utilizes a CRISPR-effector protein, such as a Cas molecule, a Cpf1 molecule, a base editor, or a prime editor. In some embodiments, the gene-editing therapy utilizes a Cas molecule domain or CRISPR domain. Accordingly, the disclosure relates, at least in some aspects, to gene-editing therapies utilizing Cas molecules that have endonuclease activity and gene-editing therapies utilizing Cas molecules that are modified to have nickase activity or be catalytically inactive (also referred to as a “dead” Cas molecule). In some embodiments, a Cas molecule includes, but is not limited to, Streptococcus pyogenes Cas9 (spCas9), Staphylococcus aureus Cas9 (saCas9), Cas12a, Cas12b, Cas13, nicking Cas9 (nCas9), or dead Cas9 (dCas9). In some embodiments, the Cpf1 molecule includes, but is not limited to, AsCas12a, FnCas12a, LbCas12a, PaCas12a, other Cpf1 orthologs, and Cas12a derivatives, such as the MAD7 system (MAD7TM, Inscripta, Inc.), or the Alt-R Cas12a (Cpf1) Ultra nuclease (Alt-R^® Cas12a Ultra; Integrated DNA Technologies, Inc.). In some embodiments, the Cpf1 domain is from Cas12a/Cpf1 obtained from Acidaminococcus sp. (referred to as “AsCas12a” or “AsCpf1”), such as Acidaminococcus sp. Strain BV3L6. In some embodiments, the gene-editing therapy utilizes a guanine deaminase. In some embodiments, the gene-editing therapy involves a cytidine deaminase. In some embodiments, the gene- editing therapy involves a uridine isomerase. In some embodiments, the gene-editing therapy involves an mRNA editing enzyme such as an adenosine deaminase (e.g., ADA1 or ADA2) or an APOBEC family member. In some embodiments, the gene-editing therapy components from a ribonucleoprotein (RNP) complex comprising an RNA-guide nuclease and a guide RNA (gRNA) that are capable of site-specific cleavage of a DNA sequence. In some embodiments, the gRNA is a chemically modified gRNA. In some embodiments, gene- editing therapies utilizes a repair template (e.g., a repair template oligonucleotide). In some embodiments, gene-editing therapies comprising an RNP capable of gene editing further comprise a repair template oligonucleotide. In some embodiments, the gene-editing therapy utilizes a recombinase. In some embodiments, the gene-editing therapy utilizes a recombinase. [0060] The term “gene therapy” refers to administration of an exogenous nucleic acid into a host cell. The exogenous nucleic acid may include one or more sequences encoding an RNA and/or protein that can be expressed in a cell which include, but is not necessarily limited to, an ASO, a mini-gene, a vector, a lentivirus, an rAAV, or any combination thereof. [0061] The term “host cell” refers to any cell that is capable of uptake of a therapeutic agent described herein. Host cells may be contacted (e.g., via transfection or by direct contact with a pharmaceutical composition described herein) with a therapeutic agent described herein. Host cells may be contacted with therapeutic agents described herein in vitro or in vivo. In the case of cultured host cells, following uptake, host cells may remain in vitro indefinitely or be transplanted into a subject or patient. Host cells may be cultured cell lines including, but not limited to, primary cells from a subject or patient, immortalized cells, and commercially available cell lines used for production of lentiviruses and recombinant adeno- associated viruses (e.g., 293T cells). Accordingly, host cells include, but are not limited to, 293T cells, neural stem cells, oligodendrocytes, ependymal cells, astrocytes, microglial cells, and virtually any cell which naturally expresses SORL1 such those derived from brain, appendix, bone marrow, colon, and liver tissues. In some instances, “host cell” may be used interchangeably with “target cell.” A host cell may be a mammalian cell, such as a human cell, a chicken cell, or an insect cell. Examples of suitable mammalian cells are, but are not limited to, HEK-293T cells, COS7 cells, Hela cells and HEK-293 cells. Examples of suitable insect cells include, but are not limited to, High5 cells and Sf9 cells. In some embodiment, the cells are insect cells as they are devoid of undesirable human proteins, and their culture does not require animal serum. Other examples of host cells, such as mammalian cells include, primate cells (e.g., vero cells), and rat cells (e.g., GH3 cells, OC23 cells) or mouse cells (e.g., MC3T3 cells). Host cells also include mammalian stem cells (e.g., human stem cells or human neural stem cells) such as, for example, pluripotent stem cells (e.g., human pluripotent stem cells including human induced pluripotent stem cells (hiPSCs)). A stem cell refers to a cell with the ability to divide for indefinite periods in culture and to give rise to specialized cells. A pluripotent stem cell refers to a type of stem cell that is capable of differentiating into all tissues of an organism, but not alone capable of sustaining full organismal development. A human induced pluripotent stem cell refers to a somatic (e.g., mature or adult) cell that has been reprogrammed to an embryonic stem cell-like state by being forced to express genes and factors important for maintaining the defining properties of embryonic stem cells (see, e.g., Takahashi and Yamanaka, Cell 126 (4): 663–76, 2006). Human induced pluripotent stem cells express stem cell markers and are capable of generating cells characteristic of all three germ layers (ectoderm, endoderm, mesoderm). Host cells also include cell lines including 293T, 3T3, 4T1, 721, 9L, A-549, A172, A20, A253, A2780, A2780ADR, A2780cis, A431, ALC, B16, B35, BCP-1, BEAS-2B, bEnd.3, BHK-21, BR 293, BxPC3, C2C12, C3H-10T1/2, C6, C6/36, Cal-27, CGR8, CHO, CML T1, CMT, COR-L23, COR-L23/5010, COR-L23/CPR, COR-L23/R23, COS-7, COV-434, CT26, D17, DH82, DU145, DuCaP, E14Tg2a, EL4, EM2, EM3, EMT6/AR1, EMT6/AR10.0, FM3, H1299, H69, HB54, HB55, HCA2, Hepa1c1c7, High Five cells, HL-60, HMEC, HT-29, HUVEC, J558L cells, Jurkat, JY cells, K562 cells, KCL22, KG1, Ku812, KYO1, LNCap, Ma-Mel 1, 2, 3....48, MC-38, MCF-10A, MCF-7, MDA-MB-231, MDA-MB-435, MDA- MB-468, MDCK II, MG63, MONO-MAC 6, MOR/0.2R, MRC5, MTD-1A, MyEnd, NALM-1, NCI-H69/CPR, NCI-H69/LX10, NCI-H69/LX20, NCI-H69/LX4, NIH-3T3, NW- 145, OPCN/OPCT Peer, PNT-1A/PNT 2, PTK2, Raji, RBL cells, RenCa, RIN-5F, RMA/RMAS, S2, Saos-2 cells, Sf21, Sf9, SiHa, SKBR3, SKOV-3, T-47D, T2, T84, THP1, U373, U87, U937, VCaP, WM39, WT-49, X63, YAC-1, and YAR cells. C8161, CCRF- CEM, MOLT, mIMCD-3, NHDF, HeLa-S3, Huh1, Huh4, Huh7, HASMC, HEKn, HEKa, MiaPaCell, Panc1, PC-3, TF1, CTLL-2, C1R, Rat6, CV1, RPTE, A10, T24, J82, A375, ARH-77, Calu1, SW480, SW620, SK-UT, CaCo2, P388D1, SEM-K2, WEHI-231, HB56, TIB55, J45.01, LRMB, Bcl-1, BC-3, IC21, DLD2, Raw264.7, NRK, NRK-52E, MEF, Hep G2, HeLa B, HeLa T4, COS, COS-1, COS-6, COS-M6A, BS-C-1 monkey kidney epithelial, BALB/3T3 mouse embryo fibroblast, 3T3 Swiss, 3T3-L1, 132-d5 human fetal fibroblasts; 10.1 mouse fibroblasts, 293-T, 3T3, 721, 9L, A2780, A2780ADR, A2780cis, A 172, A20, A253, A431, A-549, ALC, B16, B35, BCP-1 cells, BEAS-2B, bEnd.3, BHK-21, BR 293. BxPC3. C3H-10T1/2, C6/36, Cal-27, CHO, CHO-7, CHO-IR, CHO-K1, CHO-K2, CHO-T, CHO Dhfr −/−, COR-L23, COR-L23/CPR, COR-L23/5010, COR-L23/R23, COS-7, COV- 434, CML T1, CMT, CT26, D17, DH82, DU145, DuCaP, EL4, EM2, EM3, EMT6/AR1, EMT6/AR10.0, FM3, H1299, H69, HB54, HB55, HCA2, HEK-293, HeLa, Hepa1c1c7, HL- 60, HMEC, HT-29, Jurkat, JY cells, K562 cells, Ku812, KCL22, KG1, KYO1, LNCap, Ma- Mel 1-48, MC-38, MCF-7, MCF-10A, MDA-MB-231, MDA-MB-468, MDA-MB-435, MDCK II, MDCK 11, MOR/0.2R, MONO-MAC 6, MTD-1A, MyEnd, NCI-H69/CPR, NCI- H69/LX10, NCI-H69/LX20, NCI-H69/LX4, NIH-3T3, NALM-1, NW-145, OPCN/OPCT cell lines, Peer, PNT-1A/PNT 2, RenCa, RIN-5F, RMA/RMAS, Saos-2 cells, Sf-9, SkBr3, T2, T-47D, T84, THP1 cell line, U373, U87, U937, VCaP, Vero cells, WM39, WT-49, X63, YAC-1, YAR, and transgenic varieties thereof. [0062] The term “lipid nanoparticle” or “LNP” refers to spherical vesicle made of ionizable lipids. The diameter of lipid nanoparticle varies and ranges between 10 and 1000 nanometers. The core of a lipid nanoparticle comprises a matrix of solubilized lipid molecules and is stabilized by surfactants. The compositions of lipid nanoparticles vary depending on the therapeutic purpose. Examples of components, formulations, and applications of lipid nanoparticles may be found in Hou et al. Lipid nanoparticles for mRNA delivery. Nature Rev Mat.6:1078-1094 (2021). [0063] The term “microparticle” refers to a particle having an average (e.g., mean) dimension (e.g., diameter) of between about 1 micrometer (µm) and about 1 millimeter (mm) (e.g., between about 1 µm and about 100 µm, between about 1 µm and about 30 µm, between about 1 µm and about 10 µm, or between about 1 µm and about 3 µm), inclusive. [0064] The term “nanoparticle” refers to a particle having an average (e.g., mean) dimension (e.g., diameter) of between about 1 nanometer (nm) and about 1 micrometer (µm) (e.g., between about 1 nm and about 300 nm, between about 1 nm and about 100 nm, between about 1 nm and about 30 nm, between about 1 nm and about 10 nm, or between about 1 nm and about 3 nm), inclusive. [0065] The term “neurological disease” refers to any disease of the nervous system, including diseases that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Neurodegenerative diseases refer to a type of neurological disease marked by the loss of nerve cells, including, but not limited to, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), Huntington’s disease, and diseases that are associated with TDP-43 pathologies, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease (AD), and limbic predominant age- related TDP-43 encephalopathy (LATE). Examples of neurological diseases include, but are not limited to, headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of peripheral nerves, muscle and neuromuscular junctions. Addiction and mental illness, include, but are not limited to, bipolar disorder and schizophrenia, are also included in the definition of neurological diseases. Further examples of neurological diseases include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers’’ disease; alternating hemiplegia; Alzheimer’s disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet’s disease; Bell’s palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger’s disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorders; Cushing’s syndrome; cytomegalic inclusion body disease (CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier’s syndrome; Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb’s palsy; essential tremor; Fabry’s disease; Fahr’s syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich’s ataxia; frontotemporal dementia and other “tauopathies”; Gaucher’s disease; Gerstmann’s syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (see also neurological manifestations of AIDS); holoprosencephaly; Huntington’s disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile; phytanic acid storage disease; Infantile Refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh’s disease; Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; lissencephaly; locked-in syndrome; Lou Gehrig’s disease (aka motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; lyme disease-neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neurone disease; moyamoya disease; mucopolysaccharidoses; multi- infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O’Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson’s disease; paramyotonia congenita; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick’s disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type I and Type II); Rasmussen’s Encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus- associated myelopathy; Rett syndrome; Reye’s syndrome; Saint Vitus Dance; Sandhoff disease; Schilder’s disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren’s syndrome; sleep apnea; Soto’s syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; stiff- person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy; sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; tic douloureux; Todd’s paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg’s syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wilson’s disease; and Zellweger syndrome. In certain embodiments, the neurological disease being diagnosed and/or treated in accordance with the present invention is Alzheimer’s disease. [0066] As used herein, a nucleic acid sequence (e.g., coding sequence) and regulatory sequences are said to be “operably linked” when they are covalently linked in such a way as to place the expression or transcription of the nucleic acid sequence under the influence or control of the regulatory sequences. For example, if it is desired that the nucleic acid sequences be translated into a functional protein, two DNA sequences are said to be operably linked if induction of a promoter in the 5' regulatory sequences results in the transcription of the coding sequence and if the nature of the linkage between the two DNA sequences does not (1) result in the introduction of a frame-shift mutation, (2) interfere with the ability of the promoter region to direct the transcription of the coding sequences, or (3) interfere with the ability of the corresponding RNA transcript to be translated into a protein. Thus, a promoter region would be operably linked to a nucleic acid sequence if the promoter region were capable of effecting transcription of that DNA sequence such that the resulting transcript might be translated into the desired protein or polypeptide. Similarly, two or more coding regions are operably linked when they are linked in such a way that their transcription from a common promoter results in the expression of two or more proteins having been translated in frame. [0067] The term “particle” refers to a small object, fragment, or piece of a substance that may be a single element, inorganic material, organic material, or mixture thereof. Examples of particles include polymeric particles, single-emulsion particles, double-emulsion particles, coacervates, liposomes, microparticles, nanoparticles, macroscopic particles, pellets, crystals, aggregates, composites, pulverized, milled or otherwise disrupted matrices, and cross-linked protein or polysaccharide particles, each of which have an average characteristic dimension of about less than about 1 mm and at least 1 nm, where the characteristic dimension, or “critical dimension,” of the particle is the smallest cross-sectional dimension of the particle. A particle may be composed of a single substance or multiple substances. In certain embodiments, the particle is not a viral particle. In other embodiments, the particle is not a liposome. In certain embodiments, the particle is not a micelle. In certain embodiments, the particle is substantially solid throughout. In certain embodiments, the particle is a nanoparticle. In certain embodiments, the particle is a microparticle. Particles (such as microparticles and nanoparticles) may be composed of a variety of materials including ceramic, metallic, natural polymer materials (including lipids, sugars, chitosan, hyaluronic acid etc), synthetic polymer materials (including poly-lactide-coglycolide, poly- glycerol sebacate, etc), and non-polymer materials, or combinations thereof. The particles may be composed in whole or in part of polymers or non-polymer materials. Non-polymer materials, for example, may be employed in the preparation of the particles. Exemplary materials include alumina, calcium carbonate, calcium sulfate, calcium phosphosilicate, sodium phosphate, calcium aluminate, calcium phosphate, hydroxyapatite, tricalcium phosphate, dicalcium phosphate, tricalcium phosphate, tetracalcium phosphate, amorphous calcium phosphate, octacalcium phosphate, and silicates. In certain embodiments the particles may comprise a calcium salt such as calcium carbonate, a zirconium salt such as zirconium dioxide, a zinc salt such as zinc oxide, a magnesium salt such as magnesium silicate, a silicon salt such as silicon dioxide or a titanium salt such as titanium oxide or titanium dioxide. Particles may also comprise biological molecules for promoting their binding and activity in vivo such as carbohydrates and proteins (e.g., antibodies, antigen- binding proteins, and/or cell-penetrating peptides). [0068] The term “% sequence identity” or “percentage sequence identity” with respect to a reference nucleic acid sequence is defined as the percentage of nucleotides, nucleosides, or nucleobases in a query sequence that are identical with the nucleotides, nucleosides, or nucleobases in the reference nucleic acid sequence, after optimally aligning the sequences and introducing gaps or overhangs, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid sequence identity can be achieved in various ways that are within the means of one of ordinary skill in the art, for instance, using publicly available computer software programs, for example, those described in Current Protocols in Molecular Biology (Ausubel et al., eds., 1987, Supp.30, section 7.7.18, Table 7.7.1), and including, but not limited to, BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), COBALT, OPAL, Multlin, Clustal Omega, Clustal W2.0, or Clustal X2.0 software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Percentage of “sequence identity” can be determined by comparing two optimally aligned sequences over a comparison window, where the fragment of the nucleic acid sequence in the comparison window may comprise additions or deletions (e.g., gaps or overhangs) as compared to the reference sequence (which does not include additions or deletions) for optimal alignment of the two sequences. The percentage can be calculated by determining the number of positions at which the identical nucleotide, nucleoside, or nucleobase occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison, and multiplying the result by 100 to yield the percentage of sequence identity. The output is the percent identity of the subject sequence with respect to the query sequence. [0069] The term “pharmaceutically acceptable” refers to those properties and/or substances which are acceptable to the subject from a pharmacological/toxicological point of view. The phrase pharmaceutically acceptable refers to molecular entities, compositions, and properties that are physiologically tolerable and do not typically produce an allergic or other untoward or toxic reaction when administered to a subject. In some embodiments, a pharmaceutically acceptable compound is approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals and more particularly in humans. [0070] The terms “polynucleotide”, “nucleotide sequence”, “nucleic acid”, “nucleic acid molecule”, “nucleic acid sequence”, and “oligonucleotide” refer to a series of nucleotide bases (also called “nucleotides”) in DNA and RNA and mean any chain of two or more nucleotides. The skilled artisan recognizes that when referring to a gene sequence encoding an mRNA, the sequence of the mRNA is identical to the recited gene sequence, except that each instance of “T” is replaced with “U”. The polynucleotides can be single-stranded or double-stranded. A nucleotide sequence typically carries genetic information, including the information used by cellular machinery to make proteins and enzymes. These terms include double- or single-stranded genomic and cDNA, RNA, any synthetic and genetically manipulated polynucleotide, and both sense and antisense polynucleotides. This includes single- and double-stranded molecules, i.e., DNA-DNA, DNA-RNA, and RNA-RNA hybrids. Accordingly, the terms “nucleic acid” and “polynucleotide” applies to polymers comprising naturally occurring nucleotides and polymers comprising one or more non- naturally occurring nucleotides. Those of ordinary skill in the art will recognize that nucleotide sequences (DNA and RNA) may be read in triplets of nucleotides comprising codons. Therein, each codon will be read by a cell’s translational machinery to synthesize a protein product in a sequence-specific manner. It will also be appreciated by those of skill in the art that any nucleotide sequence in the present disclosure should be considered to be read from 5′ to 3′, and any protein sequence in the present disclosure should be considered to be read from the N-terminus to the C-terminus unless otherwise indicated. Those of skill in the art will recognize that polypeptide sequences may be said to correspond to nucleic acid sequences and vice versa. In this manner, it should also be recognized, for example, that when a nucleic acid encoding a SORL1 variant or ribonucleoprotein complex capable of gene editing is described or disclosed herein, the present disclosure also embraces the polypeptide corresponding to said nucleic acid. Likewise, it should be recognized that when a SORL1 variant polypeptide or a nuclease component of a ribonucleoprotein complex capable of gene editing is described or disclosed herein, the present disclosure also embraces any nucleic acid corresponding to said polypeptide. [0071] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population. [0072] The term “promoter” refers to a DNA sequence recognized by the synthetic machinery of the cell, or introduced synthetic machinery, required to initiate the specific transcription of a gene. Those of skill in the art will recognize that a promoter is operably linked to a coding sequence of a transgene by positioning the promoter in the correct location and orientation in relation to the coding sequence to control RNA polymerase initiation and expression of the gene. A number of regulatory sequences, including promoters which are native, constitutive, inducible and/or tissue-specific, are known in the art and may be utilized. [0073] A “protein,” “peptide,” or “polypeptide” comprises a polymer of amino acid residues linked together by peptide bonds. The term refers to proteins, polypeptides, and peptides of any size, structure, or function. Typically, a protein will be at least three amino acids long. A protein may refer to an individual protein or a collection of proteins that are associated through a binding interaction. Inventive proteins preferably contain only natural amino acids, although non-natural amino acids (i.e., compounds that do not occur in nature but that can be incorporated into a polypeptide chain) and/or amino acid analogs as are known in the art may alternatively be employed. Also, one or more of the amino acids in a protein may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation or functionalization, or other modification known in the art. A protein may also be a single molecule or may be a multi-molecular complex. A protein may be a fragment of a naturally occurring protein or peptide. A protein may be naturally occurring, recombinant, synthetic, or any combination of these. Herein, amino acid positions are defined by their position relative to the N-terminus. As such, the first amino acid in the primary sequence of the given protein is the most N-terminal residue. Accordingly, amino acids may be referred to by their position within the sequence or with the notation “X^y” wherein X represent an amino acid represented by its one-lettered designation (e.g., M for methionine, R for arginine, etc.) and “y” represents the position of the amino acid. [0074] The term “query sequence” refers to a segment of DNA or RNA from a cell, biological sample, or subject that is at least suspected of encoding a disease-associated mutation. In some embodiments, a query sequence may be known to comprise a disease- associated mutation and merely requires alignment procedures in order to confirm the identity of the disease-associated mutation. A query sequence may be a segment of a gene (e.g., a domain of SORL1), an entire coding sequence of a gene (e.g., the SORL1 coding sequence), or an entire genomic locus (e.g., the SORL1 locus encoding all SORL1 coding and non-coding sequences). Those of ordinary skill in the art will understand that nucleic acid sequence alignments are used in order to determine the identity of the query sequence and/or if the query sequence contains a mutation (e.g., a disease-associated mutation). It will also be understood that aligning a query sequence may be done using a bioinformatic search tool which will align the query sequence against, for example, all known nucleic acid sequences or against a reference sequence specifically chosen by the skilled artisan. Such bioinformatic search tools are described herein (e.g., BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), COBALT, OPAL, Multlin, Clustal Omega, Clustal W2.0, or Clustal X2.0 software) and are readily used by the skilled artisan trained in working with nucleic acid sequences. [0075] The term “recombinant,” as it relates to nucleic acids, refers to a nucleic acid molecule that has undergone a molecular biological manipulation, i.e., non-naturally occurring nucleic acid molecule or genetically engineered nucleic acid molecule. Furthermore, the term “recombinant DNA molecule” refers to a nucleic acid sequence which is not naturally occurring, or can be made by the artificial combination of two otherwise separated segments of nucleic acid sequence, i.e., by ligating together pieces of DNA that are not normally continuous. By “recombinantly produced” is meant artificial combination often accomplished by either chemical synthesis means, or by the artificial manipulation of isolated segments of nucleic acids, e.g., by genetic engineering techniques using restriction enzymes, ligases, and similar recombinant techniques as described by, for example, Sambrook et al., Molecular Cloning, second edition, Cold Spring Harbor Laboratory, Plainview, N.Y.; (1989), or Ausubel et al., Current Protocols in Molecular Biology, Current Protocols (1989), and DNA Cloning: A Practical Approach, Volumes I and II (ed. D. N. Glover) IREL Press, Oxford, (1985); each of which is incorporated herein by reference. Such manipulation may be done to replace a codon with a redundant codon encoding the same or a conservative amino acid, while typically introducing or removing a sequence recognition site. Alternatively, it may be performed to join together nucleic acid segments of desired functions to generate a single genetic entity comprising a desired combination of functions not found in nature. Restriction enzyme recognition sites are often the target of such artificial manipulations, but other site-specific targets, e.g., promoters, DNA replication sites, regulation sequences, control sequences, open reading frames, or other useful features may be incorporated by design. [0076] The term “recombinant viral genome” refers to any nucleic acid species comprising an engineered nucleic acid (e.g., one encoding a SORL1 variant) in addition to at least one other viral genetic sequence. Examples of viral genetic sequence that may be found in viral genomes include, but are not limited to, U3, U5, Tat-binding sequences, LTRs, ITRs, trans-activating response elements, central polypurine tracts, and Psi (^) packaging sequences. Accordingly, viral genomes are considered “recombinant” when their constituent nucleotide sequences are derived from more than one source and/or are altered in a manner that makes them structurally divergent from how they are found in nature. Recombinant viral genomes may further comprise transgenes and/or vectors described herein. [0077] The term “reference sequence” refers to a segment of nucleic acids that is used for alignment purposes against a query sequence. Accordingly, reference sequences must comprise a substantial degree of sequence homology relative to the query nucleic acid sequence in order to be used as a reference. The skilled artisan will, therefore, understand that the proper reference sequences to be used for alignment with a query sequence corresponding to a SORL1 sequence will be derived from a gene encoding SORL1 or a gene comprising a domain(s) that has sequence homology to a domain in SORL1. Examples of such genes are described herein (see, e.g., Tables 3, 5, and 7). In some embodiments, a reference sequence comprises a disease-associated mutation which can be used to confirm the presence of a disease-associated mutation in the query sequence. [0078] The term “regulatory sequence” refers to any nucleotide sequence that regulates the function and/or levels of a gene product encoded by a transgene. As used herein, a “gene product” refers to any RNA (e.g., a mRNA) or protein synthesized from a DNA species (e.g., a transgene). Various positions within a transgene may comprise regulatory sequences including the 5′ and/or 3′ ends of a coding sequence and/or the nucleotides within a coding sequence (e.g., nucleotide positions between exons). Regulatory sequences may influence the transcription rate, the translation rate, the splicing, and/or stability of a protein product of the transgene in a cell. Accordingly, the term “regulatory sequences” embrace, in a non-limiting manner, transcriptional regulatory sequences (e.g., promoter, enhancer, silencer, transcription factor binding sequence, 5' UTR, or 3' UTR), post-transcriptional regulatory sequences (e.g., acceptor/donor splicing sites and splicing regulatory sequences), and/or translation regulatory sequences (e.g., translation initiation signals, translation termination signals, mRNA degradation or decay signals, polyadenylation signals). [0079] The term “small molecule” refers to molecules, whether naturally-occurring or artificially created (e.g., via chemical synthesis), that have a relatively low molecular weight. Typically, a small molecule is an organic compound (e.g., it contains carbon). The small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.). In certain embodiments, the molecular weight of a small molecule is not more than about 1,000 g/mol, not more than about 900 g/mol, not more than about 800 g/mol, not more than about 700 g/mol, not more than about 600 g/mol, not more than about 500 g/mol, not more than about 400 g/mol, not more than about 300 g/mol, not more than about 200 g/mol, or not more than about 100 g/mol. In certain embodiments, the molecular weight of a small molecule is at least about 100 g/mol, at least about 200 g/mol, at least about 300 g/mol, at least about 400 g/mol, at least about 500 g/mol, at least about 600 g/mol, at least about 700 g/mol, at least about 800 g/mol, at least about 900 g/mol, or at least about 1,000 g/mol. Combinations of the above ranges (e.g., at least about 200 g/mol and not more than about 500 g/mol) are also possible. In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (C.F.R.)). The small molecule may also be complexed with one or more metal atoms and/or metal ions. In this instance, the small molecule is also referred to as a “small organometallic molecule.” Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, though not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; and drugs approved for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. All listed drugs are considered acceptable for use in accordance with the present invention. [0080] A SORL1 variant may be referred to as a SORL1 “mini-gene” (abbreviated as SORL1 MG) which describes a nucleic acid sequence encoding a SORL1 “mini-receptor” protein. In some embodiments, the term “mini-gene” may be used to refer to the nucleic acid corresponding to (e.g., encoding) an engineered SORL1 variant, while the term “mini- receptor” may be used to refer to the polypeptide corresponding to a nucleotide sequence of an engineered SORL1 variant. Those of ordinary skill in the art will also recognize that human genes and proteins are differentially annotated, and that reference to a “SORL1 variant” corresponds to a nucleotide sequence encoding said variant while reference to a “SORL1 variant” corresponds to a polypeptide. In some embodiments, a SORL1 variant (or an mRNA encoded by a SORL1 variant) comprises one or more nucleotide substitutions, insertions, or deletions relative to a wild type SORL1 gene (or mRNA encoded by a wild type SORL1 gene) and may be considered and/or referred to as a “mutant” SORL1 gene. The number of variant nucleotide positions (e.g., positions comprising substitutions, insertions, or deletions) in a SORL1 variant may vary. In some embodiments, a SORL1 variant comprises one or more nucleotide substitutions, insertions, or deletions relative to a wild type SORL1 gene (or mRNA encoded by a wild type SORL1 gene). In some embodiments, the one or more nucleotide substitutions, insertions, or deletions results in an amino acid substitution, insertion, or deletion in the protein encoded by the SORL1 variant. In some embodiments, SORL1 variants may comprise a plurality of mutations, such as any combination of substitutions, insertions, or deletions. In some embodiments, entire exon and/or intron sequences are removed to comprise the SORL1 variant. Accordingly, when a “SORL1/SORL1 variant” is referred to it should be recognized that the disclosure is referencing both engineered nucleic acids (e.g., transgenes, vectors, recombinant viral genomes, lentiviruses, and rAAVs) comprising a SORL1 variant nucleic acid sequence and corresponding SORL1 variant polypeptide products encoded therein. [0081] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. When a subject comprises a mutation (e.g., a mutation in the endogenous SORL1 gene) the subject may be referred to as a mutant subject. The term “patient” refers to a human subject in need of treatment of a disease. [0082] The term “target tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and/or lymph vessels, which is the object to which a compound, particle, and/or composition of the invention is delivered. A target tissue may be an abnormal or unhealthy tissue, which may need to be treated. A target tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented. In certain embodiments, the target tissue is the central nervous system. A “non- target tissue” is any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and/or lymph vessels, which is not a target tissue. [0083] The term “therapeutic agent” refers to any molecule(s) that may be administered in order to counteract or correct abnormal endosomal trafficking or a disease symptom caused by a mutation in SORL1. As such, a therapeutic agent is an exogenous molecule that induces a change in a cell expressing a mutated SORL1. The mechanism through which a therapeutic agent counteracts or corrects abnormal endosomal trafficking or a disease symptom in a cell, biological sample, or subject, caused by a mutation in SORL1 includes, but is not limited to, increasing wild-type SORL1 activity (e.g., by increasing levels and/or activity of a SORL1 mini-receptor that performs the function(s) of a wild-type SORL1), decreasing activity of a SORL1 comprising a disease-associated mutation, increasing levels and/or activity of a SORL1 splicing variant, decreasing levels and/or activity of a SORL1 splicing variant that comprises a disease-associated mutation, introducing an edit that corrects a disease-associated mutation in SORL1, increasing sAPPα levels and/or activity, increasing APP levels and/or activity at the cell surface, increasing AMPA levels and/or activity at the cell surface, decreasing tau aggregation and/or phosphorylation, decreasing sAPPβ levels and/or activity, decreasing Aβ30 levels and/or activity, decreasing Aβ40 levels and/or activity, decreasing Aβ42 levels and/or activity, stabilizing the retromer complex, increasing VPS35 levels and/or activity, increasing VPS26a levels and/or activity, increasing VPS26b levels and/or activity, or any combination thereof. Accordingly, therapeutic agents include, but is not limited to, a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone, a biologic, a SORL1 variant polypeptide or retromer complex subunit, an engineered nucleic acid encoding a SORL1 variant or retromer complex subunit, a lentivirus comprising a SORL1 variant or retromer complex subunit, or an rAAV comprising a SORL1 variant or retromer complex subunit, an ASO targeting a SORL1 sequence encoding a disease-associated mutation, or a ribonucleoprotein complex capable of correcting a disease-associated mutation in SORL1 [0084] A “therapeutically effective amount” of a therapeutic agent described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for enhancing endosomal trafficking, such as by increasing retromer levels and/or activity, increasing VPS26a levels and/or activity, increasing VPS26b levels and/or activity, increasing VPS35 levels and/or activity, increasing APP cell surface levels and/or activity, increasing AMPA receptor cell surface levels and/or activity, increasing sAPPα levels and/or activity, increasing SORL1 activity (e.g., wild-type SORL1 activity, such as by expression of a SORL1 mini-receptor), decreasing tau aggregation and/or tau phosphorylation, decreasing sAPPβ levels and/or activity, decreasing Aβ30 levels and/or activity, decreasing Aβ40 levels and/or activity, and/or decreasing Aβ42 levels and/or activity in a target tissue. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a neurological disease (e.g., a neurodegenerative disease, such as Parkinson’s Disease, Dementia, Pick’s Disease, Lewy Body Dementia, Huntington’s Disease, Alzheimer’s disease, Early-Onset Alzheimer’s disease, Late-Onset Alzheimer’s disease, Familial Alzheimer’s disease, and diseases that are associated with TDP-43 pathologies). In certain embodiments, a therapeutically effective amount is an amount sufficient for enhancing endosomal trafficking, such as by increasing retromer levels and/or activity, increasing VPS26a levels and/or activity, increasing VPS26b levels and/or activity, VPS35 levels and/or activity, increasing APP cell surface levels and/or acitivity, increasing AMPA receptor cell surface levels and/or activity, increasing sAPPα levels and/or activity, increasing SORL1 activity (e.g., wild-type SORL1 activity, such as by expression of a SORL1 mini-receptor), increasing SORL1 cell surface levels and/or activity (e.g., increasing cell surface expression of a SORL1 mini-receptor), decreasing tau aggregation and/or tau phosphorylation, decreasing sAPPβ levels and/or activity, decreasing Aβ30 levels and/or activity, decreasing Aβ40 levels and/or activity, and/or decreasing Aβ42 levels and/or activity in a cell, biological sample, or target tissue, such as one derived from a subject or patient with a neurological disease (e.g., a neurodegenerative disease, such as Parkinson’s Disease, Dementia, Pick’s Disease, Lewy Body Dementia, Huntington’s Disease, Alzheimer’s disease, Early-Onset Alzheimer’s disease, Late-Onset Alzheimer’s disease, Sporadic late-onset Alzheimer’s disease, SORL1-positive Alzheimer’s disease, APOE4- positive Alzheimer’s disease, Familial Alzheimer’s disease, frontotemporal disorders associated with neurodegeneration, Niemann Pick Type I, Neuronal Ceroid Lipofuscinosis, Hereditary Spastic Paraparesis, Amyotrophic Lateral Sclerosis, tauopathies, such as progressive supranuclear palsy, and Steele-Richardson-Olszewski Syndrome, and diseases that are associated with TDP-43 pathologies). [0085] The term “transfection” is used to refer to the uptake of foreign DNA by a cell. As such, a cell has been "transfected" when exogenous DNA has been introduced inside the cell membrane. A number of transfection techniques are generally known in the art. See, e.g., Graham et al. (1973) Virology, 52:456, Sambrook et al. (1989) Molecular Cloning, a laboratory manual, Cold Spring Harbor Laboratories, New York, Davis et al. (1986) Basic Methods in Molecular Biology, Elsevier, and Chu et al. (1981) Gene 13:197 which are incorporated by reference herein in their entirety. Such techniques can be used to introduce one or more engineered nucleic acids into suitable host cells. [0086] The term “transgene” refers to any recombinant gene or a segment thereof that includes a non-naturally occurring sequence that is to be delivered by a vector (e.g., a plasmid) or virus (e.g., a lentivirus or recombinant adeno-associated virus) and comprises an engineered nucleic acid. The non-naturally occurring sequence may in some embodiments be from a different organism, but it need not be. For example, in some embodiments, a transgene is a recombinant gene, or a segment thereof, from one organism or infectious agent (e.g., a virus) that is introduced into the genome of another organism or infectious agent. By contrast, in some embodiments, the transgene may contain segments of DNA taken from the same organism, but the segments are arranged in a non-natural configuration. In some embodiments, the non-naturally occurring sequence is an engineered non-naturally occurring sequence. As used herein, a transgene may comprise any combination of naturally-occurring and engineered DNA sequences. In some embodiments, the transgene comprises at least one region that encodes a polypeptide of interest (e.g., a therapeutic protein, such as a SORL1 mini-receptor or a nuclease component of a ribonucleoprotein complex capable of gene editing as described herein). In some embodiments, the transgene is codon optimized for expression in a particular host cell or subject, such as a human. [0087] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. [0088] The term “vector” or “expression vector” or “construct” means any molecular vehicle, such as a plasmid, phage, transposon, recombinant viral genome, cosmid, chromosome, artificial chromosome, virus, viral particle, viral vector (e.g., lentiviral vector or rAAV vector), virion, etc. which can transfer gene sequences to or between cells of interest. As disclosed herein, vectors are used for achieving expression, e.g., stable expression, of a protein in an intended target cell. A region comprising a transgene may be positioned at any suitable location within the vector that will enable expression of the gene product encoded therein. An expression vector may further comprise regulatory sequences operably linked to a coding sequence encoding a SORL1 variant or a nuclease component of a ribonucleoprotein complex capable of gene editing to facilitate expression of the encoded protein in a cell. [0089] The term “wild-type” (WT) is generally understood as an unmodified protein or protein fragment compared to a protein or protein fragment where a modification has been introduced. Examples of wild-type SORL1/SORL1 sequences are provided herein. SORL1 and Retromer Regulation of Endosomal Trafficking [0090] SORL1 is a member of the VPS10p-domain receptor family of type 1 sorting receptors and functions to regulate cargo localization in the cell. Specifically, SORL1 functions to transport proteins from the membrane to endosomes and eventually to the lysosome. SORL1 primarily localizes to the trans-Golgi and early endosomes where it interacts with the AP complex clathrin adaptor proteins to perform its function. SORL1 also shares sequence homology to lipoprotein receptors, such as members of the low-density lipoprotein receptor (LDLR) family. As such, SORL1 is thought to play important roles in lipoprotein signaling pathways, especially those involving the LDLR ligand, apolipoprotein E (ApoE). [0091] SORL1 is known in the art by a number of aliases including lipoprotein receptor 11 (LR11), LDL receptor-related protein 9 (LRP9), SORLA, gp250, SORLA-1, and C11orf32. SORL1 is expressed in a variety of different tissues with highest expression found in the brain, followed by tissues including the appendix, bone marrow, colon, and liver. [0092] In humans, SORL1 is encoded by the SORL1 gene, located on chromosome 11 (e.g., encoded by Ensembl ID NO: ENSG00000137642, Chromosome 11: 121,452,314- 121,633,763 forward strand). Exemplary genomic sequences comprising the SORL1 gene is set forth in NCBI Reference Sequence NG_023313.1 (SEQ ID NO: 119) and NG_023313.2 (SEQ ID NO: 120). Human SORL1 is comprised of 48 exons and found at chromosomal location 11q24.1. The SORL1 gene encodes an mRNA comprising the sequence set forth, for example, in NCBI Reference Sequence NM_003105.6 or NCBI Reference Sequence NM_003105.5). An exemplary SORL1 wild-type coding sequence is set forth in SEQ ID NO: 60 below: ATGGCGACACGGAGCAGCAGGAGGGAGTCGCGACTCCCGTTCCTATTCACCCTGGTCGCACTGCT GCCGCCCGGAGCTCTCTGCGAAGTCTGGACGCAGAGGCTGCACGGCGGCAGCGCGCCCTTGCCCC AGGACCGGGGCTTCCTCGTGGTGCAGGGCGACCCGCGCGAGCTGCGGCTGTGGGCGCGCGGGGAT GCCAGGGGGGCGAGCCGCGCGGACGAGAAGCCGCTCCGGAGGAAACGGAGCGCTGCCCTGCAGC CCGAGCCCATCAAGGTGTACGGACAGGTTAGTCTGAATGATTCCCACAATCAGATGGTGGTGCAC TGGGCTGGAGAGAAAAGCAACGTGATCGTGGCCTTGGCCCGAGATAGCCTGGCATTGGCGAGGCC CAAGAGCAGTGATGTGTACGTGTCTTACGACTATGGAAAATCATTCAAGAAAATTTCAGACAAGT TAAACTTTGGCTTGGGAAATAGGAGTGAAGCTGTTATCGCCCAGTTCTACCACAGCCCTGCGGACA ACAAGCGGTACATCTTTGCAGACGCTTATGCCCAGTACCTCTGGATCACGTTTGACTTCTGCAACA CTCTTCAAGGCTTTTCCATCCCATTTCGGGCAGCTGATCTCCTCCTACACAGTAAGGCCTCCAACCT TCTCTTGGGCTTTGACAGGTCCCACCCCAACAAGCAGCTGTGGAAGTCAGATGACTTTGGCCAGAC CTGGATCATGATTCAGGAACATGTCAAGTCCTTTTCTTGGGGAATTGATCCCTATGACAAACCAAA TACCATCTACATTGAACGACATGAACCCTCTGGCTACTCCACTGTCTTCCGAAGTACAGATTTCTTC CAGTCCCGGGAAAACCAGGAAGTGATCCTTGAGGAAGTGAGAGATTTTCAGCTTCGGGACAAGTA CATGTTTGCTACAAAGGTGGTGCATCTCTTGGGCAGTGAACAGCAGTCTTCTGTCCAGCTCTGGGT CTCCTTTGGCCGGAAGCCCATGAGAGCAGCCCAGTTTGTCACAAGACATCCTATTAATGAATATTA CATCGCAGATGCCTCCGAGGACCAGGTGTTTGTGTGTGTCAGCCACAGTAACAACCGCACCAATTT ATACATCTCAGAGGCAGAGGGGCTGAAGTTCTCCCTGTCCTTGGAGAACGTGCTCTATTACAGCCC AGGAGGGGCCGGCAGTGACACCTTGGTGAGGTATTTTGCAAATGAACCATTTGCTGACTTCCACCG AGTGGAAGGATTGCAAGGAGTCTACATTGCTACTCTGATTAATGGTTCTATGAATGAGGAGAACA TGAGATCGGTCATCACCTTTGACAAAGGGGGAACCTGGGAGTTTCTTCAGGCTCCAGCCTTCACGG GATATGGAGAGAAAATCAATTGTGAGCTTTCCCAGGGCTGTTCCCTTCATCTGGCTCAGCGCCTCA GTCAGCTCCTCAACCTCCAGCTCCGGAGAATGCCCATCCTGTCCAAGGAGTCGGCTCCAGGCCTCA TCATCGCCACTGGCTCAGTGGGAAAGAACTTGGCTAGCAAGACAAACGTGTACATCTCTAGCAGT GCTGGAGCCAGGTGGCGAGAGGCACTTCCTGGACCTCACTACTACACATGGGGAGACCACGGCGG AATCATCACGGCCATTGCCCAGGGCATGGAAACCAACGAGCTAAAATACAGTACCAATGAAGGGG AGACCTGGAAAACATTCATCTTCTCTGAGAAGCCAGTGTTTGTGTATGGCCTCCTCACAGAACCTG GGGAGAAGAGCACTGTCTTCACCATCTTTGGCTCGAACAAAGAGAATGTCCACAGCTGGCTGATC CTCCAGGTCAATGCCACGGATGCCTTGGGAGTTCCCTGCACAGAGAATGACTACAAGCTGTGGTC ACCATCTGATGAGCGGGGGAATGAGTGTTTGCTGGGACACAAGACTGTTTTCAAACGGCGGACCC CCCATGCCACATGCTTCAATGGAGAGGACTTTGACAGGCCGGTGGTCGTGTCCAACTGCTCCTGCA CCCGGGAGGACTATGAGTGTGACTTCGGTTTCAAGATGAGTGAAGATTTGTCATTAGAGGTTTGTG TTCCAGATCCGGAATTTTCTGGAAAGTCATACTCCCCTCCTGTGCCTTGCCCTGTGGGTTCTACTTA CAGGAGAACGAGAGGCTACCGGAAGATTTCTGGGGACACTTGTAGCGGAGGAGATGTTGAAGCG CGACTGGAAGGAGAGCTGGTCCCCTGTCCCCTGGCAGAAGAGAACGAGTTCATTCTGTATGCTGT GAGGAAATCCATCTACCGCTATGACCTGGCCTCGGGAGCCACCGAGCAGTTGCCTCTCACCGGGCT ACGGGCAGCAGTGGCCCTGGACTTTGACTATGAGCACAACTGTTTGTATTGGTCCGACCTGGCCTT GGACGTCATCCAGCGCCTCTGTTTGAATGGAAGCACAGGGCAAGAGGTGATCATCAATTCTGGCC TGGAGACAGTAGAAGCTTTGGCTTTTGAACCCCTCAGCCAGCTGCTTTACTGGGTAGATGCAGGCT TCAAAAAGATTGAGGTAGCTAATCCAGATGGCGACTTCCGACTCACAATCGTCAATTCCTCTGTGC TTGATCGTCCCAGGGCTCTGGTCCTCGTGCCCCAAGAGGGGGTGATGTTCTGGACAGACTGGGGA GACCTGAAGCCTGGGATTTATCGGAGCAATATGGATGGTTCTGCTGCCTATCACCTGGTGTCTGAG GATGTGAAGTGGCCCAATGGCATCTCTGTGGACGACCAGTGGATTTACTGGACGGATGCCTACCTG GAGTGCATAGAGCGGATCACGTTCAGTGGCCAGCAGCGCTCTGTCATTCTGGACAACCTCCCGCAC CCCTATGCCATTGCTGTCTTTAAGAATGAAATCTACTGGGATGACTGGTCACAGCTCAGCATATTC CGAGCTTCCAAATACAGTGGGTCCCAGATGGAGATTCTGGCAAACCAGCTCACGGGGCTCATGGA CATGAAGATTTTCTACAAGGGGAAGAACACTGGAAGCAATGCCTGTGTGCCCAGGCCATGCAGCC TGCTGTGCCTGCCCAAGGCCAACAACAGTAGAAGCTGCAGGTGTCCAGAGGATGTGTCCAGCAGT GTGCTTCCATCAGGGGACCTGATGTGTGACTGCCCTCAGGGCTATCAGCTCAAGAACAATACCTGT GTCAAAGAAGAGAACACCTGTCTTCGCAACCAGTATCGCTGCAGCAACGGGAACTGTATCAACAG CATTTGGTGGTGTGACTTTGACAACGACTGTGGAGACATGAGCGATGAGAGAAACTGCCCTACCA CCATCTGTGACCTGGACACCCAGTTTCGTTGCCAGGAGTCTGGGACTTGTATCCCACTGTCCTATA AATGTGACCTTGAGGATGACTGTGGAGACAACAGTGATGAAAGTCATTGTGAAATGCACCAGTGC CGGAGTGACGAGTACAACTGCAGTTCCGGCATGTGCATCCGCTCCTCCTGGGTATGTGACGGGGA CAACGACTGCAGGGACTGGTCTGATGAAGCCAACTGTACCGCCATCTATCACACCTGTGAGGCCTC CAACTTCCAGTGCCGAAACGGGCACTGCATCCCCCAGCGGTGGGCGTGTGACGGGGATACGGACT GCCAGGATGGTTCCGATGAGGATCCAGTCAACTGTGAGAAGAAGTGCAATGGATTCCGCTGCCCA AACGGCACTTGCATCCCATCCAGCAAACATTGTGATGGTCTGCGTGATTGCTCTGATGGCTCCGAT GAACAGCACTGCGAGCCCCTCTGTACGCACTTCATGGACTTTGTGTGTAAGAACCGCCAGCAGTGC CTGTTCCACTCCATGGTCTGTGACGGAATCATCCAGTGCCGCGACGGGTCCGATGAGGATGCGGCG TTTGCAGGATGCTCCCAAGATCCTGAGTTCCACAAGGTATGTGATGAGTTCGGTTTCCAGTGTCAG AATGGAGTGTGCATCAGTTTGATTTGGAAGTGCGACGGGATGGATGATTGCGGCGATTATTCTGAT GAAGCCAACTGCGAAAACCCCACAGAAGCCCCAAACTGCTCCCGCTACTTCCAGTTTCGGTGTGA GAATGGCCACTGCATCCCCAACAGATGGAAATGTGACAGGGAGAACGACTGTGGGGACTGGTCTG ATGAGAAGGATTGTGGAGATTCACATATTCTTCCCTTCTCGACTCCTGGGCCCTCCACGTGTCTGCC CAATTACTACCGCTGCAGCAGTGGGACCTGCGTGATGGACACCTGGGTGTGCGACGGGTACCGAG ATTGTGCAGATGGCTCTGACGAGGAAGCCTGCCCCTTGCTTGCAAACGTCACTGCTGCCTCCACTC CCACCCAACTTGGGCGATGTGACCGATTTGAGTTCGAATGCCACCAACCGAAGACGTGTATTCCCA ACTGGAAGCGCTGTGACGGCCACCAAGATTGCCAGGATGGCCGGGACGAGGCCAATTGCCCCACA CACAGCACCTTGACTTGCATGAGCAGGGAGTTCCAGTGCGAGGACGGGGAGGCCTGCATTGTGCT CTCGGAGCGCTGCGACGGCTTCCTGGACTGCTCGGACGAGAGCGATGAAAAGGCCTGCAGTGATG AGTTGACTGTGTACAAAGTACAGAATCTTCAGTGGACAGCTGACTTCTCTGGGGATGTGACTTTGA CCTGGATGAGGCCCAAAAAAATGCCCTCTGCTTCTTGTGTATATAATGTCTACTACAGGGTGGTTG GAGAGAGCATATGGAAGACTCTGGAGACCCACAGCAATAAGACAAACACTGTATTAAAAGTCTTG AAACCAGATACCACGTATCAGGTTAAAGTACAGGTTCAGTGTCTCAGCAAGGCACACAACACCAA TGACTTTGTGACCCTGAGGACCCCAGAGGGATTGCCAGATGCCCCTCGAAATCTCCAGCTGTCACT CCCCAGGGAAGCAGAAGGTGTGATTGTAGGCCACTGGGCTCCTCCCATCCACACCCATGGCCTCAT CCGTGAGTACATTGTAGAATACAGCAGGAGTGGTTCCAAGATGTGGGCCTCCCAGAGGGCTGCTA GTAACTTTACAGAAATCAAGAACTTATTGGTCAACACTCTATACACCGTCAGAGTGGCTGCGGTGA CTAGTCGTGGAATAGGAAACTGGAGCGATTCTAAATCCATTACCACCATAAAAGGAAAAGTGATC CCACCACCAGATATCCACATTGACAGCTATGGTGAAAATTATCTAAGCTTCACCCTGACCATGGAG AGTGATATCAAGGTGAATGGCTATGTGGTGAACCTTTTCTGGGCATTTGACACCCACAAGCAAGA GAGGAGAACTTTGAACTTCCGAGGAAGCATATTGTCACACAAAGTTGGCAATCTGACAGCTCATA CATCCTATGAGATTTCTGCCTGGGCCAAGACTGACTTGGGGGATAGCCCTCTGGCATTTGAGCATG TTATGACCAGAGGGGTTCGCCCACCTGCACCTAGCCTCAAGGCCAAAGCCATCAACCAGACTGCA GTGGAATGTACCTGGACCGGCCCCCGGAATGTGGTTTATGGTATTTTCTATGCCACGTCCTTTCTTG ACCTCTATCGCAACCCGAAGAGCTTGACTACTTCACTCCACAACAAGACGGTCATTGTCAGTAAGG ATGAGCAGTATTTGTTTCTGGTCCGTGTAGTGGTACCCTACCAGGGGCCATCCTCTGACTACGTTGT AGTGAAGATGATCCCGGACAGCAGGCTTCCACCCCGTCACCTGCATGTGGTTCATACGGGCAAAA CCTCCGTGGTCATCAAGTGGGAATCACCGTATGACTCTCCTGACCAGGACTTGTTGTATGCAATTG CAGTCAAAGATCTCATAAGAAAGACTGACAGGAGCTACAAAGTAAAATCCCGTAACAGCACTGTG GAATACACCCTTAACAAGTTGGAGCCTGGCGGGAAATACCACATCATTGTCCAACTGGGGAACAT GAGCAAAGATTCCAGCATAAAAATTACCACAGTTTCATTATCAGCACCTGATGCCTTAAAAATCAT ijķ AACAGAAAATGATCATGTTCTTCTGTTTTGGAAAAGCCTGGCTTTAAAGGAAAAGCATTTTAATGA AAGCAGGGGCTATGAGATACACATGTTTGATAGTGCCATGAATATCACAGCTTACCTTGGGAATA CTACTGACAATTTCTTTAAAATTTCCAACCTGAAGATGGGTCATAATTACACGTTCACCGTCCAAG CAAGATGCCTTTTTGGCAACCAGATCTGTGGGGAGCCTGCCATCCTGCTGTACGATGAGCTGGGGT CTGGTGCAGATGCATCTGCAACGCAGGCTGCCAGATCTACGGATGTTGCTGCTGTGGTGGTGCCCA TCTTATTCCTGATACTGCTGAGCCTGGGGGTGGGGTTTGCCATCCTGTACACGAAGCACCGGAGGC TGCAGAGCAGCTTCACCGCCTTCGCCAACAGCCACTACAGCTCCAGGCTGGGGTCCGCAATCTTCT CCTCTGGGGATGACCTGGGGGAAGATGATGAAGATGCCCCTATGATAACTGGATTTTCAGATGAC GTCCCCATGGTGATAGCCTGA (SEQ ID NO: 60) [0093] In some embodiments, a reference sequence described herein is a SORL1 wild-type coding sequence set forth in any one of SEQ ID NOs: 60-108 or 119-120. [0094] The SORL1 protein comprises: (1) a signal peptide (SEQ ID NO: 109) (cleaved off during maturation of the protein; encoded by exon 1 (SEQ ID NO: 61)); (2) a propeptide (SEQ ID NO: 110) (may be proteolytically processed during maturation of the protein, encoded by exon 1 (SEQ ID NO: 61)); (3) a Vps10p domain (SEQ ID NO: 111) (also referred to as Vps10p-β-propeller) (encoded by exons 2-13 (SEQ ID NOs: 62-73)); (4) a 10CC domain (SEQ ID NO: 112) (encoded by exons 14-16 (SEQ ID NOs: 74-76)); (5) a YWTD domain (SEQ ID NO: 113) (also referred to as YWTD-β-propeller) (encoded by exons 17-21 (SEQ ID NOs: 77-81)); (6) an epidermal growth factor (EGF) domain (SEQ ID NO: 114) (encoded by exon 22 (SEQ ID NO: 82)); (6) a CR cluster domain (SEQ ID NO: 115) (encoded by exons 23-33 (SEQ ID NOs: 83-93)); (7) a FnIII cluster, also referred to as FnIII cassette, FnIII repeats, FnIII domain (SEQ ID NO: 116) (encoded by exons 34-46 (SEQ ID NOs: 94-106)), also referred to as six Fibronectin type III (FnIII or FN3) repeats; (8) a transmembrane domain (SEQ ID NO: 117); and (9) a cytoplasmic tail domain (SEQ ID NO: 118) (encoded by exons 47-48 (SEQ ID NOs: 107-108)) (see, e.g., the sequences disclosed in Table 1 and the diagram of SORL1 shown in FIG.9). SORL1 encodes a polypeptide that is represented by NCBI Reference Sequence NP_003096.2. In some embodiments, human SORL1 is, for example, annotated under the accession number Q92673 at the UniProt database (UniProtKB - Q92673, SORL_HUMAN). An exemplary human SORL1 wild-type protein sequence is set forth in SEQ ID NO: 33 below: MATRSSRRESRLPFLFTLVALLPPGALCEVWTQRLHGGSAPLPQDRGFLVVQGDPRELRLWARGDARG ASRADEKPLRRKRSAALQPEPIKVYGQVSLNDSHNQMVVHWAGEKSNVIVALARDSLALARPKSSDV YVSYDYGKSFKKISDKLNFGLGNRSEAVIAQFYHSPADNKRYIFADAYAQYLWITFDFCNTLQGFSIPF RAADLLLHSKASNLLLGFDRSHPNKQLWKSDDFGQTWIMIQEHVKSFSWGIDPYDKPNTIYIERHEPSG YSTVFRSTDFFQSRENQEVILEEVRDFQLRDKYMFATKVVHLLGSEQQSSVQLWVSFGRKPMRAAQFV TRHPINEYYIADASEDQVFVCVSHSNNRTNLYISEAEGLKFSLSLENVLYYSPGGAGSDTLVRYFANEPF ADFHRVEGLQGVYIATLINGSMNEENMRSVITFDKGGTWEFLQAPAFTGYGEKINCELSQGCSLHLAQ RLSQLLNLQLRRMPILSKESAPGLIIATGSVGKNLASKTNVYISSSAGARWREALPGPHYYTWGDHGGII TAIAQGMETNELKYSTNEGETWKTFIFSEKPVFVYGLLTEPGEKSTVFTIFGSNKENVHSWLILQVNAT DALGVPCTENDYKLWSPSDERGNECLLGHKTVFKRRTPHATCFNGEDFDRPVVVSNCSCTREDYECDF GFKMSEDLSLEVCVPDPEFSGKSYSPPVPCPVGSTYRRTRGYRKISGDTCSGGDVEARLEGELVPCPLA EENEFILYAVRKSIYRYDLASGATEQLPLTGLRAAVALDFDYEHNCLYWSDLALDVIQRLCLNGSTGQ EVIINSGLETVEALAFEPLSQLLYWVDAGFKKIEVANPDGDFRLTIVNSSVLDRPRALVLVPQEGVMFW TDWGDLKPGIYRSNMDGSAAYHLVSEDVKWPNGISVDDQWIYWTDAYLECIERITFSGQQRSVILDNL PHPYAIAVFKNEIYWDDWSQLSIFRASKYSGSQMEILANQLTGLMDMKIFYKGKNTGSNACVPRPCSL LCLPKANNSRSCRCPEDVSSSVLPSGDLMCDCPQGYQLKNNTCVKQENTCLRNQYRCSNGNCINSIW WCDFDNDCGDMSDERNCPTTICDLDTQFRCQESGTCIPLSYKCDLEDDCGDNSDESHCEMHQCRSDEY NCSSGMCIRSSWVCDGDNDCRDWSDEANCTAIYHTCEASNFQCRNGHCIPQRWACDGDTDCQDGSD EDPVNCEKKCNGFRCPNGTCIPSSKHCDGLRDCSDGSDEQHCEPLCTHFMDFVCKNRQQCLFHSMVC DGIIQCRDGSDEDAAFAGCSQDPEFHKVCDEFGFQCQNGVCISLIWKCDGMDDCGDYSDEANCENPTE APNCSRYFQFRCENGHCIPNRWKCDRENDCGDWSDEKDCGDSHILPFSTPGPSTCLPNYYRCSSGTCV MDTWVCDGYRDCADGSDEEACPLLANVTAASTPTQLGRCDRFEFECHQPKTCIPNWKRCDGHQDCQ DGRDEANCPTHSTLTCMSREFQCEDGEACIVLSERCDGFLDCSDESDEKACSDELTVYKVQNLQWTAD FSGDVTLTWMRPKKMPSASCVYNVYYRVVGESIWKTLETHSNKTNTVLKVLKPDTTYQVKVQVQCL SKAHNTNDFVTLRTPEGLPDAPRNLQLSLPREAEGVIVGHWAPPIHTHGLIREYIVEYSRSGSKMWASQ RAASNFTEIKNLLVNTLYTVRVAAVTSRGIGNWSDSKSITTIKGKVIPPPDIHIDSYGENYLSFTLTMESD IKVNGYVVNLFWAFDTHKQERRTLNFRGSILSHKVGNLTAHTSYEISAWAKTDLGDSPLAFEHVMTRG VRPPAPSLKAKAINQTAVECTWTGPRNVVYGIFYATSFLDLYRNPKSLTTSLHNKTVIVSKDEQYLFLV RVVVPYQGPSSDYVVVKMIPDSRLPPRHLHVVHTGKTSVVIKWESPYDSPDQDLLYAVAVKDLIRKTD RSYKVKSRNSTVEYTLNKLEPGGKYHIIVQLGNMSKDSSIKITTVSLSAPDALKIITENDHVLLFWKSLA LKEKHFNESRGYEIHMFDSAMNITAYLGNTTDNFFKISNLKMGHNYTFTVQARCLFGNQICGEPAILLY DELGSGADASATQAARSTDVAAVVVPILFLILLSLGVGFAILYTKHRRLQSSFTAFANSHYSSRLGSAIF^{SSGDDLGEDDEDAPMITGFSDDVPMVIA} (SEQ ID NO: 33) [0095] In some embodiments, a reference sequence described herein is a wild-type SORL1 amino acid sequence, such as the sequence set forth in any one of SEQ ID NOs: 33 or 109-118. Representative nucleic acid sequences corresponding to exons in a wild-type SORL1 gene and amino acid sequences corresponding to domains in a wild-type SORL1 protein are shown in Table 1 below. Table 1. Exemplary Sequences of SORL1 Exons and SORL1 Domains

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[0096] In some instances, mutations in SORL1 result in neurodegenerative diseases, including, but not necessarily limited to Alzheimer’s disease. A number of loss-of-function mutations in SORL1 have been associated with both early-onset and late-onset Alzheimer’s disease. Many of these mutations are found in the eleven CR domains of SORL1, which are responsible for ligand binding. Other mutations in SORL1 associated with Alzheimer’s disease are known to reduce SORL1 expression levels. To this point, the methods described herein relate to new approaches for mapping mutations in SORL1 that are pathogenic or could be considered predictive of a subject developing a neurological disease (e.g., a neurodegenerative disease described herein). See, for example, Examples 1 and 2. As such, dysregulated SORL1 function is likely to be involved in other diseases, such as those associated with abnormal endosomal trafficking, increased amyloid plaque levels, and/or increased intracellular fibrillary tangles comprised of hyperphosphorylated tau proteins. [0097] The mechanism through which SORL1 mutations result in Alzheimer’s disease is believed to be rooted in its function as a trafficking regulator. SORL1 is understood to inhibit β-secretase-dependent release of amyloid precursor protein (APP) from endosomes. Upon release from endosomes, APP can be cleaved and processed into a form which is capable of binding other APP molecules, thereby forming plaques inside of the cell. Cell line studies show reduced expression levels of SORL1 results in increased amyloid plaque levels while increased SORL1 levels reduce amyloidogenesis. [0098] The ability of SORL1 to engage in endosomal recycling is linked to a motif in its cytoplasmic tail domain, the FANSHY motif, which is important for interaction with the retromer complex. In humans, the retromer complex consists of two subcomplexes comprising VP26, VPS29, and VPS35 (forming the “VPS trimer”) and a dimer of two nexin sorting proteins comprising SNX1 or SNX2 with SNX5 or SNX6. Retromer traffics cargo out of endosomes in a manner which is dependent on the cargo-binding activity of VPS35. Various lines of evidence show that VPS35 is decreased in specific brain regions of subjects with Alzheimer’s disease. Moreover, model system studies show retromer deficiency increases amyloidogenesis. Thus, the retromer is also implicated in neurodegenerative diseases and binding of retromer to the FANSHY motif of SORL1 is shown to be important for APP regulation. [0099] Increased retromer activity has been demonstrated to decrease the amyloidogenic cleavage of APP. Thus, increased retromer activity generates non- amyloidogenic soluble APPα (sAPPα). Accordingly, small molecule approaches have been used to upregulate retromer activity for therapeutic purposes. Some of these small molecule approaches have targeted SORL1 in attempts to indirectly upregulate retromer activity. Herein, the present disclosure provides methods and compositions related to therapeutic agents (e.g., small molecules, a biologic, gene therapies, and gene-editing therapies) that modulate (e.g., upregulate) SORL1 activity in mutant cells, mutant biological samples, and mutant subjects comprising mutations associated with neurodegenerative diseases. Mutational Analyses and Methods Thereof [0100] Aspects of the present disclosure relate to methods for identifying a cell, biological sample, or subject that expresses a SORL1 gene encoding a disease-associated mutation. [0101] In some embodiments, the present disclosure relates to methods of treating a neurological disease in a cell, biological sample, or subject comprising obtaining a query SORL1 gene sequence from the cell, biological sample, or subject, identifying the presence of a disease-associated mutation in the query SORL1 gene sequence, and administering to the cell, biological sample, or subject an agent that modulates endosomal trafficking. [0102] In some embodiments, the present disclosure relates to a method for modulating endosomal trafficking in a cell, biological sample, or subject comprising obtaining a query SORL1 gene sequence from the cell, biological sample, or subject, identifying the presence of a disease-associated mutation in the query SORL1 gene sequence, and administering to the cell, biological sample, or subject an agent that modulates endosomal trafficking. [0103] In some embodiments, the present disclosure relates to a method of identifying a patient for treatment comprising obtaining a query SORL1 gene sequence from the cell, biological sample, or subject, identifying the presence of a disease-associated mutation in the query SORL1 gene sequence, and administering to the cell, biological sample, or subject an agent that modulates endosomal trafficking. Nucleic Acid Characterization Methods [0104] In order to obtain a query sequence from a cell, biological sample, or subject and perform downstream mutational analyses, said cell, biological sample, or subject must be identified as having an increased risk of comprising a SORL1 gene encoding a disease- associated mutation. Increased risk of incidence of neurological disease (e.g., neurodegenerative disease) may be inferred based on known information about the familial history of the subject. Alternatively, increased risk of incidence of neurological disease (e.g., neurodegenerative disease) may be inferred based on to the subject exhibiting one or more symptoms of neurological disease (e.g., neurodegenerative disease). Such risk factors and clinical indicators are known. As such, reasons for suspecting or anticipating the presence of development of a neurological disease (e.g., neurodegenerative disease) in a subject are understood and routinely used by those of ordinary skill in the art. However, such reasons for probing the presence of a SORL1 mutation in a subject need not be required in order for them to benefit from the methods described herein. To this point, query sequences from a subject may be used for the analyses and methods described herein on a random, purely preventative, or optional basis. [0105] Those skilled in the art will understand that obtaining a query sequence from a cell, biological sample, or subject can be achieved through a variety of methods. In most instances, a sample of cells must be harvested from a subject by obtaining a voluntarily sample. Methods of obtaining such samples will be clear to those of skill in the art and will depend on the origins of such samples. A variety of biological samples to be used in the presently described methods are contemplated herein. In some embodiments, samples may be obtained from a sample bank comprising samples from a large group of subjects. Therein, samples of whole, intact cells will be subjected to methods for harvesting nucleic acids which are established in the art. [0106] For example, said methods may comprise cell lysis and subsequent nucleic acid purification and precipitation. Isolated nucleic acids may therein be subjected to one or more methods for characterizing or determining the presence of a disease-associated mutation(s) in a SORL1 gene. In some embodiments, a nucleic acid comprising or suspected of comprising a disease-associated mutation in a SORL1 gene is sequenced via, for example, Sanger sequence, next-generating sequencing (NGS), or RNA-seq. Accordingly, DNA and RNA can be used to detect the presence of a disease-associated mutation(s) in SORL1. Further, an isolated nucleic acid that is subject to one or more nucleic acid characterization/sequencing methods can comprise genomic DNA, RNA (e.g., mRNA), or cDNA produced by reverse transcription of RNA. [0107] In some embodiments, a nucleic acid comprising or suspected of comprising a disease-associated mutation in a SORL1 gene is amplified (e.g., using PCR) to produce a polynucleotide that comprises the query sequence. The PCR will typically involve at least a forward and a reverse primer. The primers can be of equal length or different lengths and will typically comprise at least 15 nucleotides in length. In some embodiments, a primer comprises more than 15 nucleotides, such as 20-30, 30-40, 40-50, or more than 50 nucleotides in length. Generally, primers comprise at least 10 nucleotides that are 100% complementary to the sequence they are intended to bind. In some embodiments, a primer comprises more than 10 nucleotides that are 100% complementary to the sequence it is intended to bind, such as a 10-20, 20-30, 30-40, 40-50, or more than 50 nucleotides that are 100% complementary. In some embodiments, a primer comprises a sequence that hybridizes to a sequence set forth in any one of SEQ ID NOs: 60-108 or 119-120. In some embodiments, a primer comprises a sequence that hybridizes to a mutated version of a sequence set forth in any one of SEQ ID NOs: 60-108 or 119-120, such as a SORL1 exon encoding a SORL1 amino acid sequence comprising a disease-associated mutation(s) described herein. In some embodiments, primers are used to amplify the SORL1 gene or a portion thereof (e.g., a portion comprising 40 or more nucleotides in SORL1, such as 40-60, 60-80, 80-100, 100-120, 120-140, 140-160, 160-180, 180-200, 200-300, 300-400, 400-500, 500-750, 750-1,000, 1,000-1,500, 1,500-2,000, more than 2,000, more than 3,000, more than 4,000, or more than 5,000 nucleotides in SORL1). [0108] Primers can be designed to flank a region in the query sequence comprising or suspected of comprising a disease-associated mutation in a SORL1 gene. Designing primers to flank a region comprising or suspected of comprising a disease-associated mutation in a SORL1 gene can be used to amplify a sequence comprising mutations, such as substitutions, insertions, and/or deletions. The amplicons can then be sequenced to detect the presence of the disease-associated mutation. In some embodiments, multiple sets of primers can be employed to amplify multiple different regions the SORL1 gene that comprise or are suspected of comprising disease-associated mutations. [0109] Alternatively, primers can be designed so that they hybridize selectively to a region where a disease-associated mutation in SORL1 gene is located or suspected of being located. For example, in some embodiments, primers are designed to hybridize to a region comprising a disease-associated mutation in SORL1 and are designed to be incapable of hybridizing to a region lacking the disease-associated mutation. In this way, subjecting a SORL1 sequence comprising a disease-associated mutation to PCR produces an amplicon and subjecting a SORL1 sequence lacking a disease-associated mutation does not produce an amplicon. PCR samples can subsequently subject to gel electrophoresis analysis to detect the presence of a band corresponding to the amplicons comprising the disease-associated mutation. [0110] Alternatively, in some embodiments, determining the presence of a disease-associated mutation in SORL1 comprises designing primers to produce a first amplicon comprising the disease-associated mutation and a second amplicon that lacks the disease-associated mutation. In this example, the first amplicon and the second amplicon are of different sizes which can be resolved by, for example, gel electrophoresis analysis to detect a difference in the electrophoretic mobility of between the first and second amplicons. Such methods can be used to detect insertions and/or deletions in a mutated SORL1 sequence relative to a wild- type SORL1 sequence. The appropriate controls for PCR analysis of SORL1 sequences will be employed and can include, for example, a SORL1 wild-type gene or a fragment thereof. [0111] In addition, PCR analysis can comprise real-time quantitative PCR analysis (RT- qPCR), wherein RNA transcribed from a SORL1 gene are subjected to reverse transcription to produce cDNA and subsequent cDNA amplification. Cycle threshold (CT) values are then used as a read-out, wherein amplification of a sequence comprising a disease-associated mutation in SORL1 produces amplicons corresponding to a first C_T value and amplification of a sequence lacking the disease-associated mutation in SORL1 produces a second CT value. In some embodiments, RT-qPCR analysis is used to detect an alternatively spliced transcript produced from a SORL1 gene comprising a disease-associated mutation that results in, for example, exon exclusion and/or intron inclusion. Further examples of amplification-based methods that can be used to detect a SORL1 mutation include 5′ Rapid Amplification of cDNA Ends (RACE) and 3′ RACE. [0112] Other recombinant techniques can be used to detect the presence of a disease- associated mutation in SORL1. For example, restriction endonuclease digestion can be used when a SORL1 sequence comprises or is suspected of comprising a disease-associated mutations that introduces or disrupts a site recognized by a restriction endonuclease. In these approaches, a SORL1 sequence is subjected to conditions suitable for restriction endonuclease-dependent digestion which involve contacting the SORL1 sequence with a sufficient amount of restriction endonuclease, suitable buffer, and incubation at an appropriate temperature for the restriction endonuclease to cleave the SORL1 sequence. After restriction endonuclease digestion, the digested DNA can be subjected to one or more methods that detect restriction fragments corresponding to a SORL1 sequence lacking the disease-associated mutation and/or detect restriction fragments corresponding to a SORL1 sequence comprising the disease-associated mutation, such as gel electrophoresis analysis (e.g., to detect an electrophoretic mobility difference relative to a control sample) or PCR (e.g., to amplify a restriction fragment that is produced only when a disease-associated mutation is present in a SORL1 sequence and/or to amplify a restriction fragment produced only when a disease-associated mutation is absent in a SORL1 sequence). [0113] In some embodiments, query sequences can be obtained from an existing database of sequences which contains sequence information previously derived from subjects or patients (see, e.g., SORL1 genetic databases available through AlzForum Foundation Inc which incorporated by reference for its disclosures related to SORL1 mutations). [0114] In some embodiments, detecting nucleic acid sequences comprising a mutated SORL1 gene involves detectable nucleic acid probes (e.g., fluorophore-conjugated DNA probes). Generally, a “detectable nucleic acid probe” refers to a nucleic acid sequence that specifically binds to (e.g., hybridizes with) a target sequence, and comprises a detectable moiety, for example a fluorescent moiety, radioactive moiety, chemiluminescent moiety, electroluminescent moiety, biotin, peptide tag (e.g., poly-His tag, FLAG-tag, etc.). In some embodiments, a detectable nucleic acid probe is a DNA or RNA probe. In some embodiments, the DNA or RNA probe is conjugated to a fluorophore. In some embodiments, a detectable nucleic acid probe is chemically modified. In some embodiments, nucleic acid hybridization-based methods are used for identifying the presence of a mutation in SORL1 gene in a cell, biological sample, or subject. In some embodiments, the length required for hybridization of a probe is at least 10 nucleotides in length (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 20-30, 30-40, 40-50, 50-75, 75-100, or more than 100 nucleotides). In some embodiments, the degree of sequence complementarity required for hybridization of a probe is at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 100%. In some embodiments, a biological sample may be contacted with a plurality of detectable nucleic acid probes. The number of nucleic acid probes in a plurality can vary and can include 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 probes. The nucleic acid probes may be the same or different sequences. Accordingly, first probe or a first plurality of probes can be used to detect the presence or absence of a first disease-associated mutation and a second probe or a second plurality of probes can be used to detect the presence or absence of a second disease- associated mutation. In some embodiments, a probe comprises a sequence that hybridizes to a sequence set forth in any one of SEQ ID NOs: 60-108 or 119-120. In some embodiments, a probe comprises a sequence that hybridizes to a mutated version of a sequence set forth in any one of SEQ ID NOs: 60-108 or 119-120, such as a SORL1 exon encoding a SORL1 amino acid sequence comprising a disease-associated described herein. Probes can also be contacted with a SORL1 sequence that has been subjected to gel electrophoresis separation and transfer to a membrane, such as in Southern blot or Norther blot. Alternatively, probes can be immobilized on a surface, such as a chip, and contacted with a sample comprising a SORL1 sequence (e.g., in a method comprising micro-array analysis). [0115] In some embodiments, identifying the presence of the disease-associated mutation in the query SORL1 gene sequence comprises aligning the query SORL1 gene sequence against a reference SORL1 gene sequence comprising the disease-associated mutation. Alignment may be performed using a variety of bioinformatic tools known in the art including, but not limited to, BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), COBALT, OPAL, Multlin, Clustal Omega, Clustal W2.0, or Clustal X2.0 software. In some embodiments, the reference sequence is manually selected by the individual performing the alignment such that query sequence is being deliberately aligned against only one reference sequence. Accordingly, the reference sequence may be chosen because it contains a disease-associated mutation in SORL1 that is suspected to be found in the query sequence. Alternatively, the reference sequence can be chosen because it lacks a disease-associated mutation in SORL1 (see, e.g., SEQ ID NOs: 60-108 or 119-120). In some embodiments, multiple successive rounds of alignment are performed with different reference sequences in order to iteratively probe a query sequence for the presence of various disease-associated mutations in SORL1. In some embodiments, a query sequence may be aligned concurrently against a plurality of reference sequences in order to interrogate the presence of a multiple disease-associated mutations in SORL1 at one time. Disease-Associated Mutations in SORL1 [0116] Disease-associated mutations in a SORL1 gene can comprise one or more nucleotide substitutions, one or more nucleotide deletions, and/or one or more nucleotide insertions. Accordingly, disease-associated mutation in a SORL1 gene can comprise a single nucleotide change or a plurality of nucleotide sequence alterations arising from substitutions, deletions, insertions, or a combination thereof. In some embodiments, a SORL1 gene comprising a disease-associated mutation comprise one or more nucleotide substitutions, one or more nucleotide deletions, and/or one or more nucleotide insertions relative to a wild-type SORL1 gene, such as a SORL1 gene comprising the nucleic acid sequence of any one of SEQ ID NOs: 60-108 or 119-120. In some embodiments, a SORL1 gene comprising a disease- associated mutation comprises a plurality of mutations, such as a plurality of nucleotide substitutions, a plurality of nucleotide deletions, and/or a plurality of nucleotide insertions. In some embodiments, a SORL1 gene comprising a disease-associated mutation comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, or more than 100 nucleotide positions which differ relative to a wild-type SORL1 gene. In some embodiments, a SORL1 gene comprising a disease-associated mutation comprises 1-100 nucleotide positions which differ relative to a wild-type SORL1 gene. In some embodiments, a SORL1 protein encoded by a SORL1 gene comprising a disease-associated mutation comprises one or amino acid positions which differ relative to a wild-type SORL1 protein, such as a wild-type SORL1 protein comprising an amino acid sequence set forth in any one of SEQ ID NOs: 33 or 109-118. In some embodiments, a SORL1 protein encoded by a SORL1 gene comprising a disease-associated mutation comprises a plurality of amino acid positions which differ relative to a wild-type SORL1 protein. In some embodiments, the plurality of amino acid positions comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more than 30 amino acid positions which differ relative to a wild-type SORL1 protein. In some embodiments, the plurality of amino acid positions comprises 1-30 amino acid positions which differ relative to a wild-type SORL1 protein. [0117] In some embodiments, a disease-associated mutation in a SORL1 gene results in a frame-shift. In some embodiments, a disease-associated mutation in a SORL1 gene encodes a truncated SORL1 protein. In some embodiments, a truncated SORL1 protein is encoded by a SORL1 gene comprising a mutation that introduces a premature stop codon which is in frame with the SORL1 coding sequence. In some embodiments, a truncated SORL1 protein is encoded by a SORL1 gene comprising an insertion, a substitution, or a deletion that results in a frameshift. In some embodiments, a truncated SORL1 protein or a SORL1 protein encoded by a SORL1 gene comprising a frameshift comprises a deletion of one or more amino acids, such as one or more amino acids that are involved in binding to endosomal trafficking factors (e.g., retromer complex subunits), cargo molecules, and/or SORL1 dimerization. In some embodiments, a truncated SORL1 protein or a SORL1 protein encoded by a SORL1 gene comprising a frameshift comprises a deletion of at least one SORL1 protein domain described herein. In some embodiments, a truncated SORL1 protein comprises one or more deleted domains and at least one domain that is partially deleted. [0118] In some embodiments, a splicing regulatory sequence in the SORL1 gene (e.g., a sequence comprising a splicing acceptor site, or a splicing donor site). In some embodiments, mutations in a splicing regulatory sequence results in alternative splicing of an RNA transcript encoded by the SORL1 gene. Intron-exon boundaries in the SORL1 genomic sequence set forth in SEQ ID NO: 119 is described in Table 1. A splicing donor site is typically located at the 5′ end of the intron and comprises a dinucleotide sequence of GT while a splicing acceptor site is typically located at the 3′ end of an intron and comprises a dinucleotide sequence of AG. Located between the acceptor and donor sites is typically A branch site comprising an A nucleotide residue involved in lariat formation sequence is typically positioned 50 nucleotides or less upstream of the acceptor site and separated from the acceptor site by intron sequence comprising a polypyrimidine tract. In some embodiments, a disease-associated mutation is located in a splicing acceptor site in a SORL1 gene or a splicing donor site in a SORL1 gene. In some embodiments, mutation of a splicing acceptor site or a splicing donor site in a SORL1 gene results in exon skipping and/or intron inclusion. In some embodiments, a branch site in a SORL1 intron is mutated such that it lacks the branch site A nucleotide residue (e.g., by substitution with C, G, or T, or by deletion of the branch site A nucleotide residue) or such nucleotides are inserted between the acceptor site and the branch site (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 10-15, 15-20, 20-25, or more nucleotides). In some embodiments, mutation of a branch site in a SORL1 intron results in exon skipping and/or intron inclusion. In some embodiments, a SORL1 mutant comprising a disease-associated mutation encodes a transcript lacking exon 2 and/or lacking exon 19. Alternative splicing of a SORL1 transcript as a result of a disease-associated mutation will typically result in production of a SORL1 protein comprising one or more amino acid differences. In some embodiments, alternative splicing of a SORL1 transcript results in a SORL1 intron sequences being translated, thereby yielding amino acid insertions. In some embodiments, alternative splicing of a SORL1 transcript results in a SORL1 exon being excluded, thereby yielding amino acid deletions. In some embodiments, alternative splicing of a SORL1 transcripts results in a frameshift, thereby yielding amino acid insertions, amino acid deletions, and/or amino acid substitutions in a SORL1 protein. In some embodiments, a splicing regulatory sequence comprises an exonic splicing enhancer (ESE) (see, e.g., Brinbaum et al. (2014). Systematic Dissection of Coding Exons at Single Nucleotide Resolution Supports an Additional Role in Cell-Specific Transcriptional Regulation. PLoS Genet, 10(10): e1004592 which is incorporated by reference for disclosures related to SORL1 ESE sequences). [0119] In some embodiments, a disease-associated mutation in a SORL1 gene is located in an exon. A disease-associated mutation in a SORL1 exon can comprise a substitution, an insertion, a deletion, or a combination thereof, that results in a different amino acid being encoded in a SORL1 protein. In some embodiments, a disease-associated mutation in a SORL1 exon comprises a deletion of an exon sequence. In some embodiments, a SORL1 gene comprising a disease-associated mutation in an exon comprises one or more nucleotide positions which differ relative a sequence set forth in any one of SEQ ID NOs: 60-108 or 119-120. Substitutions in a SORL1 exon that lead to disease-associated mutations can comprise non-conservative substitutions, wherein the variant amino acid has different chemical properties relative to the native amino acid at the corresponding position in wild- type SORL1. Examples of non-conservative substitutions include substitutions of a hydrophobic amino acid for a hydrophilic amino acid (e.g., a polar amino acid or charged amino acid), such as a position comprising phenylalanine being substituted for glutamine, serine, or aspartate. As a further example, a non-conservative substitution can involve a hydrophilic amino acid being substituted for a hydrophobic amino acid, such as a position comprising glutamate being substituted for tryptophan, glycine, or valine. However, non- conservative substitutions can also include hydrophilic amino acids being substituted for hydrophilic amino acids and hydrophobic amino acids being substituted for hydrophobic amino acids. For example, a position comprising arginine being substituted for glutamate or a position comprising aspartate being substituted for histidine. Substitutions in SORL1 that can be associated with a disease, disorder, or condition can also include those that result in a mutated amino acid position that comprises a residue with a markedly different side chain size and/or shape, such as a tryptophan to glycine substitution or an arginine to valine substitution. In some embodiments, an insertion of a proline residue, a deletion of a proline residue, or a substitution of a different residue for proline in SORL1 alters SORL1 structure and can be associated with a disease, disorder, or condition described herein. Examples of tools which are useful for prediction of protein structure and may be used to model SORL1 mutants comprising disease-associated mutations include AlphaFold, Rossetta, I-TASSER, Robetta, Phyre2, RaptorX, and SWISS-MODEL. Disease-associated mutations in SORL1 can also alter endosomal trafficking in cells without changing the SORL1 coding sequence. For example, synonymous mutations in a SORL1 gene when the substitutions involved in such mutations generate codons that are not efficiently translated in mammalian cells, such as human cells, which can reduce SORL1 translation kinetics, thereby effective SORL1 protein levels and/or SORL1 folding. [0120] In some embodiments, a domain which has been deleted from a SORL1 protein encoded by a SORL1 gene comprising a disease-associated mutation is a domain involved in binding to endosomal trafficking factors (e.g., retromer complex subunits), cargo molecules, and/or SORL1 dimerization. Alternatively, in some embodiments, a SORL1 protein encoded by a SORL1 gene comprising a disease-associated mutation comprises an amino acid substitution or a plurality thereof in a domain involved in binding to endosomal trafficking factors (e.g., retromer complex subunits), cargo molecules, and/or SORL1 dimerization. SORL1 residues involved in binding to endosomal trafficking factors is described herein (see, e.g., Examples 1-2). Accordingly, disease-associated mutations in SORL1 can affect one or more functions that a wild-type SORL1 performs including, but not limited to, binding to retromer complex subunits (e.g., VPS26a, VPS26b, VPS35) and/or dimerization with other SORL1 molecules. Disrupted binding of retromer complex subunits and/or SORL1 dimerization as a result of a disease-associated mutation in SORL1 can result in altered localization of APP, AMPA receptor, and/or SORL1 to the cell surface relative to a cell lacking a disease-associated mutation in the SORL1 gene. For example, in some embodiments, a disease-associated mutation in SORL1 results in decreased localization of the AMPA receptor and/or SORL1 to the cell surface relative to a cell lacking a disease- associated mutation in the SORL1 gene. In some embodiments, a disease-associated mutation in SORL1 results in an increase of APP at the cell surface relative to a cell lacking a disease- associated mutation in a SORL1 gene. Disrupted binding of retromer complex subunits and/or SORL1 dimerization as a result of a disease-associated mutation in SORL1 can also result in altered levels of sAPPα, tau aggregation, tau phosphorylation, sAPPβ, Aβ30, Aβ40, and/or Aβ42 levels relative to a cell lacking a disease-associated mutation in a SORL1 gene. For example, in some embodiments, disease-associated mutations in SORL1 can result in a decrease in sAPPα levels, an increase in tau aggregation, an increase in tau phosphorylation, an increase in sAPPβ levels, an increase in Aβ30 levels, an increase in Aβ40 levels, and/or increase in Aβ42 levels relative to a cell lacking a disease-associated mutation in a SORL1 gene. Disease-associated mutations in SORL1 can also alter the binding of SORL1 to other interacting proteins, such as those described in Monti & Andersen (2017).20 Years Anniversary for SORLA/SORL1 (1996-2016). Receptor Clin Invest, 4: e1611 which is incorporated by reference herein for its disclosures related to SORL1 ligands. [0121] In some embodiments, a disease-associated mutation occurs in the VPS10p domain, 10CC domain, YWTD domain, EGF domain, the CR domain, the FnIII domain, the transmembrane domain, or the cytoplasmic tail domain. In some embodiments, the disease- associated mutation comprises a pathogenic mutation as set forth in Table 13. [0122] In some embodiments, the disease-associated mutation occurs at any one of positions:

Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, T⁹³⁶, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³, I⁹⁸³, R⁷⁷¹, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, G⁷⁷⁷, G⁸¹⁹, G⁸⁶³, G⁹⁰⁹, G⁹⁵⁰, G⁹⁹¹, R⁸⁶⁶, R⁹⁵³, C⁸⁰¹, or C⁸¹⁶ in the YWTD doman; C¹⁰²¹, C¹⁰²⁶, C¹⁰³⁰, C¹⁰⁴⁰, C¹⁰⁴², C¹⁰⁵⁸, C¹⁰⁶⁰, or C¹⁰⁷¹ in the EGF domain; S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹²⁹⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁴⁰, G¹⁴⁹³, G¹⁵³⁶, D¹⁰⁹⁸, D¹¹⁰², D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸², D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, D¹²⁶⁷, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁴⁹, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁴⁴, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁵³, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁰, C¹⁵⁴⁹, D¹¹⁰⁵, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶,

domain; L¹⁵⁶¹, W¹⁵⁶³, L¹⁶⁵⁹, L¹⁶⁶¹, I¹⁷⁵³, I¹⁷⁵⁵, L¹⁸⁴⁸, A¹⁸⁵⁰, L¹⁹³⁸, V¹⁹⁴⁰, L²⁰³⁰, I²⁰³², V¹⁵⁷¹, L¹⁵⁷³, I¹⁶⁶⁹, L¹⁷⁶³, F¹⁷⁶⁵, V¹⁸⁵⁸, C¹⁸⁶⁰, V¹⁹⁴⁸, I¹⁹⁵⁰, V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², W¹⁷³⁵, P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, P¹⁹⁵⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹,

M⁸⁹⁰, I⁹²⁶, V⁹²⁸, I⁹³³, I⁹⁶⁶, V⁹⁶⁸, I⁹⁷³, M¹⁰⁰⁷, I¹⁰⁰⁹, L⁷⁸², V⁸²⁵, I⁸²⁶, I⁸⁶⁹, V⁸⁷⁰, L⁹¹⁵, V⁹¹⁶, I⁹⁵⁶, L⁹⁵⁷, I⁹⁹⁶, L⁹⁹⁷, L⁷⁸⁷, L⁸³¹, L⁸⁷⁵, V⁹²⁰, L⁹⁶⁰, L¹⁰⁰¹, R⁸⁷⁹, W⁸⁹⁵, N⁹²⁴, Y⁹⁶⁴, W⁹⁷⁸, Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶, Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³, I⁹⁸³, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, G⁷⁷⁷, G⁸¹⁹, G⁸⁶³, G⁹⁰⁹, G⁹⁵⁰, G⁹⁹¹, R⁸⁶⁶, R⁹⁵³, C⁸⁰¹, or C⁸¹⁶ in the YWTD domain; C¹⁰²¹, C¹⁰²⁶, C¹⁰³⁰, C¹⁰⁴⁰, C¹⁰⁴², C¹⁰⁵⁸, C¹⁰⁶⁰, or C¹⁰⁷¹ in the EGF domain; S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁹³, G¹⁵³⁶, D¹⁰⁹⁸, D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁹, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴, D¹³⁵², D¹³⁹⁶, D¹⁴⁴⁶, D¹⁴⁹⁹, or D¹⁵⁴² in the CR domain; L¹⁵⁶¹, W¹⁵⁶³, L¹⁶⁵⁹, L¹⁶⁶¹, I¹⁷⁵³, I¹⁷⁵⁵, L¹⁸⁴⁸, A¹⁸⁵⁰, L¹⁹³⁸, V¹⁹⁴⁰, L²⁰³⁰, I²⁰³², V¹⁵⁷¹, L¹⁵⁷³, I¹⁶⁶⁹, L¹⁷⁶³, F¹⁷⁶⁵, V¹⁸⁵⁸, C¹⁸⁶⁰, V¹⁹⁴⁸, I¹⁹⁵⁰, V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², W¹⁷³⁵, P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹, P¹⁹⁹⁸, R¹⁹¹⁰, C¹⁵⁸⁶, C¹⁶³¹, C²¹⁰¹, or C²¹⁰⁸ in the FnIII domain; or F²¹⁷², A²¹⁷³, S²¹⁷⁵, H²¹⁷⁶, Y²¹⁷⁷, D²¹⁹⁰, D²¹⁹¹, L²¹⁹², G²¹⁹³, E²¹⁹⁴, D²¹⁹⁵, D²¹⁹⁶, E²¹⁹⁷, D²¹⁹⁸, D²²⁰⁷, D²²⁰⁸, V²²⁰⁹, P²²¹⁰, M²²¹¹, V²²¹², I²²¹³, or A²²¹⁴ in the cytoplasmic tail domain; or any combination thereof. [0123] In some embodiments, the disease-associated mutation is a mutation implicated in a neurological disease. In some embodiments, the neurological disease is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is selected from the group consisting of Parkinson’s Disease, Dementia, Pick’s Disease, Lewy Body Dementia, Huntington’s Disease, Alzheimer’s disease, Early-Onset Alzheimer’s disease, Late-Onset Alzheimer’s disease, Familial Alzheimer’s disease, and diseases that are associated with TDP-43 pathologies. [0124] In some embodiments, the disease-associated mutation occurs in the VPS10p domain of SORL1. In some embodiments, the disease-associated mutation in the VPS10p domain confers a moderate risk of developing Alzheimer’s disease. In some embodiments, the disease-associated mutation in the VPS10p domain of SORL1 which confers a moderate risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹, Y³⁵⁰, F⁴¹⁴, L⁴⁹⁵, Y⁵³⁹, Y⁵⁴⁰, V⁵⁸³, Y⁵⁸⁴, I¹¹⁷, V¹¹⁸, A¹¹⁹, Y¹⁷⁷, I¹⁷⁸, F¹⁷⁹, L²¹⁸, L²¹⁹, L²²⁰, I²⁶⁴, Y²⁶⁵, I²⁶⁶, Y³⁰⁶, M³⁰⁷, F³⁰⁸, V³⁵⁹, F³⁶⁰, V³⁶¹, Y⁴²⁴, I⁴²⁵, A⁴²⁶,I⁵⁰⁴, I⁵⁰⁵, A⁵⁰⁶, I⁵⁴⁸, I⁵⁴⁹, V⁵⁹⁶, F⁵⁹⁷, V¹³⁵, Y¹³⁶, V¹³⁷, L¹⁸⁷, W¹⁸⁸, I¹⁸⁹, L²³¹, W²³², V²⁷⁷, F²⁷⁸, L³²⁶, W³²⁷, V³²⁸, L³⁷², Y³⁷³, I³⁷⁴, V⁴⁴¹, I⁴⁴², V⁵²⁰, Y⁵²¹, I⁵²², L⁵⁶¹, Y⁵⁶³, L⁶¹³, and V⁶¹⁵. In some embodiments, the disease-associated mutation in the VPS10p domain of SORL1 which confers a moderate risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹, F⁴¹⁴, L⁴⁹⁵, Y⁵³⁹, Y⁵⁴⁰, V⁵⁸³, Y⁵⁸⁴, I¹¹⁷, V¹¹⁸, A¹¹⁹, Y¹⁷⁷, I¹⁷⁸, F¹⁷⁹, L²¹⁸, L²¹⁹, L²²⁰, I²⁶⁴, Y²⁶⁵, I²⁶⁶, Y³⁰⁶, F³⁰⁸, V³⁵⁹, F³⁶⁰, V³⁶¹, Y⁴²⁴, I⁴²⁵, A⁴²⁶,I⁵⁰⁴, I⁵⁰⁵, A⁵⁰⁶, I⁵⁴⁸,

Y³⁷³, I³⁷⁴, V⁴⁴¹, I⁴⁴², V⁵²⁰, Y⁵²¹, I⁵²², L⁵⁶¹, Y⁵⁶³, L⁶¹³, and V⁶¹⁵. In some embodiments, the disease-associated mutation in the VPS10p domain confers a high risk of developing Alzheimer’s disease. In some embodiments, the disease-associated mutation in the VPS10p domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of S¹³⁸, D¹⁴⁰, G¹⁴², S¹⁴⁴, F¹⁴⁵, T¹⁹⁰, D¹⁹², T¹⁹⁶, S²³⁴, D²³⁶, G²³⁸, T²⁴⁰, W²⁴¹, S²⁸⁰, D²⁸², S²⁸⁶, S³²⁹, S³⁷⁵, G³⁷⁹, F³⁸², T⁴⁴³, D⁴⁴⁵, G⁴⁴⁷, T⁴⁴⁹, W⁴⁵⁰, S⁵²³, G⁵²⁷, W⁵³⁰, S⁵⁶⁴, N⁵⁶⁶, G⁵⁶⁸, T⁵⁷⁰, W⁵⁷¹, C⁴⁶⁷, and C⁴⁷³. In some embodiments, the disease-associated mutation in the VPS10p domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of S¹³⁸, G¹⁴², S¹⁴⁴, F¹⁴⁵, T¹⁹⁰, D¹⁹², T¹⁹⁶, S²³⁴, D²³⁶, G²³⁸, T²⁴⁰, W²⁴¹, S²⁸⁰, D²⁸², S²⁸⁶, S³²⁹, S³⁷⁵, G³⁷⁹, F³⁸², T⁴⁴³, D⁴⁴⁵, G⁴⁴⁷, T⁴⁴⁹, W⁴⁵⁰, S⁵²³, G⁵²⁷, W⁵³⁰, S⁵⁶⁴, N⁵⁶⁶, G⁵⁶⁸, T⁵⁷⁰, W⁵⁷¹, C⁴⁶⁷, and C⁴⁷³. In some embodiments, the disease-associated mutation in the VPS10p domain which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease, such as Alzheimer’s disease) occurs at any position between 391 – 411 and 457 – 493. [0125] In some embodiments, the disease-associated mutation occurs in the 10CC domain of SORL1. In some embodiments, the disease-associated mutation in the 10CC domain confers a high risk of developing Alzheimer’s disease. In some embodiments, the disease-associated mutation in the 10CC domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of C⁶²⁵, C⁶⁴³, C⁶⁶⁰, C⁶⁷⁵, C⁶⁷⁷, C⁶⁸⁴, C⁶⁹⁹, C⁷¹⁶, C⁷³⁶, and C⁷⁵². [0126] In some embodiments, the disease-associated mutation occurs in the YWTD domain of SORL1. In some embodiments, the disease-associated mutation in the YWTD domain confers a moderate risk of developing Alzheimer’s disease. In some embodiments, the disease-associated mutation in the YWTD domain of SORL1 which confers a moderate risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of L⁷⁹³, F⁷⁹⁵, L⁸⁰², L⁸³⁷, F⁸³⁹, L⁸⁴⁶, L⁸⁸¹, L⁸⁸³, M⁸⁹⁰, I⁹²⁶, V⁹²⁸, I⁹³³, I⁹⁶⁶, V⁹⁶⁸, I⁹⁷³, M¹⁰⁰⁷, I¹⁰⁰⁹, L⁷⁸², V⁸²⁵, I⁸²⁶, I⁸⁶⁹, V⁸⁷⁰, L⁹¹⁵, V⁹¹⁶, I⁹⁵⁶, L⁹⁵⁷, I⁹⁹⁶, L⁹⁹⁷, L⁷⁸⁷, L⁸³¹, L⁸⁷⁵, V⁹²⁰, L⁹⁶⁰, L¹⁰⁰¹, R⁸⁷⁹, W⁸⁹⁵, N⁹²⁴, Y⁹⁶⁴, and W⁹⁷⁸. In some embodiments, the disease-associated mutation in the YWTD domain confers a high risk of developing Alzheimer’s disease. In some embodiments, the disease- associated mutation in the YWTD domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶, Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, T⁹³⁶, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³, I⁹⁸³, R⁷⁷¹, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, G⁷⁷⁷, G⁸¹⁹, G⁸⁶³, G⁹⁰⁹, G⁹⁵⁰, G⁹⁹¹, R⁸⁶⁶, R⁹⁵³, C⁸⁰¹, and C⁸¹⁶. In some embodiments, the disease-associated mutation in the YWTD domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶, Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³, I⁹⁸³, R⁸¹⁴, R⁹⁰⁴,

[0127] In some embodiments, the disease-associated mutation occurs in the EGF domain of SORL1. In some embodiments, a fragment of the EGF domain is deleted. In some embodiments, the entire EGF domain is deleted. In some embodiments, the disease- associated mutation comprises an insertion of on or more cysteine residues into the EGF domain. In some embodiments, the disease-associated mutation in the EGF domain confers a high risk of developing Alzheimer’s disease. In some embodiments, the disease-associated mutation in the EGF domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of C¹⁰²¹, C¹⁰²⁶, C¹⁰³⁰, C¹⁰⁴⁰, C¹⁰⁴², C¹⁰⁵⁸, C¹⁰⁶⁰, and C¹⁰⁷¹. [0128] In some embodiments, the disease-associated mutation occurs in the CR domain of SORL1. In some embodiments, the disease-associated mutation in the CR domain confers a moderate risk of developing Alzheimer’s disease. In some embodiments, the disease-associated mutation in the CR domain of SORL1 which confers a moderate risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹²⁹⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁴⁰, G¹⁴⁹³, and G¹⁵³⁶. In some embodiments, the disease- associated mutation in the CR domain of SORL1 which confers a moderate risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁹³, and G¹⁵³⁶. [0129] In some embodiments, the disease-associated mutation in the CR domain confers a high risk of developing Alzheimer’s disease. In some embodiments, the disease- associated mutation in the CR domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of D¹⁰⁹⁸, D¹¹⁰², D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸², D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, D¹²⁶⁷, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁴⁹, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁴⁴, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁵³, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷,

In some embodiments, the disease-associated mutation in the CR domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of D¹⁰⁹⁸, D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴,

[0130] In some embodiments, the disease-associated mutation occurs in the FnIII domain of SORL1. In some embodiments, the disease-associated mutation in the FnIII domain confers a moderate risk of developing Alzheimer’s disease. In some embodiments, the disease-associated mutation in the FnIII domain of SORL1 which confers a moderate risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of L¹⁵⁶¹, W¹⁵⁶³, L¹⁶⁵⁹, L¹⁶⁶¹, I¹⁷⁵³, I¹⁷⁵⁵, L¹⁸⁴⁸, A¹⁸⁵⁰, L¹⁹³⁸, V¹⁹⁴⁰, L²⁰³⁰, I²⁰³², V¹⁵⁷¹, L¹⁵⁷³, I¹⁶⁶⁹, L¹⁷⁶³, F¹⁷⁶⁵, V¹⁸⁵⁸, C¹⁸⁶⁰, V¹⁹⁴⁸, I¹⁹⁵⁰, V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², and W¹⁷³⁵. In some embodiments, the disease-associated mutation in the FnIII domain confers a high risk of developing Alzheimer’s disease. In some embodiments, the disease-associated mutation in the FnIII domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, P¹⁹⁵⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹, P¹⁹⁹⁸, R¹⁹¹⁰, C¹⁵⁸⁶, C¹⁶³¹, C²¹⁰¹, and C²¹⁰⁸. In some embodiments, the disease-associated mutation in the FnIII domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰,

W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹, P¹⁹⁹⁸, R¹⁹¹⁰, C¹⁵⁸⁶, C¹⁶³¹, C²¹⁰¹, and C²¹⁰⁸. [0131] In some embodiments, the disease-associated mutation occurs in the tail domain of SORL1. In some embodiments, the disease-associated mutation in the tail domain confers a high risk of developing Alzheimer’s disease. In some embodiments, the disease- associated mutation in the tail domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of F²¹⁷², A²¹⁷³, N²¹⁷⁴, S²¹⁷⁵, H²¹⁷⁶, Y²¹⁷⁷, D²¹⁹⁰, D²¹⁹¹, L²¹⁹², G²¹⁹³, E²¹⁹⁴, D²¹⁹⁵, D²¹⁹⁶, E²¹⁹⁷, D²¹⁹⁸, D²²⁰⁷, D²²⁰⁸, V²²⁰⁹, P²²¹⁰, M²²¹¹, V²²¹², I²²¹³, and A²²¹⁴. In some embodiments, the disease-associated mutation occurs in the tail domain of SORL1. In some embodiments, the disease-associated mutation in the tail domain confers a high risk of developing Alzheimer’s disease. In some embodiments, the disease-associated mutation in the tail domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of F²¹⁷², A²¹⁷³, S²¹⁷⁵, H²¹⁷⁶, Y²¹⁷⁷, D²¹⁹⁰, D²¹⁹¹, L²¹⁹², G²¹⁹³, E²¹⁹⁴, D²¹⁹⁵, D²¹⁹⁶, E²¹⁹⁷, D²¹⁹⁸, D²²⁰⁷, D²²⁰⁸, V²²⁰⁹, P²²¹⁰, M²²¹¹, V²²¹², I²²¹³, and A²²¹⁴. [0132] In some embodiments, the disease-associated mutation does not occur at a position in SORL1 selected from the group consisting of 101, 115, 140, 146, 191, 205, 269, 270, 303, 332, 371, 391, 416, 446, 459, 474, 480, 508, 528, 552, 560, 577, 581, 583, 636, 639, 642, 656, 674, 679, 695, 729, 734, 743744, 762, 786, 807, 818, 833, 852, 870, 884, 885, 942, 961, 980, 1000, 1002, 1074, 1080, 1081, 1084, 1094, 1099, 1113, 1116, 1156, 1167, 1181, 1187, 1207, 1222, 1222, 1246, 1258, 1276, 1276, 1279, 1291, 1304, 1310, 1311, 1322, 1379, 1383, 1392, 1409, 1435, 1442, 1447, 1454, 1470, 1481, 1483, 1490, 1501, 1504, 1522, 1526, 1535, 1543, 1548, 1563, 1584, 1594, 1620, 1657, 1668, 1675, 1680, 1697, 1697, 1729, 1732, 1747, 1809, 1813, 1816, 1866, 1873, 1885, 1895, 1910, 1958, 1967, 2000, 2007, 2014, 2038, 2065, 2079, 2083, 2090, 2097, 2106, 2134, 2147, 2158, and 2160. [0133] A therapeutic agent or therapy described herein can be administered to a cell, biological sample, or subject characterized as having or suspected of having a disease- associated mutation in a SORL1 gene and/or a SORL1 protein. The agent administered to the cell, biological sample, or subject is considered a therapeutic agent because it used in order to counteract or lessen the effects of the disease-associated mutation in SORL1. Accordingly, when administered to a cell or biological sample, said administration occurs ex vivo. When administered to a subject, said administration occurs in vivo. [0134] Administering the agent may comprise administration of a small molecule therapy, a gene therapy, a gene-editing therapy, or a combination thereof. In some embodiments, the agent is one described in Cummings, et al. Alzheimer’s disease drug development pipeline: (2022). Alzheimer’s & Dementia: Translational Research & Clinical Interventions, 8(1): e12295. (2022). Examples of small molecules embraced by the present disclosure include an aminoguanidine hydrazone (see, e.g., WO 2020/201326 A1) or a retromer chaperone (see, e.g., WO 2021/163681 A2 and WO 2022/020391 A2). In some embodiments, the gene therapy may be an engineered nucleic acid encoding a SORL1 variant, such as a transgene, vector, lentivirus, or rAAV described herein. In some embodiments, the gene therapy may be an engineered nucleic acid encoding a SORL1 mini-gene such as a transgene, vector, lentivirus, or rAAV described herein. In some embodiments, the engineered nucleic acid comprises a polynucleotide construct described in WO2021255027A1. In some embodiments, the mini-gene is a mini-gene described in WO2023275350A1. In some embodiments, the gene therapy comprises a nucleotide sequence set forth in any one of Tables 2 and 4-6. In some embodiments, the gene therapy can be an engineered nucleic acid (e.g., a transgene) encoding retromer protein VPS35, VPS26a, or VPS26b. In some embodiments, the gene therapy is an ASO which binds to a SORL1 mRNA that comprises a disease-associated mutation. In some embodiments, the ASO is exon-skipper (see, e.g., WO2023275376A1). In some embodiments, the gene-editing therapy comprises an RNP complex capable of targeting the SORL1 gene. In some embodiments, the RNP comprises a nuclease and a guide RNA (gRNA) comprising a sequence that is complementary to SORL1. In some embodiments the gene-editing therapy corrects a disease-associated mutation in SORL1. Identifying Disease-Associated Mutations in SORL1 [0135] Other aspects of the present disclosure relate to methods for identifying mutations in SORL1 that are associated with abnormal endosomal trafficking comprising aligning a clustered domain or repeat sequence within a query SORL1 gene sequence against a reference sequence corresponding to a disease-associated gene variant and identifying mutations in the query SORL1 gene sequence that align with a disease-associated domain position in the reference sequence, wherein the disease-associated domain position comprises homology to one or more cluster domains or repeat sequences of the query SORL1 gene sequence. In some embodiments, the clustered domain or repeat sequence of SORL1 is the query SORL1 sequence such that no other SORL1 sequences outside of said sequences of interest are used in the alignment. [0136] In some embodiments, the method comprises a structure-guided sequence alignment for all protein domains in SORL1. Therein, proteins that contain domains homologous to those of SORL1 are identified including pathogenic variants for monogenic diseases. Then, analogous domain positions of the pathogenic variants found in the SORL1 protein sequence are identified. [0137] In some embodiments, the cluster domain or repeat sequence corresponds to VPS10p domain, 10CC domain, YWTD motif, EGF domain, the CR domain, the FnIII- domain, the transmembrane domain, or cytoplasmic tail domain. In some embodiments, query sequence comprises the YWTD domain of SORL1 which is aligned with a reference sequence comprising a LDLR, LRP4, LRP5, LRP6, VLDLR, or LRP2 sequence, wherein the reference sequence comprises a disease-associated mutation. In some embodiments, query sequence comprises the EGF domain of SORL1 which is aligned with a reference sequence comprising a LDLR, LRP4, LRP6, or ApoER2 reference sequence, wherein the reference sequence comprises a disease-associated mutation. In some embodiments, query sequence comprises the CR domain of SORL1 which is aligned with a reference sequence comprising a LDLR, LRP4, LRP5, TMPRSS6, TMPRSS3, C9, CORIN, or CFI sequence, wherein the reference sequence comprises a disease-associated mutation. In some embodiments, query sequence comprises the FnIII domain of SORL1 which is aligned with a reference sequence comprising a USH2A, FN1, TNXB, TNC, L1CAM, TEK, INSR, IGF1R, DCC, ROBO3, ROBO4, LEPR, PRLR, SPEG, ITGB4, CRLF1, COL6A3, ILwRG, CDON, COL12A1, EPHB4, IL31RA, IL21R, IL11RA, IL12RB1, IFNGR2, NPHS1, IL7R, ANOS1, MYBPC3, MPL, PTPRQ, OSMR, GHR, CSF3R, or CSF2RA sequence, wherein the reference sequence comprises a disease-associated mutation. In some embodiments, query sequence comprises the cytoplasmic tail domain of SORL1 which is aligned with a reference sequence comprising a LDLR sequence, wherein the reference sequence comprises a disease-associated mutation. In some embodiments, query sequence comprises the transmembrane domain of SORL1 which is aligned with a reference sequence comprising a LDLR sequence, wherein the reference sequence comprises a disease-associated mutation. [0138] In some embodiments, the query SORL1 gene sequence is obtained from a cell, biological sample, or subject. In some embodiments, the subject or the cell or biological sample are derived from a subject suspected of having, diagnosed with, or at risk of developing a neurological disease. In some embodiments, the neurological disease is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is selected from the group consisting of Parkinson’s Disease, Dementia, Pick’s Disease, Lewy Body Dementia, Huntington’s Disease, Alzheimer’s disease, Early-Onset Alzheimer’s disease, Late-Onset Alzheimer’s disease, Familial Alzheimer’s disease, and diseases that are associated with TDP-43 pathologies. In some embodiments, the neurodegenerative disease is selected from the group consisting of Alzheimer’s disease, Early-Onset Alzheimer’s disease, Late-Onset Alzheimer’s disease, and Familial Alzheimer’s disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease. Disease-Associated Mutations and Altered SORL1 Function [0139] A disease-associated mutation in a SORL1 gene and/or a SORL1 protein can effect one or more functions in a cell. In some embodiments, a SORL1 gene and/or a SORL1 protein comprising a disease-associated mutation or suspected of comprising a disease- associated mutation is assayed using a method described herein to characterize one or more of its functions. In some embodiments, the method further comprises assaying the endosomal trafficking activity of SORL1 in the biological sample. In some embodiments, the method further comprises assaying the activity and/or protein level of endogenous SORL1, sAPPα, sAPPβ, tau aggregation, tau phosphorylation, APP at the cell surface, AMPA receptor at the cell surface, Aβ30, Aβ40, Aβ42, VPS26a, VPS26b, and/or VPS35 in the biological sample. [0140] Expression information can be obtained, for example, through measuring changes in the levels and/or activity of the endogenous SORL1, the SORL1 variant, sAPPα, APP at the cell surface, AMPA receptor at the cell surface, sAPPβ, tau aggregation, tau phosphorylation, Aβ30, Aβ40, Aβ42, VPS26a, VPS26b, and/or VPS35 in a cell, biological sample, or subject through methods described herein and/or any other suitable methods known in the art. Non-limiting examples of assays for determining protein levels include western blot, flow cytometry, mass spectrometry, and ELISA. Various methods of assessing protein activity will be available to a person of ordinary skill in the art and will be largely dependent on the biological target. For instance, one may assay the localization of a protein by confocal or total internal reflection fluorescence (TIRF) microscopy. [0141] Alternatively, one may assay the binding activity of a protein by Förster Resonance Energy Transfer (FRET), mass spectrometry, chemical cross-linking experiments, co- immunoprecipitation, tandem affinity purification, electrophoretic mobility shift (EMSA) assays, enzyme-linked immunosorbent assay (ELISA), or any combination and/or variation thereof. Alternatively, one may assay the levels of post-translational modifications (e.g., hydroxylation, farnesylation, isofarnesylation, lipidation, addition of a linker for conjugation or functionalization, phosphorylation, de-phosphorylation, acetylation, de-acetylation, SUMOylation, glycosylation, nitrosylation, methylation, ubiquitination, cleavage, and degradation) of one or more proteins in a pathway that is related to or dependent on SORL1 using techniques including, but not limited to, western blot, flow cytometry, mass spectrometry, and ELISA. [0142] In some embodiments, a method comprises measuring the levels and/or activity of a SORL1 protein comprising a disease-associated mutation, sAPPα, APP at the cell surface, AMPA receptor at the cells surface, sAPPβ, tau aggregation, tau phosphorylation, Aβ30, Aβ40, Aβ42, VPS26a, VPS26b, and/or VPS35 in a biological sample obtained from a subject relative to a control. The subject can be a subject who is characterized as having or suspected of having a disease, disorder, or condition described herein. The control can be a biological sample comprising a wild-type SORL1 gene, such as a biological sample obtained from a healthy subject. In some embodiments, a method comprising measuring or having measured the levels and/or activity of a SORL1 protein comprising a disease-associated mutation, sAPPα, APP at the cell surface, AMPA receptor at the cell surface, sAPPβ, tau aggregation, tau phosphorylation, Aβ30, Aβ40, Aβ42, VPS26a, VPS26b, and/or VPS35 in a biological sample comprises a method described herein (e.g., an immunoassay, such as western blot, ELISA, or a method of assaying SORL1 shedding, such as one involving an eGluc-SORL1 reporter (see, e.g., WO 2021/255027 A1, published December 23, 2021 which is incorporated by reference herein). In some embodiments, a disease-associated mutation in a SORL1 gene is characterized by a decrease (e.g., by at least 1.1 fold, 1.25 fold, 1.5 fold, 1.75 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold, such as 1-1.5 fold, 1.5-2 fold, 2-3 fold, 3-4 fold, 4-5 fold, 5-6 fold, 6-7 fold, 7-8 fold, 8-9 fold, 9-10 fold, or more) in the levels and/or activity of the encoded SORL1 protein, sAPPα, APP at the cell surface, AMPA receptor at the cell surface, VPS26 (e.g., VPS26a and/or VPS26b), and/or VPS35 in a biological sample obtained from a subject relative to a control. In some embodiments, a disease-associated mutation in a SORL1 gene is characterized by an increase in the levels (e.g., by at least 1.1 fold, 1.25 fold, 1.5 fold, 1.75 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold, such as 1-1.5 fold, 1.5-2 fold, 2-3 fold, 3-4 fold, 4-5 fold, 5-6 fold, 6-7 fold, 7-8 fold, 8-9 fold, 9-10 fold, or more) of sAPPβ, tau aggregation, tau phosphorylation, Aβ30, Aβ40, and/or Aβ42 are detected in a biological sample obtained from a subject relative to a control. [0143] Characterizing one or more functions of a SORL1 protein comprising a disease-associated mutation can be used to inform treatment of a subject who is characterized as having the disease associated mutation. Analyses of SORL1 function as a result of a disease-associated mutation can be performed in cells (e.g., cell lines) that are engineered to comprise a mutation of interest. Analyses of SORL1 function can also be performed in cells that have been isolated from a subject who is characterized as having or suspected of having a disease-associated mutation in a SORL1 gene. Treating a subject can occur before and/or after detecting the presence of a disease-associated mutation in a SORL1 gene and/or detecting one or more altered functions of a SORL1 protein comprising a disease-associated mutation. Treatment can include administration of one or more agents described herein to a subject. Accordingly, other aspects of the present disclosure relate to a method of treating a subject characterized as having or suspected of having a disease-associated mutation in SORL1 comprising administering to the subject a therapeutic agent or composition thereof. In some embodiments, the agent is a small molecule, biologic, a gene therapy, a gene-editing therapy, or any combination thereof. [0144] A therapeutic agent described herein can be administered to a subject who is characterized as having or suspected of having any one or more of the disease-associated mutations in the SORL1 gene described herein. In some embodiments, the disease-associated mutation does not occur at a position in SORL1 selected from the group consisting of 101, 115, 140, 146, 191, 205, 269, 270, 303, 332, 371, 391, 416, 446, 459, 474, 480, 508, 528, 552, 560, 577, 581, 583, 636, 639, 642, 656, 674, 679, 695, 729, 734, 743744, 762, 786, 807, 818, 833, 852, 870, 884, 885, 942, 961, 980, 1000, 1002, 1074, 1080, 1081, 1084, 1094, 1099, 1113, 1116, 1156, 1167, 1181, 1187, 1207, 1222, 1222, 1246, 1258, 1276, 1276, 1279, 1291, 1304, 1310, 1311, 1322, 1379, 1383, 1392, 1409, 1435, 1442, 1447, 1454, 1470, 1481, 1483, 1490, 1501, 1504, 1522, 1526, 1535, 1543, 1548, 1563, 1584, 1594, 1620, 1657, 1668, 1675, 1680, 1697, 1697, 1729, 1732, 1747, 1809, 1813, 1816, 1866, 1873, 1885, 1895, 1910, 1958, 1967, 2000, 2007, 2014, 2038, 2065, 2079, 2083, 2090, 2097, 2106, 2134, 2147, 2158, and 2160. [0145] In some embodiments, the disease-associated mutation occurs at any one of positions: R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹,

V⁴⁴¹, I⁴⁴², V⁵²⁰, Y⁵²¹, I⁵²², L⁵⁶¹, Y⁵⁶³, L⁶¹³, V⁶¹⁵, S¹³⁸, D¹⁴⁰, G¹⁴², S¹⁴⁴, F¹⁴⁵, T¹⁹⁰, D¹⁹², T¹⁹⁶, S²³⁴, D²³⁶, G²³⁸, T²⁴⁰, W²⁴¹, S²⁸⁰, D²⁸², S²⁸⁶, S³²⁹, S³⁷⁵, G³⁷⁹, F³⁸², T⁴⁴³, D⁴⁴⁵, G⁴⁴⁷, T⁴⁴⁹, W⁴⁵⁰, S⁵²³, G⁵²⁷, W⁵³⁰, S⁵⁶⁴, N⁵⁶⁶, G⁵⁶⁸, T⁵⁷⁰, W⁵⁷¹, C⁴⁶⁷, or C⁴⁷³ in the VPS10p domain; C⁶²⁵, C⁶⁴³, C⁶⁶⁰, C⁶⁷⁵, C⁶⁷⁷, C⁶⁸⁴, C⁶⁹⁹, C⁷¹⁶, C⁷³⁶, and C⁷⁵² in the 10CC domain; L⁷⁹³, F⁷⁹⁵, L⁸⁰², L⁸³⁷, F⁸³⁹, L⁸⁴⁶, L⁸⁸¹, L⁸⁸³, M⁸⁹⁰, I⁹²⁶, V⁹²⁸, I⁹³³, I⁹⁶⁶, V⁹⁶⁸, I⁹⁷³, M¹⁰⁰⁷, I¹⁰⁰⁹, L⁷⁸², V⁸²⁵, I⁸²⁶, I⁸⁶⁹, V⁸⁷⁰, L⁹¹⁵, V⁹¹⁶, I⁹⁵⁶, L⁹⁵⁷, I⁹⁹⁶, L⁹⁹⁷, L⁷⁸⁷, L⁸³¹, L⁸⁷⁵, V⁹²⁰, L⁹⁶⁰, L¹⁰⁰¹, R⁸⁷⁹, W⁸⁹⁵, N⁹²⁴, Y⁹⁶⁴, W⁹⁷⁸, Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶, Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, T⁹³⁶, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³, I⁹⁸³, R⁷⁷¹, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, G⁷⁷⁷, G⁸¹⁹, G⁸⁶³, G⁹⁰⁹, G⁹⁵⁰, G⁹⁹¹, R⁸⁶⁶, R⁹⁵³, C⁸⁰¹, or C⁸¹⁶ in the YWTD doman; C¹⁰²¹, C¹⁰²⁶,

S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹²⁹⁸, G¹³³⁵, G¹³⁴⁶ G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁴⁰, G¹⁴⁹³, G¹⁵³⁶, D¹⁰⁹⁸, D¹¹⁰², D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸², D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, D¹²⁶⁷, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁴⁹, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁴⁴, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁵³, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁰, C¹⁵⁴⁹, D¹¹⁰⁵, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴, D¹³⁵², D¹³⁹⁶, D¹⁴⁴⁶, D¹⁴⁹⁹, or D¹⁵⁴² in the CR domain; L¹⁵⁶¹, W¹⁵⁶³, L¹⁶⁵⁹, L¹⁶⁶¹, I¹⁷⁵³, I¹⁷⁵⁵, L¹⁸⁴⁸, A¹⁸⁵⁰, L¹⁹³⁸, V¹⁹⁴⁰, L²⁰³⁰, I²⁰³², V¹⁵⁷¹, L¹⁵⁷³, I¹⁶⁶⁹, L¹⁷⁶³, F¹⁷⁶⁵, V¹⁸⁵⁸, C¹⁸⁶⁰, V¹⁹⁴⁸, I¹⁹⁵⁰, V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², W¹⁷³⁵, P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, P¹⁹⁵⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹, P¹⁹⁹⁸, R¹⁹¹⁰, C¹⁵⁸⁶, C¹⁶³¹, C²¹⁰¹, or C²¹⁰⁸ in the FnIII domain; or F²¹⁷², A²¹⁷³, N²¹⁷⁴, S²¹⁷⁵, H²¹⁷⁶, Y²¹⁷⁷, D²¹⁹⁰, D²¹⁹¹, L²¹⁹², G²¹⁹³, E²¹⁹⁴, D²¹⁹⁵, D²¹⁹⁶, E²¹⁹⁷, D²¹⁹⁸, D²²⁰⁷, D²²⁰⁸, V²²⁰⁹, P²²¹⁰, M²²¹¹, V²²¹², I²²¹³, or A²²¹⁴ in the cytoplasmic tail domain; or any combination thereof. [0146] In some embodiments, the disease-associated mutation occurs at any one of positions: R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹,

Y³⁰⁶, F³⁰⁸, V³⁵⁹, F³⁶⁰, V³⁶¹, Y⁴²⁴, I⁴²⁵, A⁴²⁶,I⁵⁰⁴, I⁵⁰⁵, A⁵⁰⁶, I⁵⁴⁸, I⁵⁴⁹, V⁵⁹⁶, F⁵⁹⁷, V¹³⁵, Y¹³⁶, V¹³⁷, L¹⁸⁷, W¹⁸⁸, I¹⁸⁹, L²³¹, W²³², V²⁷⁷, F²⁷⁸, L³²⁶, W³²⁷, V³²⁸, L³⁷², Y³⁷³, I³⁷⁴, V⁴⁴¹, I⁴⁴², V⁵²⁰, Y⁵²¹, I⁵²², L⁵⁶¹, Y⁵⁶³, L⁶¹³, V⁶¹⁵, S¹³⁸, G¹⁴², S¹⁴⁴, F¹⁴⁵, T¹⁹⁰, D¹⁹², T¹⁹⁶, S²³⁴, D²³⁶, G²³⁸, T²⁴⁰, W²⁴¹, S²⁸⁰, D²⁸², S²⁸⁶, S³²⁹, S³⁷⁵, G³⁷⁹, F³⁸², T⁴⁴³, D⁴⁴⁵, G⁴⁴⁷, T⁴⁴⁹, W⁴⁵⁰, S⁵²³, G⁵²⁷, W⁵³⁰, S⁵⁶⁴, N⁵⁶⁶, G⁵⁶⁸, T⁵⁷⁰, W⁵⁷¹, C⁴⁶⁷, or C⁴⁷³ in the VPS10p domain; C⁶²⁵, C⁶⁴³, C⁶⁶⁰, C⁶⁷⁵, C⁶⁷⁷, C⁶⁸⁴, C⁶⁹⁹, C⁷¹⁶, C⁷³⁶, and C⁷⁵² in the 10CC domain; L⁷⁹³, F⁷⁹⁵, L⁸⁰², L⁸³⁷, F⁸³⁹, L⁸⁴⁶, L⁸⁸¹, L⁸⁸³, M⁸⁹⁰, I⁹²⁶, V⁹²⁸, I⁹³³, I⁹⁶⁶, V⁹⁶⁸, I⁹⁷³, M¹⁰⁰⁷, I¹⁰⁰⁹, L⁷⁸², V⁸²⁵, I⁸²⁶, I⁸⁶⁹, V⁸⁷⁰, L⁹¹⁵, V⁹¹⁶, I⁹⁵⁶, L⁹⁵⁷, I⁹⁹⁶, L⁹⁹⁷, L⁷⁸⁷, L⁸³¹, L⁸⁷⁵, V⁹²⁰, L⁹⁶⁰, L¹⁰⁰¹, R⁸⁷⁹, W⁸⁹⁵, N⁹²⁴, Y⁹⁶⁴, W⁹⁷⁸, Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶, Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³, I⁹⁸³, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, G⁷⁷⁷, G⁸¹⁹, G⁸⁶³, G⁹⁰⁹, G⁹⁵⁰, G⁹⁹¹, R⁸⁶⁶, R⁹⁵³, C⁸⁰¹, or C⁸¹⁶ in the YWTD domain; C¹⁰²¹, C¹⁰²⁶, C¹⁰³⁰, C¹⁰⁴⁰, C¹⁰⁴², C¹⁰⁵⁸, C¹⁰⁶⁰, or C¹⁰⁷¹ in the EGF domain; S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁹³, G¹⁵³⁶, D¹⁰⁹⁸, D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁹, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴, D¹³⁵², D¹³⁹⁶, D¹⁴⁴⁶, D¹⁴⁹⁹, or D¹⁵⁴² in the CR domain; L¹⁵⁶¹, W¹⁵⁶³, L¹⁶⁵⁹, L¹⁶⁶¹, I¹⁷⁵³, I¹⁷⁵⁵, L¹⁸⁴⁸, A¹⁸⁵⁰, L¹⁹³⁸, V¹⁹⁴⁰, L²⁰³⁰, I²⁰³², V¹⁵⁷¹, L¹⁵⁷³, I¹⁶⁶⁹, L¹⁷⁶³, F¹⁷⁶⁵, V¹⁸⁵⁸, C¹⁸⁶⁰, V¹⁹⁴⁸, I¹⁹⁵⁰, V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², W¹⁷³⁵, P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹,

combination thereof. [0147] In some embodiments, the disease-associated mutation is a mutation implicated in a neurological disease. In some embodiments, the neurological disease is a neurodegenerative disease, optionally wherein the neurodegenerative disease is selected from the group consisting of Parkinson’s Disease, Dementia, Pick’s Disease, Lewy Body Dementia, Huntington’s Disease, Alzheimer’s disease, Early-Onset Alzheimer’s disease, Late-Onset Alzheimer’s disease and Familial Alzheimer’s disease. Therapeutic Agents [0148] Therapeutic agents of the disclosure can be used to modulate the levels and/or activity of a SORL1 protein comprising a disease-associated mutation in a cell, biological sample, or subject. Therapeutic agents can also be used to target processes implicated in a neurodegenerative disease (e.g., Alzheimer’s disease), such as plaque formation, fibril formation, and/or inflammation. Examples of therapeutic agents of the disclosure include small molecules, biologics, gene-editing therapies, and gene therapies, such as inhibitory nucleic acids and SORL1 variants. One or more the therapeutic agents described herein can be administered to a cell, biological sample, or subject characterized as having or suspected of having a disease-associated mutation in SORL1. [0149] Modulating endosomal trafficking can include, for example, altering the levels and/or activity of a mutant SORL1, sAPPα, APP, AMPA, sAPPβ, tau aggregation, tau phosphorylation, Aβ38, Aβ40, Aβ42, VPS26 (e.g., VPS26a and/or VPS26b), and/or VPS35 in a cell, biological sample, or subject characterized as having or suspected of having a disease-associated mutation in SORL1. In some embodiments, modulating endosomal trafficking comprises increasing sAPPα levels and/or activity in a cell, biological sample, or subject. In some embodiments, modulating endosomal trafficking comprises increasing APP surface expression in a cell, biological sample, or subject. In some embodiments, modulating endosomal trafficking comprises decreasing levels and/or activity of sAPPβ in a cell, biological sample, or subject. In some embodiments, modulating endosomal trafficking comprises decreasing levels of tau aggregation and/or tau phosphorylation in a cell, biological sample, or subject. In some embodiments, modulating endosomal trafficking comprises decreasing levels and/or activity of amyloid β-peptide species Aβ38, Aβ40, and Aβ42, which are regarded as markers of low endosomal activity, in a cell, biological sample, or subject. In some embodiments, modulating endosomal trafficking comprises decreasing levels and/or activity of a SORL1 protein comprising a disease-associated mutation described herein in a cell, biological sample, or subject. In some embodiments, modulating endosomal trafficking comprises increasing VPS26 (e.g., VPS26a and/or VPS26b) levels and/or activity in a cell, biological sample, or subject. In some embodiments, modulating endosomal trafficking comprises increasing VPS35 levels and/or activity in a cell, biological sample, or subject. In some embodiments, modulating endosomal trafficking comprises increasing AMPA receptor surface expression in a cell, biological sample, or subject. In some embodiments, modulating endosomal trafficking in a cell, biological sample, or subject comprises increasing (e.g., by at least 1.1 fold, 1.25 fold, 1.5 fold, 1.75 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold, such as 1-1.5 fold, 1.5-2 fold, 2-3 fold, 3- 4 fold, 4-5 fold, 5-6 fold, 6-7 fold, 7-8 fold, 8-9 fold, 9-10 fold, or more) in the levels and/or activity of the encoded SORL1 protein, sAPPα, APP at the cell surface, AMPA receptor at the cell surface, VPS26 (e.g., VPS26a and/or VPS26b), and/or VPS35 in the cell, biological sample, or subject relative to a control cell, biological sample, or subject characterized as having or suspected of having a disease-associated mutation SORL1. In some embodiments, modulating endosomal trafficking in a cell, biological sample, or subject comprises decreasing (e.g., by at least 1.1 fold, 1.25 fold, 1.5 fold, 1.75 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold, such as 1-1.5 fold, 1.5-2 fold, 2-3 fold, 3-4 fold, 4-5 fold, 5-6 fold, 6-7 fold, 7-8 fold, 8-9 fold, 9-10 fold, or more) of sAPPβ, tau aggregation, tau phosphorylation, Aβ30, Aβ40, and/or Aβ42 in the cell, biological sample, or subject relative to a control cell, biological sample, or subject characterized as having or suspected of having a disease-associated mutation SORL1. In some embodiments, modulating endosomal trafficking in a subject comprises modulating the levels and/or activity of sAPPα, sAPPβ, aggregated tau, phosphorylated tau, APP, AMPA receptor, Aβ30, Aβ40, Aβ42, VPS26a, VPs26b, and/or VPS35 in the cerebral cortex of the subject. In some embodiments, modulating endosomal trafficking in a subject comprises modulating the levels and/or activity of sAPPα, sAPPβ, aggregated tau, phosphorylated tau, APP, AMPA receptor, Aβ30, Aβ40, Aβ42, VPS26a, VPs26b, and/or VPS35 in the hippocampus of the subject. [0150] In some embodiments, modulating SORL1 activity through administration of a therapeutic agent described herein comprises expressing a SORL1 mini-receptor and/or editing a SORL1 gene comprising a disease-associated mutation to increase the interaction of SORL1 with a SORL1-interacting protein, such as those described in Monti & Andersen (2017).20 Years Anniversary for SORLA/SORL1 (1996-2016). Receptor Clin Invest, 4: e1611 which is incorporated by reference herein for its disclosures related to SORL1 ligands. [0151] Combination therapies can also be used to modulate endosomal trafficking. As an example, inhibiting expression of a SORL1 protein comprising a disease-associated mutation can be achieved by administration of an inhibitory nucleic acid that binds to a nucleic acid (e.g., an RNA transcript) encoding the SORL1 protein comprising the disease-associated mutation while a SORL1 variant protein can be expressed to replace the function of the SORL1 protein comprising the disease-associated mutation. As a further example, expression of a SORL1 protein comprising a disease-associated mutation can be decreased by using a gene-editing therapy while a SORL1 variant protein can be expressed to replace the function of the SORL1 protein comprising the disease-associated mutation. Further, aminoguanidine hydrazone or retromer chaperone small molecule therapies can be administered to stabilize and/or increase retromer activity while inhibition of a SORL1 protein comprising a disease- associated mutation (e.g., via administration of an inhibitory nucleic acid and/or a gene editing therapy) and/or expression of a SORL1 variant is used to modulate SORL1-dependent functions. Small Molecules [0152] Aspects of the disclosure relate to small molecules that can be used as therapeutic agents in the treatment of a subject characterized as having or suspected of having a disease- associated mutation in SORL1 as describe herein. Examples of small molecules embraced by the present disclosure include an aminoguanidine hydrazone (see, e.g., WO 2020/201326, published October 8, 2020,which is incorporated by reference herein for its disclosures related to aminoguanidine hydrazone compounds and methods making and administering such compounds). [0153] Further examples of small molecules include a retromer chaperone (see, e.g., WO 2021/163681 A2, published August 19, 2021 and WO 2022/020391 A2, published January 27, 2022, each of which is incorporated by reference herein for its disclosures related to retromer chaperone compounds and methods making and administering such compounds). Generally, retromer chaperones bind to the retromer complex or one or more subunits thereof. Upon binding, retromer chaperones can protect the retromer complex from degradation and increase its steady-state concentration in the cell. In some embodiments, a retromer chaperone is a thiophene thiourea derivative, such as R33 (see, e.g., Formula (I) below, also known as TPT-172) which has a molecule weight 172 in free base form or R55 (see, e.g., Formula (II) below, also known as TPT-260) which has a molecule weight 260 in free base form. In some embodiments, the 2,5-disubstituted thiophene scaffold in R55 can be replaced with a phenyl ring. In some embodiments, guanylhydrazones can be substituted for isothioureas.

Formula (I) Formula (II) [0154] Additional examples of small molecules that can be administered to a subject include, without limitation, AGB101, Atuzaginstat (COR388), AVP-786, AXS-05, Blarcamesine (ANAVEX2-73), Brexpiprazole, Donepezil, Escitalopram, Guanfacine, GV- 971, Hydralazine, Icosapent ethyl, TRx0237, Metformin, Nabilone, NE3107, Nilotinib BE, Octohydro- aminoacridine Succinate, Semaglutide, Simufilam (PTI-125), Tricaprilin, Valiltramiprosate (ALZ-801), AD-35, Allopregnanolone, APH-1105, Baricitinib, BPN14770, Bromocriptine, Bryostatin 1, BXCL-501, CORT108297, Thiethylperazine, CST-2032, CY6463, DAOIB, Dapagliflozin, Dasatinib, Deferiprone, Valiltramiprosate (ALZ-801), Dronabinol, Edonerpic (T-817MA), Elayta (CT1812), Varoglutamstat (PQ912), Fosgonimeton (ATH-1017), GB301, Edicotinib (JNJ- 40346527), Nicotinamide, MIB-626, Lenalidomide, Levetiracetam, Memantine, MIB-626, Montelukast, Neflamapimod (VX-745), LY3372689, Posiphen, Prazosin, PU-AD, Simufilam (PTI-125), Troriluzole (BHV4157), Allopregnanolone, ASN51, Contraloid acetate, BEY2153, NNI-362, XPro1595, and REM0046127. In some embodiments, a small molecule is a compound administered for reducing cellular effects associated with aggregation and/or dysfunction of amyloid proteins (e.g., Valiltramiprosate (ALZ-801), APH-1105, MIB-626, Thiethylperazine, BEY2153, Valiltramiprosate (ALZ-801), REM0046127, or Varoglutamstat (PQ912)). In some embodiments, a small molecule is a compound administered for reducing cellular effects associated with aggregation and/or dysfunction of tau proteins (e.g., TRx0237, LY3372689, Nicotinamide, ASN51, BEY2153, or REM0046127). In some embodiments, a small molecule is a compound administered for promoting synaptic plasticity and/or neuroprotection (e.g., AGB101, Atuzaginstat (COR388), Blarcamesine (ANAVEX2-73), Simufilam (PTI-125), BPN14770, Bryostatin 1, CY6463, Edonerpic (T-817MA), Elayta (CT1812), Levetiracetam, Neflamapimod (VX-745), Simufilam (PTI-125), Troriluzole (BHV4157), Atuzaginstat (COR588), or REM0046127). In some embodiments, a small molecule is a compound administered for reducing neuroinflammation (e.g., Atuzaginstat (COR588), Blarcamesine (ANAVEX2-73), GV-971, Icosapent ethyl, NE3107, Semaglutide, Baricitinib, Dasatinib, Lenalidomide, Montelukast, Edicotinib (JNJ- 40346527), or XPro1595). In some embodiments, a small molecule is a compound administered for promoting neurogenesis (e.g., Allopregnanolone, Sovateltide, (PMZ-1620), or NNI-362). Biologics [0155] Aspects of the disclosure relate to administration of biologics to a subject characterizing as having or suspected of having a disease-associated mutation in SORL1. Biologics that can be administered to a subject can comprise one or more cells, such as isolated cells and/or engineered tissues. Biologics that can be administered to a subject can also comprise biomolecules produced and purified from cells, such as nucleic acids, peptides, and/or proteins. Accordingly, biologics can be used to refer to gene-editing therapies and gene therapies of the disclosure as well as other therapeutic agents further described herein. [0156] In some embodiments, a biologic comprises an antigen-binding fragment. Examples of proteins that comprise an antigen-binding fragment include, without limitation, antibodies, antibody-drug conjugates, and chimeric antigen receptors. An antigen binding fragment can be administered as an isolated molecule (e.g., an antibody), by a nucleic acid encoding the antigen-binding fragment (e.g., a recombinant virus comprising a transgene encoding an antibody), or by a cell (e.g., a cell comprising a chimeric antigen receptor). In some embodiments, a biologic is Aducanumab, Donanemab, Gantenerumab, Lecanemab, Solanezumab, AL002, Bepranemab, Canakinumab, Crenezumab, Daratumumab, Donanemab, E2814, Pepinemab (VX15), Semorinemab (RO7105705), TB006, ACU193, Lu AF87908, LY3372993, JNJ-63733657, or an antigen-binding fragment thereof. Antibodies and antigen-binding fragments can be administered to a subject to target proteins involved in neurodegeneration, such as those involved in the formation of plaques and fibrils in brain tissues. In some embodiments, an antibody or antigen-binding fragment binds to Aβ, including Aβ oligomers, Aβ plaques, and Aβ protofibril fibers, such as Aducanumab, Donanemab, Gantenerumab, Lecanemab, Solanezumab, Canakinumab, Crenezumab, Donanemab, ACU193, LY3372993, or JNJ-63733657. In some embodiments, an antibody or antigen-binding fragment binds to tau, such as Bepranemab, E2814, Semorinemab (RO7105705), Lu AF87908, or TB006. In some embodiments, an antibody or antigen- binding fragment is administered to reduce inflammation associated with the formation of plaques and fibrils in brain tissues, such as Daratumumab, AL002, TB006, or Pepinemab (VX15). [0157] In some embodiments, a biologic comprises one or more cells. Cells that can be used as therapeutic agents in methods described herein include, without limitation, stem cells, progenitor cells, and immune cells (e.g., a killer cell, a T-cell, a B-cell, or an NK cell). In some embodiments, a stem cell or a progenitor cell is one that can grow and differentiate into a cell of the central nervous system. In some embodiments, a stem cell is an induced pluripotent stem cell. In some embodiments, a stem cell or a progenitor cell that is obtained from a subject. In some embodiments, a stem cell obtained from a subject is a multipotent stem cell, a placenta-derived multipotent stem cell, an adipose-derived multipotent stem cell, or an umbilical cord blood-derived multipotent stem cell. Cells can also be engineered prior to being administered to a subject, such as by engineering the cells to comprise a therapeutic agent described herein and/or to comprise genetic modifications that promote therapeutic effects in vivo (e.g., modifications that promote differentiation to replace degenerated tissue and/or express a therapeutic agent that targets plaques, fibrils, or mutated SORL1 proteins). In some embodiments, a cell is allogenic or autologous to a subject. In some embodiments, a cell is multipotent stem cell, or an immune cell. Generally, cells will be administered to a subject in a composition comprising a population of cells. In some embodiments, a cell population administered to a subject comprises at least 100-1,000, 1,000-5,000, 5,000- 10,000, 10,000-20,000, 20,000-50,000, 50,000-100,000, 100,000-500,000, or 500,000- 1,000,000 cells. In some embodiments, a cell population administered to a subject comprises at least 10³ cells/kg of the subject’s bodyweight (e.g., 10³-10⁴ cells/kg, 10⁴-10⁵ cells/kg, 10⁵- 10⁶ cells/kg, 10⁶ -10⁷ cells/kg, 10⁷ cells/kg-10⁸ cells/kg, or more). Gene-Editing Therapies [0158] Aspects of the disclosure relate to gene-therapies that can be used as therapeutic agents in the treatment of a subject characterized as having or suspected of having a disease-associated mutation in SORL1 as describe herein. [0159] Editing a DNA target typically comprises introducing at least one site of DNA damage in a DNA target. Non-limiting examples of DNA damage include DNA alkylation, base deamination, base depurination, incidence of abasic sites, single-stranded breaks (SSBs), and double-stranded breaks (DSBs). Various conditions can induce sites of DNA damage, including, but not limited to, subjecting DNA to chemical agents (e.g., alkylating agents, DSB-inducers, SSB-inducers, etc.), ionizing radiation, oxidative damage, and treatment with nucleases (e.g., zinc-finger nucleases, transcription-activator like effector nucleases (TALENs), and RNA-guided nucleases). Generally, a DNA target will comprise a genomic sequence (e.g., a genomic sequence comprising a SORL1 gene that comprises or is suspected of comprising a disease-associated mutation described herein). However, in some embodiments, a DNA target is located in an exogenous nucleic acid, such as a vector or plasmid that has been introduced into a cell and is not integrated into one of the cells chromosomes. [0160] DNA breaks (e.g., SSBs and/or DSBs) in a DNA target will typically be generated either at a “target position” or a “target site” or at a position that is proximal to a target position or target site. As used herein, “a target position” refers to a nucleotide position in a SORL1 gene that is subjected to a gene-editing therapy for the purposes of editing (e.g., by substituting, deleting, or inserting) a nucleotide at the target nucleotide position. A “target site” refers to a sequence in a DNA target that comprises one or more target positions. Further, as used herein, a “DNA break at a position that is proximal to a target position or target site” refers to a site of a DNA break that is within 1,000 nucleotides upstream or downstream of a target position or one or more target positions in a sequence comprising a target site. In some embodiments, a DNA break at a position that is proximal to a target position or target site is 500-1,000 nucleotides upstream or downstream. In some embodiments, a DNA break at a position that is proximal to a target position or target site is 500 nucleotides or less upstream or downstream. In some embodiments, a DNA break at a position that is proximal to a target position or target site is 1-10, 10-20, 20-30, 30-40, 60-70, 70-80, 80-90, 90-100, 100-125, 125-150, 150-175, 175-200, or 200-250 nucleotides upstream or downstream. In some embodiments, a DNA break is generated in a sequence that binds by a zinc-finger nuclease or a TALEN which is located at a target position, a target site, a position proximal to a target position, or a position proximal to a target site. In some embodiments, a DNA break is generated in a sequence that binds by a gRNA at a target position, a target site, a position proximal to a target position, or a position proximal to a target site. In some embodiments, introducing a DNA break in a DNA target comprises contacting the DNA target with a Cas molecule and a gRNA. [0161] CRISPR is a family of DNA sequences (CRISPR clusters) in bacteria and archaea comprising nucleic acid fragments corresponding to prior infections by a virus. The nucleic acid fragments are used by the prokaryotic cell to detect and destroy DNA from subsequent attacks by similar viruses. In nature, CRISPR clusters are transcribed and processed into crRNA. In certain types of CRISPR systems (e.g., type II CRISPR systems), correct processing of pre-CRISPR RNA (pre-crRNA) involves a tracrRNA, endogenous ribonuclease 3 (rnc), and a Cas9 protein. The tracrRNA serves as a guide for ribonuclease 3- aided processing of pre-crRNA. Subsequently, Cas9/crRNA/tracrRNA cleaves a linear or circular dsDNA target complementary to the RNA. However, gRNAs can be engineered to incorporate aspects of both the crRNA and tracrRNA into a single RNA species (e.g., a single-guide RNA (sgRNA)). [0162] Examples of Cas molecules include Cas9, and variants thereof, and Cas12a, and variants thereof. In some embodiments, a Cas molecule is a Cas9 endonuclease or a Cas9 variant, such as a Cas9 nickase or a catalytically inactive Cas9. Examples of Cas9 molecules include, without limitation, SpCas9, SaCas9, StCas9, NmCas9, CjCas9, and SpyCas9. In some embodiments, a Cas molecule is a Cas12a endonuclease or a Cas12a variant, such as a Cas12a nickase or a catalytically inactive Cas12a. Examples of Cas12a molecules include, without limitation, AsCas12a, FnCas12a, LbCas12a, PaCas12a, the MAD7™ system (MAD7^TM, Inscripta, Inc.), and the Alt-R Cas12a Ultra nuclease (Alt-R® Cas12a Ultra; Integrated DNA Technologies, Inc.). In some embodiments, a Cas molecule is fused to an adenosine deaminase, a guanine deaminase, or a cytosine deaminase at the N- or C-terminus of the Cas molecule. Examples of adenosine deaminases include a TadA enzyme. Examples of cytosine deaminases include, without limitation, APOBEC deaminase, pmCDA1, and activation-induced cytidine deaminase (AID). In some embodiments, a Cas molecule fused to a deaminase comprises a linker, such as a flexible linker (e.g., a Ser-Gly linker) that connects the deaminase to the Cas molecule. In some embodiments, the Cas molecule fused to a deaminase is catalytically dead or comprises nickase activity. In some embodiments, a Cas molecule is fused to a cytosine deaminase, wherein either the Cas molecule or the cytosine deaminase is fused to a uracil glycosylase inhibitor. Examples of base editors comprising a Cas molecule fused to a deaminase include, without limitation, BE1, BE2, BE3, HF-BE3, BE4, BE4max, BE4-Gam, YE1-BE3, EE-BE3, YE2-BE3, YEE-CE3, VQR-BE3, VRER- BE3, SaBE3, SaBE4, SaBE4-Gam, Sa(KKH)-BE3, Target-AID, Target-AID-NG, xBE3, eA3A-BE3, BE-PLUS, TAM, CRISPR-X, ABE7.9, ABE7.10, ABE7.10*, ABE8, ABE8e, ABE8.20-m, xABE, ABESa, VQR-ABE, VRER-ABE, Sa(KKH)-ABE, and CRISPR-SKIP. [0163] In some embodiments, a Cas molecule comprises endonuclease activity that cleaves both strands of the DNA target, thereby introducing at least one DSB. However, in some embodiments, a Cas molecule is used to generate at least one SSB in a DNA target. In some embodiments, a SSB in a DNA target is generated using a Cas molecule with nickase activity. In some embodiments, a plurality of DNA breaks is generated in a DNA target. In some embodiments, the plurality of DNA breaks comprises two DSBs, two SSBs, or one DSB and one SSB. In some embodiments, the plurality of DNA breaks comprises a first DNA break and a second DNA break which flank a target position or target site. In some embodiments, each DNA break in the plurality is generated using a respective gRNA. In some embodiments, introducing more than one DNA break comprises using two different Cas molecule, wherein each Cas molecule binds to a different gRNA and/or recognizes a different PAM. [0164] In some embodiments, a PAM in a DNA target comprises 3-10 nucleotides in length. In some embodiments, a Cas molecule binds to a PAM comprising a sequence of: NGG; NNAGAAW; NNGRRT; NNNNGATT; NVNDCCY; BRTTTTT; NR(A or G)TTTT; NNAAAR(G or A); N(N or A)G; NAAN; NAAAAY; NHDTCCA; NNNVRYM; NNNNRYAC; NAA; GNNNNCNNA; NNGTGA; NNNNGTA; NNGGG; NNNCAT; NNRHHHY; NRRNAT; NNNNCNAA; NNNNCMCA; NNNNCRAA; NNNNGMAA; NNNCC; NGGNG; NNNNCNDD; NYAAA; NRGNN; N(C or D)GGN(T or A or G or C)NN; NRTAW; N(C or K or A)AARC; NAAAG; NV(A or G or C)R(A or G)ACCN; NNGAC; NATGNT; N(T or V)NTAAW(A or T); NNGW(A or T)AY(T or C); NCAA(H(Y or A)B(Y or G); NH(T or C or A)AAAA; NNNATTT; NATAWN(A or T or S); NATARCH; B(T or G or C)GGD(A or T or G)TNN; N(G or T or M)GGAH(T or A or C)N(A or C or K)N; NRG; N(B or A)GG; NGGD(A or K)W(T or A); N(T or C or R)AGAN(A or K or C)NN; NGGD(A or T or G)H(T or M); NGGDT; NGGD(A or T or G)GNN; NNGTAM(A or C)Y; NNGH(W or C)AAA; NTGAR(G or A)N(A or Y or G)N(Y or R); NNGAAAN; NNGAD; NHARMC; NNAAAG; NHGYNAN(A or B); NNAGAAA; NHAAAAA; NH(T or M)AAAAA; NHGYRAA; NNAAACN; NN(H or G)D(A or K)GGDN(A or B); NNNNCTA; NNNNCVGAA; NNNNGYAA; NNNNATN(W or S)ANN; NNWHR(G or A)TA(not G)AA; YHHNGTH; NNNNCDAANN; NNNNCTAA; N(C or D)NNTCCN; NNNNCCAA; NAGRGN(T or V)N(T or C); NNAH(T or M)ACN; CN(C or W or G)AV(A or S)GAC; NAR(G or A)H(W or C)H(A or T or C)GN(C or T or R); NAGNGC; NATCCTN; NGTGANN; HGCNGCR; NAR(A or G)W(T or A)AC; N(C or D)M(A or C)RN(A or B)AY(C or T); NNNCAC; BGGGTCD; NNRRCC; NRRNTT; KARDAT; BRRTTTW; NARNCCN; NAR(A or G)TC; NAAN(A or T or S)RCN; HHAAATD; NNNNGNA; TTV; TTTV; YYV; KKYV; TTTM; TTYV; TTTN; TTTTA; TTN; BTTV; YTV; YTN; NYTV; DTTD; ATTN; RTTNT; HATT; ATTW; RTTN; TVT; TG; TN; TR; TA; TTCN; TTAT; TTTR; TTR; YTTR; YTTN; CTT; TTC; CCD; RTR; VTTR; TBN; VTTN; NGTT; CGTT; AGG; CGG; GTT; or RGTG, wherein: “N” is any nucleotide or base; “W” is adenine (A) or thymine (T); “R” is A or guanine (G); “V” is A, cytosine (C), or G; “Y” is C or T; “M” is C or A; “K” is G or T; “D” is A, G, or T; “S” is G or C; “B” is C, G, or T; and “H” is A, C, or T. A PAM sequence can be located in any of the SORL1 sequences described herein (see, e.g., SEQ ID NOs: 60-108 and 119-120) or a mutant version thereof which comprises a disease-associated mutation. [0165] Cas molecules can be chosen for a gene editing therapy based on PAM availability near a SORL1 sequence comprising a disease associated mutation. Typically, a Cas molecule will be paired with a PAM that is separated from a disease-associated mutation by 1,000 nucleotide positions or less. In some embodiments, a Cas molecule is chosen based on a location of a cognate PAM that is separated from the disease-associated mutation by 1- 10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-125, 125-150, 150- 175, 175-200, 200-300, 300-400, or 400-500 nucleotide positions. Therein, a Cas molecule and/or a deaminase that is fused to a catalytically dead Cas molecule will generate a mutagenic event (e.g., a nick and/or or a base deamination) at a nucleotide position that is separated from a PAM by 10 nucleotides or less, such as 1, 2, 3, 4, 5, 6, 7, 8, or 9 nucleotides. [0166] A sequence in a gRNA that hybridizes with a sequence in a DNA target will typically comprise no more than 40 nucleotides. In some embodiments, a sequence in a gRNA that hybridizes with a DNA target comprises 10-35 nucleotides, such as 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides. In some embodiments, a sequence in a gRNA that hybridizes with a DNA target comprises at least 15 nucleotides that are 100% identical to a sequence in a DNA target, such as 15-18, 18-20, 20-22, or 22-24 nucleotides that are 100% identical to a sequence in a DNA target. In some embodiments, a gRNA that hybridizes with a SORL1 sequence comprising a disease-associated mutation comprises a sequence of 10-35 nucleotides that has one or more mismatches (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more mismatches, such as insertions, deletions, and/or substitutions) relative to a sequence set forth in any one SEQ ID NOs: 60-108 or 119-120, or a reverse complement thereof. Engineering a gRNA sequence to comprise mismatches relative to a DNA target can be used to promote specific cleavage of a SORL1 sequence comprising a disease associated mutation. In some embodiments, a gRNA comprising a sequence that binds to a sequence comprising a disease-associated mutation in SORL1 comprises a mutant version of any one of the sequences set forth in SEQ ID NOs: 61-108 or 119-120, or a reverse complement thereof, wherein the mutant version of the sequence comprises one or more substitutions, insertions, or deletions that encode a disease-associated mutation described herein. [0167] A Cas molecule and a gRNA can be encoded on the same nucleic acid, or they can be encoded on separate nucleic acids. The nucleic acid encoding a Cas molecule, or a gRNA can comprise DNA, RNA, a DNA-RNA hybrid, or be a modified nucleic acid, such as a chemically modified nucleic acid. Introducing a nucleic acid encoding a Cas molecule and/or a gRNA into a cell can involve transfection, electroporation, or via a recombinant virus described herein. Alternatively, a Cas molecule and a gRNA can be introduced into a cell as a pre-formed complex, such as by electroporation. [0168] In some embodiments, a gRNA comprises one or more chemical modifications. In some embodiments, the one or more chemical modifications comprises chemically modified nucleosides and/or sugar-phosphate backbone chemical modifications. In some embodiments, the one or more chemical modifications in a gRNA comprises a phosphorothioate moiety, a 2′-O-Me–modification, a 2′-F-modification, and/or a thioPACE moiety. In some embodiments, the one or more chemical modifications comprises modified nucleotides at the 3′ end and/or the 5′ of the gRNA and/or modified nucleotides that are located internally (e.g., in the sequence that binds the DNA target). Therapeutic Edits [0169] Editing a SORL1 gene comprising a disease-associated mutation can be used to genetically engineer a target position or a target site to comprise a wild-type SORL1 sequence, such as the sequence set forth in any one of SEQ ID NOs: 60-108 or 119-120. In some embodiments, editing a disease-associated mutation in SORL1 can correct (e.g., convert to a wild-type counterpart sequence set forth in any one of SEQ ID NOs: 60-108 or 119-120) one or more nucleotide positions in exon sequences encoding the VPS10p domain, 10CC domain, YWTD domain, EGF domain, the CR domain, the FnIII domain, the transmembrane domain, or the cytoplasmic tail domain. In some embodiments, the disease-associated mutation comprises a pathogenic mutation as set forth in Table 13. In some embodiments, the disease-associated mutation in SORL1 encodes an amino acid substitution, insertion, or deletion at any one or more of the following amino acid positions: R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹, Y³⁵⁰, F⁴¹⁴, L⁴⁹⁵, Y⁵³⁹, Y⁵⁴⁰, V⁵⁸³,

C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁴⁹, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁴⁴, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁵³, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁰, C¹⁵⁴⁹, D¹¹⁰⁵, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴,

V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², W¹⁷³⁵, P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, P¹⁹⁵⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰²,

P²²¹⁰, M²²¹¹, V²²¹², I²²¹³, or A²²¹⁴ in the cytoplasmic tail domain; or any combination thereof. In some embodiments, the disease-associated mutation occurs at any one of positions: R⁶³,

Y⁵⁴⁰, V⁵⁸³, Y⁵⁸⁴, I¹¹⁷, V¹¹⁸, A¹¹⁹, Y¹⁷⁷, I¹⁷⁸, F¹⁷⁹, L²¹⁸, L²¹⁹, L²²⁰, I²⁶⁴, Y²⁶⁵, I²⁶⁶, Y³⁰⁶, F³⁰⁸, V³⁵⁹, F³⁶⁰, V³⁶¹, Y⁴²⁴, I⁴²⁵, A⁴²⁶,I⁵⁰⁴, I⁵⁰⁵, A⁵⁰⁶, I⁵⁴⁸, I⁵⁴⁹, V⁵⁹⁶, F⁵⁹⁷, V¹³⁵, Y¹³⁶, V¹³⁷, L¹⁸⁷, W¹⁸⁸, I¹⁸⁹, L²³¹, W²³², V²⁷⁷, F²⁷⁸, L³²⁶, W³²⁷, V³²⁸, L³⁷², Y³⁷³, I³⁷⁴, V⁴⁴¹, I⁴⁴², V⁵²⁰, Y⁵²¹, I⁵²², L⁵⁶¹, Y⁵⁶³, L⁶¹³, V⁶¹⁵, S¹³⁸, G¹⁴², S¹⁴⁴, F¹⁴⁵, T¹⁹⁰, D¹⁹², T¹⁹⁶, S²³⁴, D²³⁶, G²³⁸, T²⁴⁰, W²⁴¹, S²⁸⁰, D²⁸², S²⁸⁶, S³²⁹, S³⁷⁵, G³⁷⁹, F³⁸², T⁴⁴³, D⁴⁴⁵, G⁴⁴⁷, T⁴⁴⁹, W⁴⁵⁰, S⁵²³, G⁵²⁷, W⁵³⁰, S⁵⁶⁴, N⁵⁶⁶, G⁵⁶⁸, T⁵⁷⁰, W⁵⁷¹, C⁴⁶⁷, or C⁴⁷³ in the VPS10p domain; C⁶²⁵, C⁶⁴³, C⁶⁶⁰, C⁶⁷⁵, C⁶⁷⁷, C⁶⁸⁴, C⁶⁹⁹, C⁷¹⁶, C⁷³⁶, or C⁷⁵² in the 10CC domain; L⁷⁹³, F⁷⁹⁵, L⁸⁰², L⁸³⁷, F⁸³⁹, L⁸⁴⁶, L⁸⁸¹, L⁸⁸³, M⁸⁹⁰, I⁹²⁶, V⁹²⁸, I⁹³³, I⁹⁶⁶, V⁹⁶⁸, I⁹⁷³, M¹⁰⁰⁷, I¹⁰⁰⁹, L⁷⁸², V⁸²⁵, I⁸²⁶, I⁸⁶⁹, V⁸⁷⁰, L⁹¹⁵, V⁹¹⁶, I⁹⁵⁶, L⁹⁵⁷, I⁹⁹⁶, L⁹⁹⁷, L⁷⁸⁷, L⁸³¹, L⁸⁷⁵, V⁹²⁰, L⁹⁶⁰, L¹⁰⁰¹, R⁸⁷⁹, W⁸⁹⁵, N⁹²⁴, Y⁹⁶⁴, W⁹⁷⁸, Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶, Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰²,

YWTD domain; C¹⁰²¹, C¹⁰²⁶, C¹⁰³⁰, C¹⁰⁴⁰, C¹⁰⁴², C¹⁰⁵⁸, C¹⁰⁶⁰, or C¹⁰⁷¹ in the EGF domain; S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁹³, G¹⁵³⁶, D¹⁰⁹⁸, D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁹, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴,

V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², W¹⁷³⁵, P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³,

some embodiments, the disease-associated mutation does not occur at an amino acid position in SORL1 selected from the group consisting of 101, 115, 140, 146, 191, 205, 269, 270, 303, 332, 371, 391, 416, 446, 459, 474, 480, 508, 528, 552, 560, 577, 581, 583, 636, 639, 642, 656, 674, 679, 695, 729, 734, 743744, 762, 786, 807, 818, 833, 852, 870, 884, 885, 942, 961, 980, 1000, 1002, 1074, 1080, 1081, 1084, 1094, 1099, 1113, 1116, 1156, 1167, 1181, 1187, 1207, 1222, 1222, 1246, 1258, 1276, 1276, 1279, 1291, 1304, 1310, 1311, 1322, 1379, 1383, 1392, 1409, 1435, 1442, 1447, 1454, 1470, 1481, 1483, 1490, 1501, 1504, 1522, 1526, 1535, 1543, 1548, 1563, 1584, 1594, 1620, 1657, 1668, 1675, 1680, 1697, 1697, 1729, 1732, 1747, 1809, 1813, 1816, 1866, 1873, 1885, 1895, 1910, 1958, 1967, 2000, 2007, 2014, 2038, 2065, 2079, 2083, 2090, 2097, 2106, 2134, 2147, 2158, and 2160. [0170] For example, a deaminase fused to a Cas molecule that recognizes a PAM near the mutation can be used to edit a target position and/or a target site to for correcting disease-associated mutations. Generally, the edit will comprise a C-to-T change resulting in a C:G base pair being converted to a T:A base pair when using a cytosine deaminase and the edit will comprise a A-to-G change resulting in a A:T base pair being converted to a G:C base pair when using an adenosine deaminase. [0171] In some embodiments, a Cas molecule fused to a deaminase can be used to correct one or more nucleotide substitutions in a SORL1 gene which encodes substituted amino acids in a SORL1 protein, result in alternative splicing, result in a frame-shift, and/or result in a truncation. In some embodiments, editing a target position using a SORL1 gene with a Cas protein fused to an adenosine deaminase can be used to to disable a pre-mature stop codon, introduce a nonsynonymous mutation into a codon to change the amino acid encoded by the codon, or disable a splicing acceptor site A residue that promoters alternative splicing during transcription of a SORL1 gene. In some embodiments, editing a target position in a SORL1 gene comprises using a Cas molecule fused to a cytosine deaminase (e.g., a Cas molecule-cytosine deaminase fusion comprising a uracil glycosylase inhibitor), such as to introduce a nonsynonymous mutation into a codon to change the amino acid encoded by the codon or restore a splicing donor site U residue (encoded by the C-to-T change made by the cytosine deaminase) so that an RNA transcript is spliced to comprise a sequence encoding a wild-type SORL1 protein. In some embodiments, editing a target position in a SORL1 gene comprises using a Cas molecule fused to a guanine deaminase, such as to introduce a nonsynonymous mutation into a codon to change the amino acid encoded by the codon or mutate a G residue in a splicing donor or splicing acceptor site so that an RNA transcript is spliced to comprise a sequence encoding a wild-type SORL1 protein. [0172] Correcting disease-associated mutations in a SORL1 gene can comprise editing a target position and/or a target site with a Cas molecule, a gRNA, and a repair template. A “template” refers to a nucleic acid that serves as a substrate for HDR and promotes integration of one or more nucleic acids into a SORL1 sequence comprising a disease-associated mutation and may be alternatively referred to herein as a template oligonucleotide or a template nucleic acid. Templates of the disclosure will generally comprise a heterologous nucleic acid flanked by a first homology arm and a second homology arm. A “homology arm” refers to a sequence configured to stably and/or specifically hybridize to a SORL1 sequence and a “heterologous nucleic acid” refers to a nucleic acid comprising one or more sequences which are not found in the DNA target comprising a SORL1 sequence comprising a disease-associated mutation. “Homology- directed repair” or “HDR” refers to a process that synthesizes new DNA in a first nucleic acid using the information comprised in a second nucleic acid. HDR is mediated by a variety of proteins. Briefly, nucleases produce single-stranded overhangs on the first nucleic acid. The overhangs hybridize with a sequence in the second nucleic acid which comprise homology to the overhangs. Repair polymerases extend the overhangs of the first nucleic acid using the second nucleic acid as a template. Gaps in the polymerized strands of the first nucleic acid are filled by gap polymerases and ligases. Thus, the second nucleic acid can restore the original sequence of the first nucleic acid when it is used as a template for DNA synthesis. However, HDR is not limited in this regard as this process can also result in substitution of one or more nucleotides, deletion of one or more nucleotides, and/or insertion of one or more nucleotides. [0173] A template can comprise DNA, RNA, or any combination of DNA and RNA nucleotides and comprise 15,000 nucleotides or less in length. In some embodiments, a template comprises 5,000 nucleotides or less (e.g., 20-30, 30-40, 25-50, 40-50, 50-75, 75- 100, 50-100, 100-150, 100-200,150-200, 200-300, 300-400, 400-500, 500-600, 600-700, 700- 800, 800-900, 900-1,000, 1,000-1,500, 1,500-2,000, 2,000-2,500, 2,500-3,000, 3,000-3,500, 3,500-4,000, 4,000-4,500, or 4,500-5,000 nucleotides). A homology arm will typically comprise 2,000 nucleotides or less in length. In some embodiments, a homology arm comprises 1,000 nucleotides or less. In some embodiments, a homology arm comprises 500 nucleotides or less (e.g., 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-100, 25-100, 100-250, 100-125, 125-150, 150-200, 200-500, 200-250, 250-300, 300-350, 350-400, 400- 450, or 450-500 nucleotides) in length. A heterologous nucleic acid will typically comprise 10,000 nucleotides or less in length. In some embodiments, a heterologous nucleic acid comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 5-10, 5-15, 5-20, 10-20, 10-25, 15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50, 25-50, 50-60, 55-65, 50-75, 60-70, 65-75, 70-80, 75-85, 80-90, 85-95, 95-100, 75-100, 100-400, 400-800, 800-1000, 900- 1000, 950-1000, 1000-1300, 1100-1400, 1200-1500, 1300-1600, 1400-1700, 1500-1800, 1600-1900, 1700-2000, 1800-2100, 1900-2200, 2000-2500, 2100-2600, 2200-2700, 2300- 2800, 2400-2900, or 2500-3000 nucleotides in length. In some embodiments, a heterologous nucleic acid comprises 1,000 nucleotides or less in length. In some embodiments, a heterologous nucleic acid comprises 500 nucleotides or less in length. In some embodiments, a heterologous nucleic acid comprises 100 nucleotides or less in length. [0174] A nucleic acid comprising a template can comprise a double-stranded nucleic acid, a single-stranded nucleic acid, or one or more stretches of double-stranded sequence and one or more stretches of single-stranded sequence. In some embodiments, a template is linear. In some embodiments, a template is circular. In some embodiments, a template comprises one or more single-stranded nicks. In some embodiments, a template is a vector, such as a plasmid (e.g., a circular plasmid, a nanoplasmid, or a minicircle plasmid), a cosmid, or an artificial chromosome. In some embodiments, a nucleic acid comprising a template is a self-cleaving nucleic acid which is circular prior to liberating the template as a linear template nucleic acid. In some embodiments, a template comprises one or more chemical modifications. Examples of chemical modifications include chemically modified nucleosides and sugar-phosphate backbone chemical modifications. In some embodiments, a template comprises one or more nucleotides comprising a chemically modified sugar, a chemically modified nucleobase, and/or a chemically modified phosphate group. In some embodiments, a template comprises a phosphate analog. In some embodiments, a template comprises one or more chemically modified internucleotide linkages. In some embodiments, chemical modifications in a template are in homology arm and/or a heterologous nucleic acid. In some embodiments, chemical modifications in a nucleic acid can be used to improve cellular uptake, improve stability, reduce immunogenicity, improve potency, improve target hybridization, and/or reduce susceptibility to cleavage by endogenous nucleases of a template. [0175] In some embodiments, a template is operably linked to at least one regulatory sequence in a nucleic acid. The at least one regulatory sequence can comprise 1, 2, 3, 4, or more regulatory sequences. The at least one regulatory sequence can comprise any one or more of the regulatory sequences described herein including, but not limited to, regulatory sequences capable of promoting transcription (e.g., any one or more of a promoter, an enhancer, a transcription factor binding sequence, a transcriptional start sequence, etc.) and/or terminating transcription (e.g., any one or more of a transcription termination sequence, etc.). In some embodiments, one or more regulatory sequences are operably linked to a sequence comprising a first homology arm, a heterologous nucleic acid, and a second homology arm. In some embodiments, regulatory sequences can be used to control stability, expression, and/or degradation of a template in a cell. In some embodiments, a template is operably linked to a promoter. In some embodiments, a promoter is operably linked to a template for the purposes of expressing the template as an RNA in a cell. [0176] In some embodiments, a homology arm comprises homology to a region of a SORL1 sequence comprising a PAM. In some embodiments, a homology arm comprises homology to a region of a SORL1 sequence that comprises a sequence that hybridizes to a gRNA. However, in some embodiments, a homology arm comprises homology to a sequence proximal to a sequence that hybridizes to a gRNA. A “sequence proximal to a sequence capable of hybridizing to a gRNA” refers to sequences that are approximately 1-1,000 nucleotides or more nucleotides upstream or downstream of the sequence in a SORL1 sequence that is capable of hybridizing to the gRNA. In some embodiments, a sequence proximal to a sequence capable of hybridizing to a gRNA in a DNA target are 1-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-100, 25-100, 100-250, 100-125, 125-150, 150- 200, 200-500, 200-250, 250-300, 300-350, 350-400, 400-450, or 450-500 nucleotides upstream or downstream of the sequence that hybridizes to the gRNA. In some embodiments, a first homology arm and a second homology arm comprise an equal number of nucleotides. In other embodiments, a first homology arm and a second homology arm comprise a nonequal number of nucleotides. In some embodiments, the lengths of the first and second homology arms may differ by approximately 1-5, 5-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-125, 125-150, 150-175, 175-200, 200-225, 225-250, 250- 275, 275-300, 300-325, 325-350, 350-375, 375-400, 400-425, 425-450, 450-475, 475-500, or more nucleotides in length. In some embodiments, the homology arm that is longest comprises homology to a sequence in a DNA target comprising a PAM. [0177] In some embodiments, a homology comprises one or more stretches of sequence that are identical to a region of a SORL1 sequence and/or one or more stretches of sequence sequences that differ from a region in the region of the SORL1 sequence by at least one nucleotide. In some embodiments, the one or more stretches of sequence that are identical to the region of the SORL1 sequence can comprise 2-20, 20-50, 50-100, 100-200, 200-500, or more nucleotides in length. In some embodiments, the at least one nucleotide differing from the region in the SORL1 sequence comprises one or more insertions, one or more deletions, and/or one or more substitutions relative to the region. In some embodiments, the at least one nucleotide differing from the region in the SORL1 sequence is positioned closer to the end of the homology arm that is closest to a heterologous nucleic acid in the template (e.g., 200 nucleotides or less away of the heterologous nucleic acid, such as 100-200 nucleotides, 50- 100 nucleotides, 50-25 nucleotides, 15-25 nucleotides, 10-15 nucleotides, 5-10 nucleotides, 4 nucleotides, 3 nucleotides, 2 nucleotides, or 1 nucleotide away from the heterologous nucleic acid). Examples of SORL1 sequences that homology arms can be designed to hybridize to include the sequences set forth in any one of SEQ ID NOs: 60-108 or 119-120, or a reverse complement thereof, or a mutant version of any one of SEQ ID NOs: 60-108 or 119-120 which comprises one or more insertions, one or more deletions, and/or one substitutions corresponding to a disease-associated mutation described herein, or a reverse complement thereof. Alternatively, homology arms can be designed to hybridize to non-coding sequences in the SORL1 gene, such as sequences found at Chromosome 11: 121,452,314-121,633,763 forward strand (see, e.g., SEQ ID NOs: 119 or 120) or the reverse complement thereof. [0178] Heterologous nucleic acids will typically be designed to correct disease-associated mutations in SORL1. Correcting disease-associated mutations in SORL1 using HDR-based editing can comprise introducing insertions, deletions, and/or substitutions into a SORL1 sequence comprising a disease-associated mutation described herein. Accordingly, a heterologous nucleic acid in a template will typically comprise less than 100% sequence identity to a SORL1 sequence comprising a disease-associated mutation that is located between the corresponding genomic sequences that the homology arms of the template are designed to hybridize to. In some embodiments, a heterologous nucleic acid comprises a wild-type version of one or more SORL1 exons, such as a sequence set forth in any one or more SEQ ID NOs: 60-108 or 119-120 or a reverse complement thereof. In some embodiments, a heterologous nucleic acid comprises a portion of a wild-type SORL1 exon (e.g., 1-10%, 10-20%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-99.5% of the nucleotides found in an exon sequence set forth in any one of SEQ ID NOs: 61-108) or a reverse complement thereof. In some embodiments, a heterologous nucleic acid comprises a sequence encoding any one of the amino acid sequences set forth in any one of SEQ ID NOs: 33 or 109-118, or comprise a reverse complement of a sequence encoding any one of the amino acid sequences set forth in any one of SEQ ID NOs: 33 or 109-118. In some embodiments, a heterologous nucleic acid comprises a sequence in a SORL1 intron (see, e.g., Table 1 and SEQ ID NO: 119) or a reverse complement thereof. Accordingly, gene editing therapies of the disclosure which comprise templates can be used to mutate coding sequences and/or non-coding sequences in a SORL1 sequence comprising a disease-associated mutation to promote production of a SORL1 protein lacking a disease-associated mutations at one or more positions (e.g., to promote production of a wild-type SORL1 protein). Inhibitory Nucleic Acids [0179] Aspects of the disclosure also relate to inhibitory nucleic acids that can be used as a therapeutic agent in a gene therapy approach for the treatment of a subject characterized as having or suspected of having a disease-associated mutation in SORL1 as describe herein. An inhibitory nucleic acid will typically hybridize with a nucleic acid sequence in a SORL1 gene and/or an RNA transcript encoding a SORL1 protein comprising a disease-associated mutation. [0180] In some embodiments, an inhibitory nucleic acid comprises about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 20-30, 30-40, 40-50, or more nucleotides. The length and the degree of sequence complementarity will be designed so that the inhibitory nucleic acid base- pairs in a specific and/or stable manner with a nucleic acid sequence encoding a SORL1 protein comprising a disease-associated mutation. An inhibitory nucleic acid can be designed to be bind specifically to a nucleic acid sequence encoding a SORL1 protein comprising a disease-associated mutation, such as by designing the inhibitory nucleic acid to be 100% complementary to the nucleic acid sequence encoding a SORL1 protein comprising a disease-associated mutation. In some embodiments, an inhibitory nucleic acid comprises 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 20-30, 30-40, 40-50, or more nucleotides that is complementary to a nucleic acid sequence (e.g., a target sequence). In some embodiments, an inhibitory nucleic acid comprises one or more mismatches (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more mismatches, such as insertions, deletions, and/or substitutions) relative to a sequence set forth in any one SEQ ID NOs: 60-108 or 119-120, wherein the one or more mismatches occur at positions comprising disease-associated mutations in SORL1. In some embodiments, the one or more mismatches relative to a sequence set forth in any one of SEQ ID NOs: 60-108 or 119-120 correspond to mutated positions encoding a SORL1 mutant comprising a disease associated mutation in the VPS10p domain, 10CC domain, YWTD domain, EGF domain, the CR domain, the FnIII domain, the transmembrane domain, or the cytoplasmic tail domain (e.g., a mutant SORL1 protein comprising a mutation at any one or more of the following amino acid positions: R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹, Y³⁵⁰, F⁴¹⁴, L⁴⁹⁵, Y⁵³⁹, Y⁵⁴⁰, V⁵⁸³, Y⁵⁸⁴, I¹¹⁷, V¹¹⁸, A¹¹⁹, Y¹⁷⁷, I¹⁷⁸, F¹⁷⁹, L²¹⁸, L²¹⁹, L²²⁰, I²⁶⁴, Y²⁶⁵, I²⁶⁶, Y³⁰⁶, M³⁰⁷, F³⁰⁸, V³⁵⁹, F³⁶⁰, V³⁶¹, Y⁴²⁴, I⁴²⁵, A⁴²⁶,I⁵⁰⁴, I⁵⁰⁵, A⁵⁰⁶, I⁵⁴⁸, I⁵⁴⁹, V⁵⁹⁶, F⁵⁹⁷, V¹³⁵, Y¹³⁶, V¹³⁷, L¹⁸⁷, W¹⁸⁸, I¹⁸⁹, L²³¹, W²³², V²⁷⁷, F²⁷⁸, L³²⁶, W³²⁷, V³²⁸, L³⁷², Y³⁷³, I³⁷⁴, V⁴⁴¹, I⁴⁴², V⁵²⁰, Y⁵²¹, I⁵²², L⁵⁶¹, Y⁵⁶³, L⁶¹³, V⁶¹⁵, S¹³⁸, D¹⁴⁰, G¹⁴², S¹⁴⁴, F¹⁴⁵, T¹⁹⁰, D¹⁹², T¹⁹⁶, S²³⁴, D²³⁶, G²³⁸, T²⁴⁰, W²⁴¹, S²⁸⁰, D²⁸², S²⁸⁶, S³²⁹, S³⁷⁵, G³⁷⁹, F³⁸²,

I¹⁰⁰⁹, L⁷⁸², V⁸²⁵, I⁸²⁶, I⁸⁶⁹, V⁸⁷⁰, L⁹¹⁵, V⁹¹⁶, I⁹⁵⁶, L⁹⁵⁷, I⁹⁹⁶, L⁹⁹⁷, L⁷⁸⁷, L⁸³¹, L⁸⁷⁵, V⁹²⁰, L⁹⁶⁰, L¹⁰⁰¹, R⁸⁷⁹, W⁸⁹⁵, N⁹²⁴, Y⁹⁶⁴, W⁹⁷⁸, Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶, Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, T⁹³⁶, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³, I⁹⁸³, R⁷⁷¹, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, G⁷⁷⁷, G⁸¹⁹, G⁸⁶³, G⁹⁰⁹, G⁹⁵⁰, G⁹⁹¹, R⁸⁶⁶, R⁹⁵³, C⁸⁰¹, or C⁸¹⁶ in the YWTD doman; C¹⁰²¹, C¹⁰²⁶, C¹⁰³⁰, C¹⁰⁴⁰, C¹⁰⁴², C¹⁰⁵⁸, C¹⁰⁶⁰, or C¹⁰⁷¹ in the EGF domain; S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹²⁹⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁴⁰, G¹⁴⁹³, G¹⁵³⁶, D¹⁰⁹⁸, D¹¹⁰², D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸², D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, D¹²⁶⁷, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁴⁹, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁴⁴, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁵³, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁰, C¹⁵⁴⁹, D¹¹⁰⁵, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴, D¹³⁵², D¹³⁹⁶, D¹⁴⁴⁶, D¹⁴⁹⁹, or D¹⁵⁴² in the CR domain; L¹⁵⁶¹, W¹⁵⁶³, L¹⁶⁵⁹, L¹⁶⁶¹, I¹⁷⁵³, I¹⁷⁵⁵, L¹⁸⁴⁸, A¹⁸⁵⁰, L¹⁹³⁸, V¹⁹⁴⁰, L²⁰³⁰, I²⁰³², V¹⁵⁷¹, L¹⁵⁷³, I¹⁶⁶⁹, L¹⁷⁶³, F¹⁷⁶⁵, V¹⁸⁵⁸, C¹⁸⁶⁰, V¹⁹⁴⁸, I¹⁹⁵⁰, V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², W¹⁷³⁵, P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷ W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, P¹⁹⁵⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹, P¹⁹⁹⁸,

cytoplasmic tail domain; or any combination thereof. In some embodiments, the disease-associated mutation occurs at any one of positions: R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹, F⁴¹⁴, L⁴⁹⁵, Y⁵³⁹, Y⁵⁴⁰, V⁵⁸³, Y⁵⁸⁴, I¹¹⁷, V¹¹⁸, A¹¹⁹, Y¹⁷⁷, I¹⁷⁸, F¹⁷⁹, L²¹⁸, L²¹⁹, L²²⁰, I²⁶⁴, Y²⁶⁵, I²⁶⁶, Y³⁰⁶, F³⁰⁸, V³⁵⁹, F³⁶⁰, V³⁶¹, Y⁴²⁴, I⁴²⁵, A⁴²⁶,I⁵⁰⁴, I⁵⁰⁵, A⁵⁰⁶, I⁵⁴⁸, I⁵⁴⁹, V⁵⁹⁶, F⁵⁹⁷, V¹³⁵, Y¹³⁶, V¹³⁷, L¹⁸⁷, W¹⁸⁸, I¹⁸⁹, L²³¹, W²³², V²⁷⁷, F²⁷⁸, L³²⁶, W³²⁷, V³²⁸, L³⁷², Y³⁷³, I³⁷⁴, V⁴⁴¹, I⁴⁴², V⁵²⁰, Y⁵²¹, I⁵²², L⁵⁶¹, Y⁵⁶³, L⁶¹³, V⁶¹⁵, S¹³⁸, G¹⁴², S¹⁴⁴, F¹⁴⁵, T¹⁹⁰, D¹⁹², T¹⁹⁶, S²³⁴, D²³⁶, G²³⁸, T²⁴⁰, W²⁴¹, S²⁸⁰, D²⁸², S²⁸⁶, S³²⁹, S³⁷⁵, G³⁷⁹, F³⁸², T⁴⁴³, D⁴⁴⁵, G⁴⁴⁷, T⁴⁴⁹, W⁴⁵⁰, S⁵²³, G⁵²⁷, W⁵³⁰, S⁵⁶⁴, N⁵⁶⁶, G⁵⁶⁸, T⁵⁷⁰, W⁵⁷¹, C⁴⁶⁷, or C⁴⁷³ in the VPS10p domain; C⁶²⁵, C⁶⁴³, C⁶⁶⁰, C⁶⁷⁵, C⁶⁷⁷, C⁶⁸⁴, C⁶⁹⁹, C⁷¹⁶, C⁷³⁶, or C⁷⁵² in the 10CC domain; L⁷⁹³, F⁷⁹⁵, L⁸⁰², L⁸³⁷, F⁸³⁹, L⁸⁴⁶, L⁸⁸¹, L⁸⁸³, M⁸⁹⁰, I⁹²⁶, V⁹²⁸, I⁹³³, I⁹⁶⁶, V⁹⁶⁸, I⁹⁷³, M¹⁰⁰⁷, I¹⁰⁰⁹, L⁷⁸², V⁸²⁵, I⁸²⁶, I⁸⁶⁹, V⁸⁷⁰, L⁹¹⁵, V⁹¹⁶, I⁹⁵⁶, L⁹⁵⁷, I⁹⁹⁶, L⁹⁹⁷, L⁷⁸⁷, L⁸³¹, L⁸⁷⁵, V⁹²⁰, L⁹⁶⁰, L¹⁰⁰¹, R⁸⁷⁹, W⁸⁹⁵, N⁹²⁴, Y⁹⁶⁴, W⁹⁷⁸, Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶, Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³, I⁹⁸³, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, G⁷⁷⁷, G⁸¹⁹, G⁸⁶³, G⁹⁰⁹, G⁹⁵⁰, G⁹⁹¹, R⁸⁶⁶, R⁹⁵³, C⁸⁰¹, or C⁸¹⁶ in the YWTD domain; C¹⁰²¹, C¹⁰²⁶, C¹⁰³⁰, C¹⁰⁴⁰, C¹⁰⁴², C¹⁰⁵⁸, C¹⁰⁶⁰, or C¹⁰⁷¹ in the EGF domain; S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁹³, G¹⁵³⁶, D¹⁰⁹⁸, D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁹, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴,

I¹⁷⁵³, I¹⁷⁵⁵, L¹⁸⁴⁸, A¹⁸⁵⁰, L¹⁹³⁸, V¹⁹⁴⁰, L²⁰³⁰, I²⁰³², V¹⁵⁷¹, L¹⁵⁷³, I¹⁶⁶⁹, L¹⁷⁶³, F¹⁷⁶⁵, V¹⁸⁵⁸, C¹⁸⁶⁰, V¹⁹⁴⁸, I¹⁹⁵⁰, V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², W¹⁷³⁵, P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³,

[0181] In some embodiments, an inhibitory nucleic acid is an antisense oligonucleotide (ASO). In some embodiments, an ASO comprises a short (approximately 15 to 30 nucleotides) sequence that is complementary to a nucleic acid sequence encoding a SORL1 protein comprising a disease-associated mutation. In some embodiments, nucleotides could be modified by replacing the ribose with an alternate saccharide moiety, such as 2’- deoxyribose, or 2’-O-(2-methoxyethyl) ribose, methylation, and/or replacing phosphodiester bonds between nucleotides with phosphorothioate linkages. In some embodiments, modifications of several nucleotides at both the 3’ and 5’ ends of ASOs inhibit degradation by ubiquitous terminally active RNA nucleases and, therefore, improve the stability and thus half-life of the antisense oligo. However, in some embodiments, it may be desirable that at least some part of the ASO will, once complexed with the mRNA encoding a SORL1 protein comprising a disease-associated mutation, promote the activity of Ribonuclease H to promote the enzymatic degradation of the mRNA once it is complexed with the ASO. In some embodiments, antisense oligonucleotides block the translation of a SORL1 protein comprising a disease-associated mutation by hybridizing to an mRNA sequence encoding the SORL1 protein, thereby inhibiting protein synthesis by ribosomal machinery. In some embodiments, an ASO blocks access of Exon Splice Repressors (ESR) to the mRNA transcript of SORL1. In some embodiments, an ASO blocks the binding of splice repressors and thereby induces inclusion of exon 2 or of exon 19 in SORL1 leading to an increase of the level of full-length SORL1 transcripts. Exemplary ASOs targeting Exons 2 and 19 in SORL1 are shown in Table 2. Table 2: ASOs targeting Exons 2 and 19 in SORL1

*lowercase text indicates intron sequence and upper case text indicates exon sequence [0182] In some embodiments, an inhibitory nucleic acid is an interfering RNA. In some embodiments, an interfering RNA comprises a sequence that is complementary with between 5 and 50 continuous nucleotides (e.g., 5, 6, 7, 8, 9, 10, 11, 12 ,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, about 30, about 35, about 40, or about 50 continuous nucleotides) of a nucleic acid sequence encoding a SORL1 protein comprising a disease-associated mutation. Examples of interfering RNAs include siRNAs, shRNAs, and miRNA. In some embodiments, an inhibitory RNA molecule can be unmodified or modified. In some embodiments, an inhibitory RNA molecule comprises one or more modified oligonucleotides, e.g., phosphorothioate-, 2′-O-methyl-, etc.-modified oligonucleotides, as such modifications have been recognized in the art as improving the stability of oligonucleotides in vivo. Therapeutic SORL1 Variants [0183] Aspects of the present disclosure relate to engineered SORL1 variants comprising a shortened version of SORL1. Engineered SORL1 variants can be used in gene therapy approaches for treating neurological diseases (e.g., neurodegenerative diseases, such as Parkinson’s Disease, Dementia, Pick’s Disease, Lewy Body Dementia, Huntington’s Disease, Alzheimer’s disease, Early-Onset Alzheimer’s disease, Late-Onset Alzheimer’s disease, Sporadic late-onset Alzheimer’s disease, SORL1-positive Alzheimer’s disease, APOE4- positive Alzheimer’s disease, Familial Alzheimer’s disease, frontotemporal disorders associated with neurodegeneration, Niemann Pick Type I, Neuronal Ceroid Lipofuscinosis, Hereditary Spastic Paraparesis, Amyotrophic Lateral Sclerosis, tauopathies such as progressive supranuclear palsy, and Steele-Richardson-Olszewski Syndrome, and diseases that are associated with TDP-43 pathologies). As such, engineered SORL1 variants may be used to treat virtually any disease or disorder associated with abnormal endosomal trafficking, increased amyloid plaque levels, and/or increased intracellular fibrillary tangles comprised of hyperphosphorylated tau proteins, including neurological diseases (e.g., neurodegenerative diseases, such as Parkinson’s Disease, Dementia, Pick’s Disease, Lewy Body Dementia, Huntington’s Disease, Alzheimer’s disease, Early-Onset Alzheimer’s disease, Late-Onset Alzheimer’s disease, Sporadic late-onset Alzheimer’s disease, SORL1- positive Alzheimer’s disease, APOE4-positive Alzheimer’s disease, Familial Alzheimer’s disease, frontotemporal disorders associated with neurodegeneration, Niemann Pick Type I, Neuronal Ceroid Lipofuscinosis, Hereditary Spastic Paraparesis, Amyotrophic Lateral Sclerosis, tauopathies such as progressive supranuclear palsy, and Steele-Richardson- Olszewski Syndrome, and diseases that are associated with TDP-43 pathologies). In some embodiments, engineered SORL1 variants are designed to be used as a viral gene therapy as further described herein. SORL1 Variant Proteins [0184] Several advantages are associated with the engineered SORL1 variants disclosed herein as compared to the full-length receptor. First, the SORL1 variants do not decrease sAPPα, which is a beneficial property since sAPPα is a non-amyloidogenic product. Second, the nucleotide sequences for the SORL1 variants are small enough to be packaged into a feasible vector for gene therapy, for example, an AAV vector. Third, a SORL1 variant may be used as a form of gene therapy offering high specificity in modulating retromer activity. Accordingly, engineered SORL1 variants retain functions beneficial for the treatment of Alzheimer’s disease, such as participation in endosomal recycling and the ability to decrease the amyloidogenic processing of APP. In some embodiments, it might also be feasible to combine applications of both retromer and SORL1 variant gene therapies. For example, the SORL1 variant may be administered in combination with other therapies, such as small molecule therapies. [0185] SORL1 variants of the present disclosure have been engineered to comprise select domains found in the wild-type SORL1 gene sequence in order to shorten the coding sequence while retaining specific functional properties of SORL1. In some embodiments, a SORL1 variant comprises (from N-terminus to C-terminus) at least two SORL1 FnIII domains, a SORL1 transmembrane domain, and a SORL1 cytoplasmic tail domain. In some embodiments, a SORL1 variant comprises three, four, five, or six FnIII domains. In some embodiments, a SORL1 variant comprises (from N-terminus to C-terminus) two SORL1 FnIII domains, a SORL1 transmembrane domain, and a SORL1 cytoplasmic tail domain. In some embodiments, a SORL1 variant comprises (from N-terminus to C-terminus) three SORL1 FnIII domains, a SORL1 transmembrane domain, and a SORL1 cytoplasmic tail domain. In some embodiments, a SORL1 variant comprises (from N-terminus to C-terminus) four SORL1 FnIII domains, a SORL1 transmembrane domain, and a SORL1 cytoplasmic tail domain. In some embodiments, a SORL1 variant comprises (from N-terminus to C-terminus) five SORL1 FnIII domains, a SORL1 transmembrane domain, and a SORL1 cytoplasmic tail domain. In some embodiments, a SORL1 variant comprises (from N-terminus to C-terminus) six SORL1 FnIII domains, a SORL1 transmembrane domain, and a SORL1 cytoplasmic tail domain. In some embodiments, a SORL1 variant comprises a linker sequence. In some embodiments, a linker sequence is located between any one of the protein’s domains. In some embodiments, a linker sequence is found between each of the domains of the SORL1 variant. In some embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 21. In some embodiments, a SORL1 variant comprises a stalk domain. [0186] In some embodiments, at least one of the SORL1 FnIII domains is selected from the group consisting of FnIII-1, FnIII-2, FnIII-3, FnIII-4, FnIII-5, and FnIII-6. In some embodiments, more than one of the SORL1 FnIII domains is selected from the group consisting of FnIII-1, FnIII-2, FnIII-3, FnIII-4, FnIII-5, and FnIII-6. In some embodiments, a SORL1 variant comprises a FnIII-1 domain. In some embodiments, a SORL1 variant comprises a FnIII-2 domain. In some embodiments, a SORL1 variant comprises a FnIII-3 domain. In some embodiments, a SORL1 variant comprises a FnIII-4 domain. In some embodiments, a SORL1 variant comprises a FnIII-5 domain. In some embodiments, a SORL1 variant comprises a FnIII-6 domain. [0187] In some embodiments, a SORL1 variant may comprise multiple copies of a given FnIII domain. In some embodiments, a SORL1 variant comprises two, three, four, five, or six FnIII-1 domains. In some embodiments, a SORL1 variant comprises two, three, four, five, or six FnIII-2 domains. In some embodiments, a SORL1 variant comprises two, three, four, five, or six FnIII-3 domains. In some embodiments, a SORL1 variant comprises two, three, four, five, or six FnIII-4 domains. In some embodiments, a SORL1 variant comprises two, three, four, five, or six FnIII-5 domains. In some embodiments, a SORL1 variant comprises two, three, four, five, or six FnIII-6 domains. [0188] In some embodiments, a SORL1 variant may comprise any combination of two, three, four, five, or six FnIII domains selected from the group consisting of FnIII-1, FnIII-2, FnIII-3, FnIII-4, FnIII-5, and FnIII-6. In some embodiments, a SORL1 variant comprises a FnIII-1 domain and at least one FnIII-2 domain, and/or at least one FnIII-3 domain, and/or at least one FnIII-4 domain, and/or at least one FnIII-5 domain, and/or at least one FnIII-6 domain. In some embodiments, a SORL1 variant comprises a FnIII-2 domain and at least one FnIII-3 domain, and/or at least one FnIII-4 domain, and/or at least one FnIII-5 domain, and/or at least one FnIII-6 domain. In some embodiments, a SORL1 variant comprises a FnIII-3 domain and at least one FnIII-4 domain, and/or at least one FnIII-5 domain, and/or at least one FnIII-6 domain. In some embodiments, a SORL1 variant comprises a FnIII-4 domain and at least one FnIII-5 domain, and/or at least one FnIII-6 domain. In some embodiments, a SORL1 variant comprises a FnIII-5 domain and one FnIII-6 domain. [0189] In some embodiments, one or more polypeptide domains of a SORL1 variant, or nucleotide sequences comprising a SORL1 variant gene, will comprise a sequence bearing a percentage (%) of sequence identity either to a given wild-type SORL1/SORL1 sequence, or to a given SORL1/SORL1 variant sequence. [0190] In some embodiments, at least one of the SORL1 FnIII domains comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NO: 15-20. In some embodiments, at least one of the SORL1 FnIII domains comprises the amino acid sequence set forth in any one of SEQ ID NOs: 15-20. [0191] In some embodiments, the SORL1 transmembrane domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 22. In some embodiments, the SORL1 transmembrane domain comprises the amino acid sequence set forth in SEQ ID NO: 22. [0192] In some embodiments, the SORL1 cytoplasmic tail domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 23 or 127. In some embodiments, the SORL1 cytoplasmic tail domain comprises the amino acid sequence set forth in SEQ ID NO: 23 or 127. [0193] In some embodiments, at least one of the SORL1 FnIII domains comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 15-20, the SORL1 transmembrane domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 22, and the SORL1 cytoplasmic tail domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 23 or 127. [0194] In some embodiments, at least one of the SORL1 FnIII domains comprises the amino acid sequence set forth in any one of SEQ ID NOs: 15-20, the SORL1 transmembrane domain comprises the amino acid sequence set forth in SEQ ID NO: 22, and the SORL1 cytoplasmic tail domain comprises the amino acid sequence set forth in SEQ ID NO: 23 or 127. [0195] In some embodiments, SORL1 variants comprise a wild-type FANSHY motif encoded within the cytoplasmic tail domain. In some embodiments, SORL1 variants comprise a mutation in the FANSHY motif encoded within the cytoplasmic tail domain. In some embodiments, the polynucleotide sequence of the mutant FANSHY motif encodes at least one amino acid mutation. In some embodiments, the polynucleotide sequence of the mutant FANSHY motif encodes at least one alanine substitution. In some embodiments, the polynucleotide sequence of the mutant FANSHY motif encodes a mutation at the phenylalanine residue. In some embodiments, the polynucleotide sequence of the mutant FANSHY motif encodes a mutation at the alanine residue. In some embodiments, the polynucleotide sequence of the mutant FANSHY motif encodes a mutation at the asparagine residue. In some embodiments, the polynucleotide sequence of the mutant FANSHY motif encodes a mutation at the serine residue. In some embodiments, the polynucleotide sequence of the mutant FANSHY motif encodes a mutation at the histidine residue. In some embodiments, the polynucleotide sequence of the mutant FANSHY motif encodes a mutation at the tyrosine residue. In some embodiments, the polynucleotide sequence of the mutant FANSHY motif encodes an alanine substitution at the phenylalanine residue. In some embodiments, the polynucleotide sequence of the mutant FANSHY motif encodes an alanine substitution at the serine residue. In some embodiments, the polynucleotide sequence of the mutant FANSHY motif encodes an alanine substitution at the histidine residue. In some embodiments, the polynucleotide sequence of the mutant FANSHY motif encodes an alanine substitution at the tyrosine residue. In some embodiments, the polynucleotide sequence of the FANSHY motif encodes a mutation in each of the residues. In some embodiments, the polynucleotide sequence of the FANSHY motif encodes an alanine substitution at the phenylalanine, asparagine, serine, histidine, and tyrosine residues. [0196] In some embodiments, a SORL1 variant further comprises an N-terminal or C- terminal tag. In some embodiments, the N-terminal or C-terminal tag is hemagglutinin (HA) or FLAG. In some embodiments, the N-terminal or C-terminal tag is one, two, three, four, five, or six instances of HA (referred to as, in the example of 6 instances of HA, either 6X- HA, 6HA, or 6-HA). In some embodiments, the N-terminal or C-terminal tag is one, two, or three instances of FLAG (referred to as, in the example of 3 instances of FLAG, 3X-FLAG, 3FLAG, or 3-FLAG). In some embodiments, a SORL1 variant comprises an N-terminal HA tag. In some embodiments, the SORL1 variant comprises an N-terminal 3X-FLAG tag. In some embodiments, the N-terminal or C-terminal tag is GST, Myc, polyHis, TAP, V5, biotin, MBP, or SpyTag. In some embodiments, the N-terminal or C-terminal tag is one, two, three, four, five, six, seven, eight, or nine instances of Myc. In some embodiments, the N-terminal or C-terminal tag is one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve instances of His. In some embodiments, the N-terminal or C-terminal tag is one, two, or three instances of V5. [0197] In some embodiments, a SORL1 variant polypeptide is no longer than 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, or 700 amino acids. In some embodiments, a SORL1 variant polypeptide is no longer than 685 amino acids. In some embodiments, a SORL1 variant polypeptide is no longer than 700 amino acids. In some embodiments, a SORL1 variant polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 13-22, 24, 27-28, or 127. In some embodiments, a SORL1 variant polypeptide comprises the amino acid sequence set forth in any one of SEQ ID NOs: 13-22, 24, 27-28, or 127. In some embodiments, a SORL1 variant comprises one or more amino acid sequences set forth in Table 3. Table 3. Examples of amino acid sequences corresponding to SORL1 variants.

[0198] In some embodiments, a SORL1 variant comprises an amino acid sequence set forth below: >Minigene-WT translated aa sequence ELTVYKVQNLQWTADFSGDVTLTWMRPKKMPSASCVYNVYYRVVGESIWKTLETHSNKTNTVLKVL KPDTTYQVKVQVQCLSKAHNTNDFVTLRTPEGLPDAPRNLQLSLPREAEGVIVGHWAPPIHTHGLIREY IVEYSRSGSKMWASQRAASNFTEIKNLLVNTLYTVRVAAVTSRGIGNWSDSKSITTIKGKVIPPPDIHIDS YGENYLSFTLTMESDIKVNGYVVNLFWAFDTHKQERRTLNFRGSILSHKVGNLTAHTSYEISAWAKTD LGDSPLAFEHVMTRGVRPPAPSLKAKAINQTAVECTWTGPRNVVYGIFYATSFLDLYRNPKSLTTSLHN KTVIVSKDEQYLFLVRVVVPYQGPSSDYVVVKMIPDSRLPPRHLHVVHTGKTSVVIKWESPYDSPDQD LLYAIAVKDLIRKTDRSYKVKSRNSTVEYTLNKLEPGGKYHIIVQLGNMSKDSSIKITTVSLSAPDALKII TENDHVLLFWKSLALKEKHFNESRGYEIHMFDSAMNITAYLGNTTDNFFKISNLKMGHNYTFTVQARC LFGNQICGEPAILLYDELGSGADASATQAARSTDVAAVVVPILFLILLSLGVGFAILYTKHRRLQSSFTAF ANSHYSSRLGSAIFSSGDDLGEDDEDAPMITGFSDDVPMVIA (SEQ ID NO: 27) >Minigene-FANSHY mutant translated aa sequence ELTVYKVQNLQWTADFSGDVTLTWMRPKKMPSASCVYNVYYRVVGESIWKTLETHSNKTNTVLKVL KPDTTYQVKVQVQCLSKAHNTNDFVTLRTPEGLPDAPRNLQLSLPREAEGVIVGHWAPPIHTHGLIREY IVEYSRSGSKMWASQRAASNFTEIKNLLVNTLYTVRVAAVTSRGIGNWSDSKSITTIKGKVIPPPDIHIDS YGENYLSFTLTMESDIKVNGYVVNLFWAFDTHKQERRTLNFRGSILSHKVGNLTAHTSYEISAWAKTD LGDSPLAFEHVMTRGVRPPAPSLKAKAINQTAVECTWTGPRNVVYGIFYATSFLDLYRNPKSLTTSLHN KTVIVSKDEQYLFLVRVVVPYQGPSSDYVVVKMIPDSRLPPRHLHVVHTGKTSVVIKWESPYDSPDQD LLYAIAVKDLIRKTDRSYKVKSRNSTVEYTLNKLEPGGKYHIIVQLGNMSKDSSIKITTVSLSAPDALKII TENDHVLLFWKSLALKEKHFNESRGYEIHMFDSAMNITAYLGNTTDNFFKISNLKMGHNYTFTVQARC LFGNQICGEPAILLYDELGSGADASATQAARSTDVAAVVVPILFLILLSLGVGFAILYTKHRRLQSSFTA AAAAAASSRLGSAIFSSGDDLGEDDEDAPMITGFSDDVPMVIA (SEQ ID NO: 28) [0199] In some embodiments, a SORL1 variant participates in endosomal recycling and either directly or indirectly, decreases the amyloidogenic processing of APP in a cell. In some embodiments, a SORL1 variant mimics the profile of an endosomal enhancer, such that the mini-receptor can be regarded as an endosomal enhancer. In some embodiments, a SORL1 variant has normal or, in other words, wild-type binding affinity for the retromer complex or a subunit thereof. In some embodiments, a SORL1 polypeptide variant has reduced or no binding affinity for the retromer complex or a subunit thereof. [0200] In some embodiments, engineered SORL1 variants increase sAPPα levels and/or activity in a cell, biological sample, or subject. In some embodiments, engineered SORL1 variants increase APP surface expression in a cell, biological sample, or subject. In some embodiments, engineered SORL1 variants decrease levels and/or activity sAPPβ in a cell, biological sample, or subject. In some embodiments, engineered SORL1 variants decrease levels tau aggregation and/or tau phosphorylation in a cell, biological sample, or subject. In some embodiments, engineered SORL1 variants decrease levels and/or activity of amyloid β-peptide species Aβ38, Aβ40, and Aβ42, which are regarded as markers of low endosomal activity, in a cell, biological sample, or subject. In some embodiments, SORL1 variants increase levels and/or activity of SORL1 (e.g., SORL1 encoded by an endogenous gene comprised in the genome of the cell) in a cell, biological sample, or subject. In some embodiments, increasing levels and/or activity of SORL1 (e.g., SORL1 encoded by an endogenous gene comprised in the genome of the cell) in a cell, biological sample, or subject comprises expressing a SORL1 variant that can dimerize with a SORL1 mutant comprising a disease-associated mutation. In some embodiments, SORL1 variants increase VPS26 (e.g., VPS26a and/or VPS26b) levels and/or activity of SORL1 in a cell, biological sample, or subject. In some embodiments, SORL1 variants increase VPS35 levels and/or activity in a cell, biological sample, or subject. In some embodiments, SORL1 variants increase VPS35 levels and/or activity in a cell, biological sample, or subject. In some embodiments, engineered SORL1 variants increase AMPA receptor surface expression in a cell, biological sample, or subject. [0201] In some embodiments, SORL1 variants described herein modulate the activity and/or levels of at least one of sAPPα, APP at the cell surface, AMPA receptor at the cell surface, sAPPβ, tau aggregation, tau phosphorylation, Aβ38, Aβ40, Aβ42, VPS26 (e.g., VPS26a and/or VPS26b) and/or VPS35 relative to a counterpart cell (e.g., a cell lacking an engineered nucleic acid encoding the SORL1 variant, such as a cell comprising one or more mutations associated with a neurological disease) which does not comprise the SORL1 variant. In some embodiments, SORL1 variants described herein increase the activity and/or levels of at least one of sAPPα, APP at the cell surface, AMPA receptor at the cell surface, VPS26 (e.g., VPS26a and/or VPS26b) and/or VPS35 in a cell by at least 1.1 fold. In some embodiments, SORL1 variants described herein increase the activity and/or levels of at least one of sAPPα, APP at the cell surface, AMPA receptor at the cell surface, VPS26 (e.g., VPS26a and/or VPS26b) and/or VPS35 in a cell by at least about 1.25 fold, 1.5 fold, 1.75 fold, 2 fold, 2.5 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, or more. In some embodiments, SORL1 variants described herein increase the activity and/or levels of at least one of sAPPα, APP at the cell surface, AMPA receptor at the cell surface, VPS26 (e.g., VPS26a and/or VPS26b) and/or VPS35 in a cell by at least about 1-2 fold, 2-3 fold, 3-4 fold, 4-5 fold, 5-10 fold, 10-20 fold, or more. In some embodiments, SORL1 variants described herein decrease the activity and/or levels of at least one of sAPPβ, tau aggregation, tau phosphorylation, Aβ38, Aβ40, and/or Aβ42 in a cell by at least 1.1 fold. In some embodiments, SORL1 variants described herein decrease the activity and/or levels of at least one of sAPPβ, tau aggregation, tau phosphorylation, Aβ38, Aβ40, and/or Aβ42 in a cell by at least about 1.25 fold, 1.5 fold, 1.75 fold, 2 fold, 2.5 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, or more. In some embodiments, SORL1 variants described herein decrease the activity and/or levels of at least one of sAPPβ, tau aggregation, tau phosphorylation, Aβ38, Aβ40, and/or Aβ42 in a cell by at least about 1-2 fold, 2-3 fold, 3-4 fold, 4-5 fold, 5-10 fold, 10-20 fold, or more. In some embodiments, SORL1 variants described herein modulate the activity and/or levels of at least one of sAPPα, APP at the cell surface, AMPA receptor at the cell surface, sAPPβ, tau aggregation, tau phosphorylation, Aβ38, Aβ40, Aβ42, VPS26 (e.g., VPS26a and/or VPS26b) and/or VPS35 by modulating the endosomal trafficking in the cell and/or by increasing SORL1 levels and/or SORL1 activity. In some embodiments, the increase in SORL1 levels and/or activity comprises expression of functional SORL1 variants from an engineered nucleic acid. In some embodiments, the increase in SORL1 levels and/or SORL1 activity comprises increasing the expression and/or activity of endogenous SORL1 (e.g., SORL1 which is encoded by a gene located in the genome of the cell, such as a natural SORL1 gene under the control of its natural promoter). In some embodiments, SORL1 variants described herein modulate the activity and/or levels of SORL1 (e.g., a SORL1 variant and/or an endogenous SORL1) by at least 1.1 fold. In some embodiments, SORL1 variants described herein modulate the activity and/or levels of SORL1 (e.g., a SORL1 variant and/or an endogenous SORL1) by at least about 1.25 fold, 1.5 fold, 1.75 fold, 2 fold, 2.5 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, or more. In some embodiments, SORL1 variants described herein modulate the activity and/or levels of SORL1 (e.g., a SORL1 variant and/or an endogenous SORL1) by at least about 1-2 fold, 2-3 fold, 3-4 fold, 4-5 fold, 5-10 fold, 10-20 fold, or more. [0202] Various methods of assessing protein levels are known in the art and will be available to a person of ordinary skill in the art in order to assay SORL1 variants and the downstream effects of said variants. Non-limiting examples of assays for determining protein levels include western blot, flow cytometry, mass spectrometry, and ELISA. Various methods of assessing protein activity will be available to a person of ordinary skill in the art and will be largely dependent on the biological target. For instance, one may assay the localization of a protein by confocal or total internal reflection fluorescence (TIRF) microscopy. Alternatively, one may assay the binding activity of a protein by Förster Resonance Energy Transfer (FRET), mass spectrometry, chemical cross-linking experiments, co-immunoprecipitation, tandem affinity purification, electrophoretic mobility shift (EMSA) assays, enzyme-linked immunosorbent assay (ELISA), or any combination and/or variation thereof. Alternatively, one may assay the levels of post-translational modifications (e.g., hydroxylation, farnesylation, isofarnesylation, lipidation, addition of a linker for conjugation or functionalization, phosphorylation, de-phosphorylation, acetylation, de-acetylation, SUMOylation, glycosylation, nitrosylation, methylation, ubiquitination, cleavage, and degradation) of one or more proteins in a pathway that is related to or dependent on SORL1 using techniques, including, but not limited to, western blot, flow cytometry, mass spectrometry, and ELISA. [0203] In some embodiments, the SORL1 variants form a homodimer as a result of an interaction between their FnIII domains. In some embodiments, the total pool of SORL1 variant polypeptides in a biological sample, cell, or subject are present as dimers. In some embodiments, a fraction of the total pool of SORL1 variant polypeptide in a biological sample, cell, or subject are present as dimers. In some embodiments, 1-10%, 10-20%, 20- 30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 90-99% of the total pool of SORL1 variant polypeptides in a biological sample, cell, or subject are present as dimers. In some embodiments, as few as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the total pool of SORL1variants in a biological sample, cell, or subject are present as dimers. In some embodiments, a dimer comprises two molecules of a SORL1 variant. In some embodiments, a dimer comprises an endogenous SORL1 protein (e.g., a SORL1 molecule encoded by a gene positioned in the genome of a cell, such as a gene encoding a full-length SORL1) and a SORL1 variant. In some embodiments, a dimer comprises a SORL1 variant and endogenous SORL1, wherein the endogenous SORL1 comprises a mutation that is associated with a neurological disease (e.g., a neurodegenerative disease). In some embodiments, dimerization of a SORL1 variant with an endogenous SORL1 comprising a mutation associated with a neurological disease modulates the endosomal trafficking pathways of a cell, such as by modulating the levels and/or activity of sAPPα, APP at the cell surface, AMPA receptor at the cell surface, sAPPβ, tau aggregation, tau phosphorylation, Aβ38, Aβ40, Aβ42, VPS26 (e.g., VPS26a and/or VPS26b) and/or VPS35 levels and/or activity in a cell, biological sample, or subject. In some embodiments, SORL1 variant dimers localize to retromer-coated endosomal structures whereas SORL1 variant monomers reside in different perinuclear compartments of the cell, such as the trans-Golgi network. In some embodiments, SORL1 variant dimers form complexes with the retromer and subunits thereof. In some embodiments, SORL1 variant dimers stabilize the retromer complex in a biological sample, cell, or subject. Further to the SORL1 variants and nucleic acids comprising SORL1 variants, SORL1 mini- receptors have been previously described in WO 2023/275350 A1, published January 5, 2023 and PCT/US2023/083576 which are incorporated by reference herein. Engineered Nucleic Acids and Transgenes Thereof [0204] Aspects of the present disclosure relate to engineered nucleic acids comprising polynucleotide sequences that can be used as gene therapies (e.g., those encoding SORL1 variants, retromer complex subunits, and/or ASOs) and/or gene-editing therapies. [0205] In some embodiments, an engineered nucleic acid comprises one or more components of a gene-editing therapy described herein. In some embodiments, the one or more components can comprise a gRNA or a nucleic acid sequence encoding a gRNA and a nucleic acid sequence encoding a Cas molecule. In some embodiments, the Cas molecule is fused to a deaminase (e.g., a cytosine deaminase, such as a cytosine deaminase fused to a uracil glycosylase inhibitor, an adenosine deaminase, or a guanine deaminase). In some embodiments, the one or more components further comprises a repair template described herein. [0206] In some embodiments, an engineered nucleic acid comprises a SORL1 variant sequence described herein. In some embodiments, a SORL1 variant comprised in an engineered nucleic acid described here is a codon optimized sequence. In some embodiments, an engineered nucleic acid comprising a sequence encoding a SORL1 variant is codon optimized to reduce the number of or completely remove CpG islands. In some embodiments, CpG islands are reduced or removed from a regulatory sequence (e.g., a promoter). In some embodiments, codon optimizing a SORL1 variant sequence comprises removing CpG islands, removing antisense open reading frames, producing a codon optimized version of the sequence which has a similar (e.g., a difference of 10%, 5%, or less) GC content to a wild- type SORL1 or a SORL1 variant with a wildtype FANSHY motif described herein, or any combination thereof. In some embodiments, codon optimizing a SORL1 variant further comprises introducing changes to the SORL1 sequence which avoids the introduction of cryptic splice sites and/or promoters or promoter-like elements. [0207] In some embodiments, an engineered nucleic acid comprises a sequence encoding a retromer complex subunit. An exemplary VPS26a coding sequence is set forth in SEQ ID NO: 128 below. An exemplary VPS26b coding sequence is set forth in SEQ ID NO: 129 below. An exemplary VPS35 coding sequence is set forth in SEQ ID NO: 130 below. > VPS26a coding sequence ATGAGTTTTCTTGGAGGCTTTTTTGGTCCAATTTGTGAGATCGATATTGTTCTTAATGATGGGGAAA CCAGGAAAATGGCAGAAATGAAAACTGAAGATGGCAAAGTAGAAAAACACTATCTCTTCTATGAC GGAGAATCCGTTTCAGGAAAGGTAAACCTAGCCTTTAAGCAACCTGGAAAGAGGCTAGAACACCA AGGAATTAGAATTGAATTTGTAGGTCAAATTGAACTTTTCAATGACAAGAGTAATACTCATGAATT TGTAAACCTAGTGAAAGAACTAGCCTTACCTGGAGAACTGACTCAGAGCAGAAGTTATGATTTTG AATTTATGCAAGTTGAAAAGCCATATGAATCTTACATCGGTGCCAATGTCCGCTTGAGGTATTTTC TTAAAGTGACAATAGTGAGAAGACTGACAGATTTGGTAAAAGAGTATGATCTTATTGTTCACCAG CTTGCCACCTATCCTGATGTTAACAACTCTATTAAGATGGAAGTGGGCATTGAAGATTGTCTACAT ATAGAATTTGAATATAATAAATCAAAGTATCATTTAAAGGATGTGATTGTTGGAAAAATTTACTTC TTATTAGTAAGAATAAAAATACAACATATGGAGTTACAGCTGATCAAAAAAGAGATCACAGGAAT TGGACCCAGTACCACAACAGAAACAGAAACAATCGCCAAATATGAAATAATGGATGGTGCACCA GTAAAAGGTGAATCAATTCCAATAAGGCTATTTTTAGCAGGATATGACCCAACTCCAACAATGAG AGATGTGAACAAAAAATTTTCAGTAAGGTACTTTTTGAATTTAGTGCTTGTTGATGAGGAAGACCG GAGGTACTTCAAACAGCAGGAGATAATTTTATGGAGAAAAGCTCCTGAAAAACTGAGGAAACAG AGAACAAACTTTCACCAGCGATTTGAATCTCCAGAATCACAGGCATCTGCCGAACAGCCTGAAAT GTGA (SEQ ID NO: 128) > VPS26b coding sequence ATGAGCTTCTTCGGCTTCGGGCAGAGCGTGGAGGTGGAAATCCTTCTGAACGATGCAGAGAGTAG GAAGCGGGCCGAGCACAAGACGGAGGACGGGAAGAAGGAGAAATATTTCCTCTTCTACGACGGG GAGACGGTCTCCGGGAAGGTGAGCCTTGCCCTCAAGAACCCCAACAAGCGGCTGGAGCACCAGGG CATCAAGATCGAGTTCATCGGGCAGATCGAACTCTACTACGATCGCGGGAACCACCATGAGTTTGT GTCCCTGGTGAAGGACCTGGCCCGGCCTGGAGAGATCACCCAGTCGCAGGCCTTCGACTTTGAGTT TACCCACGTGGAGAAGCCGTATGAGTCCTACACAGGGCAGAATGTGAAGCTACGCTATTTCCTTCG TGCTACCATCAGCCGCCGCCTCAATGATGTTGTCAAAGAGATGGACATTGTAGTTCACACACTCAG CACATACCCAGAGCTGAACTCTTCCATCAAGATGGAGGTTGGGATTGAGGACTGTCTGCACATTGA ATTTGAGTACAATAAATCCAAATACCACTTGAAAGATGTCATTGTAGGGAAGATATACTTCCTGCT GGTGAGAATCAAAATCAAGCACATGGAGATAGACATCATCAAGCGAGAAACGACGGGTACAGGC CCCAACGTGTACCATGAGAATGACACGATAGCCAAGTACGAGATCATGGACGGGGCACCAGTGCG AGGAGAGTCCATCCCGATCCGGCTCTTCCTGGCCGGGTATGAGCTCACGCCCACCATGCGGGACAT CAACAAGAAGTTCTCTGTGCGCTATTACCTCAACCTGGTGCTGATAGACGAGGAGGAGCGGCGCT ACTTCAAGCAGCAGGAAGTGGTGTTGTGGCGGAAGGGTGACATCGTACGGAAGAGCATGTCCCAC CAGGCGGCCATCGCCTCACAGCGCTTTGAGGGCACCACCTCCCTGGGTGAGGTGCGGACCCCCAG CCAGCTGTCTGACAACAACTGCAGGCAGTAG (SEQ ID NO: 129) > VPS35 coding sequence ATGCCTACAACACAGCAGTCCCCTCAGGATGAGCAGGAAAAGCTCTTGGATGAAGCCATACAGGC TGTGAAGGTCCAGTCATTCCAAATGAAGAGATGCCTGGACAAAAACAAGCTTATGGATGCTCTAA AACATGCTTCTAATATGCTTGGTGAACTCCGGACTTCTATGTTATCACCAAAGAGTTACTATGAAC TTTATATGGCCATTTCTGATGAACTGCACTACTTGGAGGTCTACCTGACAGATGAGTTTGCTAAAG GAAGGAAAGTGGCAGATCTCTACGAACTTGTACAGTATGCTGGAAACATTATCCCAAGGCTTTAC CTTTTGATCACAGTTGGAGTTGTATATGTCAAGTCATTTCCTCAGTCCAGGAAGGATATTTTGAAA GATTTGGTAGAAATGTGCCGTGGTGTGCAACATCCCTTGAGGGGTCTGTTTCTTCGAAATTACCTT CTTCAGTGTACCAGAAATATCTTACCTGATGAAGGAGAGCCAACAGATGAAGAAACAACTGGTGA CATCAGTGATTCCATGGATTTTGTACTGCTCAACTTTGCAGAAATGAACAAGCTCTGGGTGCGAAT GCAGCATCAGGGACATAGCCGAGATAGAGAAAAAAGAGAACGAGAAAGACAAGAACTGAGAATT TTAGTGGGAACAAATTTGGTGCGCCTCAGTCAGTTGGAAGGTGTAAATGTGGAACGTTACAAACA GATTGTTTTGACTGGCATATTGGAGCAAGTTGTAAACTGTAGGGATGCTTTGGCTCAAGAATATCT CATGGAGTGTATTATTCAGGTTTTCCCTGATGAATTTCACCTCCAGACTTTGAATCCTTTTCTTCGG GCCTGTGCTGAGTTACACCAGAATGTAAATGTGAAGAACATAATCATTGCTTTAATTGATAGATTA GCTTTATTTGCTCACCGTGAAGATGGACCTGGAATCCCAGCGGATATTAAACTTTTTGATATATTTT CACAGCAGGTGGCTACAGTGATACAGTCTAGACAAGACATGCCTTCAGAGGATGTTGTATCTTTAC AAGTCTCTCTGATTAATCTTGCCATGAAATGTTACCCTGATCGTGTGGACTATGTTGATAAAGTTCT AGAAACAACAGTGGAGATATTCAATAAGCTCAACCTTGAACATATTGCTACCAGTAGTGCAGTTTC AAAGGAACTCACCAGACTTTTGAAAATACCAGTTGACACTTACAACAATATTTTAACAGTCTTGAA ATTAAAACATTTTCACCCACTCTTTGAGTACTTTGACTACGAGTCCAGAAAGAGCATGAGTTGTTA TGTGCTTAGTAATGTTCTGGATTATAACACAGAAATTGTCTCTCAAGACCAGGTGGATTCCATAAT GAATTTGGTATCCACGTTGATTCAAGATCAGCCAGATCAACCTGTAGAAGACCCTGATCCAGAAG ATTTTGCTGATGAGCAGAGCCTTGTGGGCCGCTTCATTCATCTGCTGCGCTCTGAGGACCCTGACC AGCAGTACTTGATTTTGAACACAGCACGAAAACATTTTGGAGCTGGTGGAAATCAGCGGATTCGC TTCACACTGCCACCTTTGGTATTTGCAGCTTACCAGCTGGCTTTTCGATATAAAGAGAATTCTAAA GTGGATGACAAATGGGAAAAGAAATGCCAGAAGATTTTTTCATTTGCCCACCAGACTATCAGTGC TTTGATCAAAGCAGAGCTGGCAGAATTGCCCTTAAGACTTTTTCTTCAAGGAGCACTAGCTGCTGG GGAAATTGGTTTTGAAAATCATGAGACAGTCGCATATGAATTCATGTCCCAGGCATTTTCTCTGTA TGAAGATGAAATCAGCGATTCCAAAGCACAGCTAGCTGCCATCACCTTGATCATTGGCACTTTTGA AAGGATGAAGTGCTTCAGTGAAGAGAATCACGAACCTCTGAGGACTCAGTGTGCCCTTGCTGCAT CCAAACTTCTAAAGAAACCTGATCAGGGCCGAGCTGTGAGCACCTGTGCACATCTCTTCTGGTCTG GCAGAAACACGGACAAAAATGGGGAGGAGCTTCACGGAGGCAAGAGGGTAATGGAGTGCCTAAA AAAAGCTCTAAAAATAGCAAATCAGTGCATGGACCCCTCTCTACAAGTGCAGCTTTTTATAGAAAT TCTGAACAGATATATCTATTTTTATGAAAAGGAAAATGATGCGGTAACAATTCAGGTTTTAAACCA GCTTATCCAAAAGATTCGAGAAGACCTCCCGAATCTTGAATCCAGTGAAGAAACAGAGCAGATTA ACAAACATTTTCATAACACACTGGAGCATTTGCGCTTGCGGCGGGAATCACCAGAATCCGAGGGG CCAATTTATGAAGGTCTCATCCTTTAA (SEQ ID NO: 130) [0208] In some embodiments, an engineered nucleic acid encodes a retromer subunit comprising the amino acid sequence set forth in any one of SEQ ID NOs: 131-133 as shown below. > VPS26a MSFLGGFFGPICEIDIVLNDGETRKMAEMKTEDGKVEKHYLFYDGESVSGKVNLAFKQPGKRLEHQGI RIEFVGQIELFNDKSNTHEFVNLVKELALPGELTQSRSYDFEFMQVEKPYESYIGANVRLRYFLKVTIVR RLTDLVKEYDLIVHQLATYPDVNNSIKMEVGIEDCLHIEFEYNKSKYHLKDVIVGKIYFLLVRIKIQHME LQLIKKEITGIGPSTTTETETIAKYEIMDGAPVKGESIPIRLFLAGYDPTPTMRDVNKKFSVRYFLNLVLV DEEDRRYFKQQEIILWRKAPEKLRKQRTNFHQRFESPESQASAEQPEM (SEQ ID NO: 131) > VPS26b MSFFGFGQSVEVEILLNDAESRKRAEHKTEDGKKEKYFLFYDGETVSGKVSLALKNPNKRLEHQGIKIE FIGQIELYYDRGNHHEFVSLVKDLARPGEITQSQAFDFEFTHVEKPYESYTGQNVKLRYFLRATISRRLN DVVKEMDIVVHTLSTYPELNSSIKMEVGIEDCLHIEFEYNKSKYHLKDVIVGKIYFLLVRIKIKHMEIDII KRETTGTGPNVYHENDTIAKYEIMDGAPVRGESIPIRLFLAGYELTPTMRDINKKFSVRYYLNLVLIDEE ERRYFKQQEVVLWRKGDIVRKSMSHQAAIASQRFEGTTSLGEVRTPSQLSDNNCRQ (SEQ ID NO: 132) > VPS35 MPTTQQSPQDEQEKLLDEAIQAVKVQSFQMKRCLDKNKLMDALKHASNMLGELRTSMLSPKSYYEL YMAISDELHYLEVYLTDEFAKGRKVADLYELVQYAGNIIPRLYLLITVGVVYVKSFPQSRKDILKDLVE MCRGVQHPLRGLFLRNYLLQCTRNILPDEGEPTDEETTGDISDSMDFVLLNFAEMNKLWVRMQHQGH SRDREKRERERQELRILVGTNLVRLSQLEGVNVERYKQIVLTGILEQVVNCRDALAQEYLMECIIQVFP DEFHLQTLNPFLRACAELHQNVNVKNIIIALIDRLALFAHREDGPGIPADIKLFDIFSQQVATVIQSRQDM PSEDVVSLQVSLINLAMKCYPDRVDYVDKVLETTVEIFNKLNLEHIATSSAVSKELTRLLKIPVDTYNNI LTVLKLKHFHPLFEYFDYESRKSMSCYVLSNVLDYNTEIVSQDQVDSIMNLVSTLIQDQPDQPVEDPDP EDFADEQSLVGRFIHLLRSEDPDQQYLILNTARKHFGAGGNQRIRFTLPPLVFAAYQLAFRYKENSKVD DKWEKKCQKIFSFAHQTISALIKAELAELPLRLFLQGALAAGEIGFENHETVAYEFMSQAFSLYEDEISD SKAQLAAITLIIGTFERMKCFSEENHEPLRTQCALAASKLLKKPDQGRAVSTCAHLFWSGRNTDKNGEE LHGGKRVMECLKKALKIANQCMDPSLQVQLFIEILNRYIYFYEKENDAVTIQVLNQLIQKIREDLPNLES SEETEQINKHFHNTLEHLRLRRESPESEGPIYEGLIL (SEQ ID NO: 133) [0209] Administration of an engineered nucleic acid encoding a retromer subunit to a subject have been previously described (see, e.g., WO 2021/163681 A2, published August 19, 2021, which is incorporated by reference herein for disclosures related to engineered nucleic acids encoding retromer subunits and methods of administering engineered nucleic acids to a subject). [0210] In some embodiments, engineered nucleic acids (e.g., those encoding a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) can be a component of a transgene. Typically, a transgene, such as one comprised in a lentivirus or rAAV described herein, will be comprise sequences for expression of a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) and will be designed to have an overall size that can be packaged into a recombinant virus (e.g., a lentivus or rAAV). A transgene comprising a sequence encoding a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) can include or can be modified to include one or more regulatory sequences, including, but not limited to, transcription regulatory sequences (e.g., promoter, enhancer, silencer, transcription factor binding sequence, 5' UTR, or 3' UTR), post-transcriptional regulatory sequences (e.g., acceptor/donor splicing sites and splicing regulatory sequences), and/or translation regulatory sequences (e.g., translation initiation signals, translation termination signals, mRNA degradation or decay signals, polyadenylation signals) (see, e.g., Tables 4 and 5). [0211] A sequence encoding a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, such as those comprised in a transgene) can be introduced into another nucleic acid using recombinant DNA techniques. In some embodiments, a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, such as those comprised in a transgene) can be introduced into a vector. In some embodiments, a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, such as those comprised in a transgene) can be introduced into the genome of another organism or infectious agent. [0212] In some embodiments, the SORL1 variant transgene comprises a polynucleotide having at least 70%, at least 75%, at least 80%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% sequence identity, relative to a nucleic acid sequence as set forth in any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43-59. In some embodiments, the SORL1 variant transgene comprises a polynucleotide comprising a nucleic acid sequence as set forth in any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43-59. [0213] In some embodiments, an engineered nucleic acid comprising a SORL1 variant comprises one or more nucleic acid sequences set forth in Table 4. Table 4. Examples of Nucleic Acid Sequences corresponding to SORL1 variants.

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ıIJĸ CTGATATCGAGCTTGCTACAAGGGACTTTCCGCTGGGGACTTTCCAGGGAGGCGT GGCCTGGGCGGGACTGGGGAGTGGCGAGCCCTCAGATCCTGCATATAAGCAGCT GCTTTTTGCCTGTACTGGGTCTCTCTGGTTAGACCAGATCTGAGCCTGGGAGCTCT CTGGCTAACTAGGGAACCCACTGCTTAAGCCTCAATAAAGCTTGCCTTGAGTGCT TCAAGTAGTGTGTGCCCGTCTGTTGTGTGACTCTGGTAACTAGAGATCCCTCAGA CCCTTTTAGTCAGTGTGGAAAATCTCTAGCAGTAGTAGTTCATGTCATCTTATTAT TCAGTATTTATAACTTGCAAAGAAATGAATATCAGAGAGTGAGAGGCCTTGACAT TGCTAGCGTTTACCGTCGACCTCTAGCTAGAGCTTGGCGTAATCATGGTCATAGCT GTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGA AGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTG CGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTA ATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCT TCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAG CTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAACGCAGGAA AGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCG TTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGAC GCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTC CCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATAC CTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAG GTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCC CCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCC GGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAG AGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGC TACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCG GAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTG GTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGA TCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAA GGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTA AAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGT TACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATC CATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCA TCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATT TATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAA CTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGT TCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTC ACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGA GTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGAT CGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTG CATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTA CTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCG GCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCA TTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATC CAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCA CCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAA TAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGA AGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAA AAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTGACGTC GACGGATCGGGAGATCAACTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGC AATAGCATCACAAATTTCACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTGG TTTGTCCAAACTCATCAATGTATCTTATCATGTCTGGATCAACTGGATAACTCAAG CTAACCAAAATCATCCCAAACTTCCCACCCCATACCCTATTACCACTGCCAATTAC CTGTGGTTTCATTTACTCTAAACCTGTGATTCCTCTGAATTATTTTCATTTTAAAGA AATTGTATTTGTTAAATATGTACTACAAACTTAGTAGT (SEQ ID NO: 32) >pAAV CAG ggggggggggggggggggttggccactccctctctgcgcgctcgctcgctcactgaggccgggcgaccaaaggtcgcccgacgc HA-Sorl1mini ccgggctttgcccgggcggcctcagtgagcgagcgagcgcgcagagagggagtggccaactccatcactaggggttcctagatctg WPRE3 (2.1) aattccgttacataacttacggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttccc atagtaacgccaatagggactttccattgacgtcaatgggtggactatttacggtaaactgcccacttggcagtacatcaagtgtatcatat gccaagtacgccccctattgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggactttcctacttgg cagtacatctacgtattagtcatcgctattaccatggtcgaggtgagccccacgttctgcttcactctccccatctcccccccctccccacc

[0214] In some embodiments, an engineered nucleic acid comprises a nucleotide sequence which is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43- 59. In some embodiments, an engineered nucleic acid comprises a nucleotide sequence of any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43-59. [0215] Accordingly, it should be recognized that, while examples of engineered nucleic acids are described herein (e.g., see SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43- 59), any nucleic acid (e.g., an engineered nucleic acid encoding a therapeutic agent, such as a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) for delivering and/or expressing a therapeutic agent (e.g., a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) in a cell, biological sample, or subject is provided by the present disclosure. In some embodiments, such a nucleic may comprise a substitution, addition, and/or deletion of at least one nucleotide relative to any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43-59. In some embodiments, such a nucleic acid may comprise a plurality (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 10-20, 20-30, 30-40, 40-50, 50-100, 100-250, 250-500, 500-1000, 1000-2000, 2000-3000, 3000-4000, etc.) of nucleotide positions which differ relative to any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43-59. In some embodiments, such a nucleic acid may comprise at least 75% or more (e.g., 80-85%, 85-90%, 90-95%, 95%, 96%, 97%, 98%, or 99%) sequence identity to any one of SEQ ID NOs1-12, 25-26, 29-32, 35-37, or 43-59, such that the nucleic acid comprises a sequence encoding: a SORL1 variant; at least one regulatory sequence; and/or one or more additional sequences (e.g., AAV ITRs, lentivirus LTRs, etc.) described herein. [0216] As a non-limiting example, in some embodiments, a nucleic acid may comprise at least 75% identity to SEQ ID NO: 29 in that it comprises the same SORL1 variant sequence but does not comprise one or more sequences (e.g., a regulatory sequence, vector backbone sequence, etc.) therein, such as one or more of the LTRs, an HIV-1 psi (^) packaging sequence, a rev response element (RRE), a central polypurine tract with a downstream central termination sequence (cPPT/CTS), a CAG promoter, an Ig-kappa leader sequence, a Woodchuck post-transcriptional regulatory element (WPRE), a second lentivirus LTR, an M13 rev sequence, a lac operator, a lac promoter, a CAP binding site, an origin of replication (ori), an ampicillin resistance (AmpR) gene, an AmpR promoter, and/or a SV40 poly(A) signal. As a further non-limiting example, in some embodiments, a nucleic acid may comprise at least 75% identity to SEQ ID NO: 31 in that it comprises the same SORL1 variant sequence but does not comprise one or more of the sequences therein, such as the AAV ITRs, a CAG promoter, an Ig-kappa leader sequence, a transgene comprising a polynucleotide encoding a SORL1 variant, a Woodchuck post-transcriptional regulatory element 3 (WPRE3), a bovine growth hormone (bGH) polyA signal, a second AAV ITR, an origin of replication (ori), a neomycin/kanamycin resistance gene, an ampicillin resistance (AmpR) gene promoter, and/or a f1 ori. In some embodiments, generating a nucleic acid comprising at least 75% identity to a sequence described herein (e.g., any one of SEQ ID NOs: 29-32, 35-37, or 43-59) comprises substituting a regulatory sequence (e.g., a promoter, enhancer, polyA signal, etc., see, e.g., Table 5), lentivirus LTRs or AAV ITRs (e.g., for those of a different viral serotype), a different SORL1 coding sequence (e.g., a different SORL1 variant), and/or adding or removing a C- or N-terminal tag or linker encoded SORL1 variant sequence, such as by selecting from the non-limiting examples of nucleic acids described herein or those known in the art. Regulatory Sequences [0217] Aspects of the present disclosure relate to engineered nucleic acids comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a SORL1 mini-receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) that may be engineered to comprise one or more regulatory sequences to which the sequence encoding the therapeutic agent is operably linked. [0218] A regulatory sequence can be a transcription regulatory sequence (e.g., a promoter, an enhancer, a transcription factor binding sequence, a transcriptional start sequence, transcription termination sequence, etc.), a translation regulatory sequence (e.g., a 5’ UTR, a translation initiation regulatory sequence, a Kozack sequence, a Shine-Dalgarno sequence, a start codon, a ribosome binding site, a 3’ UTR, a translation termination sequence, a stop codon, etc.), or a splicing regulatory sequence (e.g., binding sites for small nuclear ribonucleoproteins, splicing acceptor sites, splicing donor sites, etc.). [0219] In some embodiments, engineered nucleic acids comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a SORL1 mini-receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including transgenes or vectors thereof) may comprise constitutive promoters which maintain constant expression of a gene regardless of the conditions or physiological state of a cell. Examples of constitutive promoters include, without limitation, the retroviral Rous sarcoma virus (RSV) LTR promoter (optionally with the RSV enhancer), the cytomegalovirus (CMV) promoter (optionally with the CMV enhancer) (see, e.g., Boshart et al., Cell, 41:521-530 (1985)), the SV40 promoter, the dihydrofolate reductase promoter, the β-actin promoter, the phosphoglycerol kinase (PGK) promoter, the CAG promoter, and the human elongation factor-1 alpha (EF1α) promoter [Invitrogen]. In some embodiments, the promoter is an RNA pol II promoter. In some embodiments, the promoter is an RNA pol III promoter, such as U6 or H1. In some embodiments, a promoter is an RNA pol II promoter. In some embodiments, the promoter comprises a CMV enhancer (CMVe, see, e.g., SEQ ID NO: 47), such as a CAG promoter (see, e.g., SEQ ID NO: 46). In some embodiments, the promoter is a chicken β- actin (CBA) promoter. In some embodiments, the promoter is a CMVe and a CBA promoter, such as, for example, one that corresponds to the sequence set forth in SEQ ID NOs: 46-48. In some embodiments, a promoter is a CAG promoter, such as, for example, one of the sequences set forth in SEQ ID NO: 46. [0220] In some embodiments, engineered nucleic acids comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a SORL1 mini-receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including transgenes and vectors thereof) may comprise inducible promoters. Inducible promoters allow regulation of gene expression and can be regulated by exogenously supplied compounds, environmental factors, such as temperature, or the presence of a specific physiological state. Inducible promoters and inducible systems are available from a variety of commercial sources, including, without limitation, Invitrogen, Clontech, and Ariad. Many other systems have been described and can be readily selected by one of skill in the art. Examples of inducible promoters regulated by exogenously supplied promoters include the zinc-inducible sheep metallothionine (MT) promoter, the dexamethasone (Dex)-inducible mouse mammary tumor virus (MMTV) promoter, the T7 polymerase promoter system (WO 98/10088); the ecdysone insect promoter (No et al., Proc. Natl. Acad. Sci. USA, 93:3346- 3351 (1996)), the tetracycline-repressible system (Gossen et al., Proc. Natl. Acad. Sci. USA, 89:5547-5551 (1992)), the tetracycline-inducible system (Gossen et al., Science, 268:1766- 1769 (1995), see also Harvey et al., Curr. Opin. Chem. Biol., 2:512-518 (1998)), the RU486- inducible system (Wang et al., Nat. Biotech., 15:239-243 (1997) and Wang et al., Gene Ther., 4:432-441 (1997)) and the rapamycin-inducible system (Magari et al., J. Clin. Invest., 100:2865-2872 (1997)). Still other types of inducible promoters which may be useful in this context are those which are regulated by a specific physiological state. [0221] In some embodiments, the native promoter for the SORL1 variant transgene will be used (e.g., the SORL1 native promoter). In some embodiments, the native promoter for retromer complex subunit will be used. The native promoter may be preferred when it is desired that expression of the SORL1 variant or retromer complex subunit should mimic the native expression. The native promoter may be used when expression of the SORL1 variant or retromer complex subunit must be regulated temporally, developmentally, in a tissue- specific manner, or in response to specific transcriptional stimuli. In a further embodiment, other native expression control elements, such as enhancer elements, polyadenylation sites or Kozak consensus sequences may also be used to mimic the native expression. [0222] In some embodiments, the promoter of a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a SORL1 mini-receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including transgenes thereof) imparts tissue-specific gene expression capabilities. In some cases, the tissue-specific regulatory sequences bind tissue-specific transcription factors that induce transcription in a tissue specific manner. Such tissue-specific regulatory sequences (e.g., promoters, enhancers, etc.) are well known in the art. Exemplary tissue-specific regulatory sequences include, but are not limited to the following tissue specific promoters: a neuron-specific promoter, retinoschisin proximal promoter, interphotoreceptor retinoid-binding protein enhancer (RS/IRBPa), rhodopsin kinase (RK), liver-specific thyroxin binding globulin (TBG) promoter, an trypsin promoter, a glucagon promoter, a somatostatin promoter, a pancreatic polypeptide (PPY) promoter, a synapsin-1 (Syn) promoter, a creatine kinase (MCK) promoter, a mammalian desmin (DES) promoter, a α-myosin heavy chain (α-MHC) promoter, or a cardiac Troponin T (cTnT) promoter. Other exemplary promoters include Beta-actin promoter, hepatitis B virus core promoter, Sandig et al., Gene Ther., 3:1002-9 (1996); alpha-fetoprotein (AFP) promoter, Arbuthnot et al., Hum. Gene Ther., 7:1503-14 (1996)), bone osteocalcin promoter (Stein et al., Mol. Biol. Rep., 24:185-96 (1997)); bone sialoprotein promoter (Chen et al., J. Bone Miner. Res., 11:654-64 (1996)), CD2 promoter (Hansal et al., J. Immunol., 161:1063-8 (1998); immunoglobulin heavy chain promoter; T cell receptor α-chain promoter, neuronal such as neuron-specific enolase (NSE) promoter (Andersen et al., Cell. Mol. Neurobiol., 13:503-15 (1993)), neurofilament light-chain gene promoter (Piccioli et al., Proc. Natl. Acad. Sci. USA, 88:5611-5 (1991)), and the neuron- specific vgf gene promoter (Piccioli et al., Neuron, 15:373-84 (1995)), among others which will be apparent to the skilled artisan. [0223] Other examples of promoters which may be operably linked to a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a SORL1 mini-receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) described herein include a BDNF promoter, an NGF promoter, an EGF promoter, a growth factor promoter, an axon-specific promoter, a dendrite-specific promoter, a brain-specific promoter, a hippocampal-specific promoter, a kidney-specific promoter, an elafin promoter, a cytokine promoter, an interferon promoter, an α1 antitrypsin promoter, a brain cell-specific promoter, a neural cell-specific promoter, a central nervous system cell-specific promoter, a peripheral nervous system cell-specific promoter, an interleukin promoter, a serpin promoter, a hybrid CMV promoter, a hybrid β-actin promoter, an EF1 promoter, a U1a promoter, a U1b promoter, a Tet-inducible promoter, a VP16 LexA promoter, or a mammalian or avian β- actin promoter. [0224] In some embodiments, the promoter operably linked to a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a SORL1 mini-receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including transgenes thereof) further comprises an exonic sequence. In some embodiments, a promoter further comprises an intronic sequence. In some embodiments, a promoter further comprises a chicken beta-actin intron and/or an artificial intron. In some embodiments, a promoter further comprises a chimeric intron. In some embodiments, a promoter further comprises an intron set forth in SEQ ID NO: 58. In some embodiments, a promoter does not comprise an exonic sequence and/or an intronic sequence. [0225] In some embodiments, a polyadenylation (poly(A)) sequence or poly(A) signal which is inserted following the polynucleotide encoding a therapeutic agent sequence(s) (e.g., a biologic, a SORL1 variant, such as a SORL1 mini-receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including transgenes thereof) and before any other 3’ regulatory sequence (e.g., a 3’ AAV ITR or lentiviral LTR sequence, transcription termination site, etc.). In some embodiments, a poly(A) signal or poly(A) sequence is inserted following the transgene coding sequence(s) and before any other 3' regulatory sequence (e.g., a 3' AAV ITR or lentiviral LTR sequence), which signals for the polyadenylation of transcribed mRNA molecules. In some embodiments, the poly(A) signal or poly(A) sequence is heterologous (e.g., a naturally occurring poly(A) signal or sequence that is not a naturally occurring SORL1 or retromer complex subunit poly(A) signal or sequence). In some embodiments, a poly(A) sequence or poly(A) signal is a synthetic poly(A) sequence or poly(A) signal (e.g., a non- naturally occurring poly(A) sequence that is, e.g., 20-100 nucleotides long). Examples of poly(A) signal sequences include, but are not limited to, bovine growth hormone (bGH) poly(A) signal sequence, SV-40 poly(A) signal sequence, and synthetic poly(A) signal sequences, which are known to cause polyadenylation of eukaryotic transgenes and efficient termination of translation (Azzoni A R et al., J Gene Med.2007; 9(5):392-402). [0226] For nucleic acids encoding proteins (e.g., SORL1 variants, retromer complex subunits, or a Cas molecule), a sequence that enhances transgene expression may further be inserted following the coding sequence(s) and before the 3' AAV ITR or lentiviral LTR and poly(A) signal sequences. An exemplary sequence includes, but is not limited to, a woodchuck hepatitis virus (WHV) post-transcriptional regulatory element (WPRE) (Higashimoto T et al., Gene Ther.2007; 14(17):1298-304). In some embodiments, the WPRE is a polynucleotide having at least 70%, at least 75%, at least 80%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% sequence identity, relative to a nucleic acid sequence as set forth in any one of SEQ ID NOs: 51 or 53. In some embodiments, the WPRE is set forth in any one of SEQ ID NOs: 51 or 53. In some embodiments, a WPRE is a WPRE variant. In some embodiments, a WPRE comprises between 1 and 20, 5 and 10, 2 and 15, 10 and 30, or 20 and 100 nucleotide substitutions, insertions, or deletions relative to a wild type WPRE. A WPRE variant may comprise one or more nucleotide substitutions, insertions, or deletions that reduce expression of a WHV-X protein encoded by the WPRE. In some embodiments, the WPRE is WPRE3 (see, e.g., SEQ ID NO: 53). [0227] In some embodiments, engineered nucleic acids comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a SORL1 mini-receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including transgenes thereof, including transgenes thereof) further comprises one or more (e.g., 1, 2, 3, etc.) introns. In some embodiments, an intron is included in the promoter, for example, a CAG promoter (see, e.g., SEQ ID NO: 46) or chicken beta-actin promoter (see, e.g., SEQ ID NO: 48). In some embodiments, an intron is included in the poly(A) signal sequence. In some embodiments, an intron is included in the coding sequence of a transgene. [0228] In some embodiments, engineered nucleic acids comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a SORL1 mini-receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including transgenes thereof) comprises one or more regulatory sequences set forth in Table 5. Table 5. Examples of Regulatory Sequences

Expression Vectors [0229] Aspects of the present disclosure relate to vectors for the expression of a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a SORL1 mini-receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including transgenes thereof). In some embodiments, the engineered nucleic acid encoding a of a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a SORL1 mini-receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including transgenes thereof) is provided to a cell and expressed from a vector. [0230] In some embodiments, a vector comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a nucleic acid encoding a SORL1 mini-receptor, a nucleic acid encoding a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including transgenes thereof) can be maintained in high levels in a cell using a selection method, such as one involving an antibiotic resistance gene. In some embodiments, a vector comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a SORL1 mini-receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including transgenes thereof) can comprise a partitioning sequence which ensures stable inheritance of the vector. In some embodiments, a vector comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a SORL1 mini-receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including transgenes thereof) is a high copy number vector. In some embodiments, a vector comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a SORL1 mini-receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including transgenes thereof) becomes integrated into the genome of a cell. In some embodiments, a vector is provided as a recombinant viral genome. In some embodiments, a recombinant viral genome within a virus particle is the vector comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a SORL1 mini-receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including transgenes thereof) as provided herein. In some embodiments, a recombinant viral genome within a lentiviral particle is a vector comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a SORL1 mini- receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including transgenes thereof). In some embodiments, a recombinant viral genome within a recombinant adeno-associated viral particle is a vector comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a SORL1 mini-receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including transgenes thereof). [0231] A transgene comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a SORL1 mini-receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) can be provided in virtually any lentiviral vector. In some embodiments, a transgene comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, such as a SORL1 mini-receptor, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) is provided in a lentiviral vector, wherein the transgene is flanked by LTRs. In some embodiments, the lentiviral vector comprising a a SORL1 variant, such as a sequence encoding a SORL1 mini-receptor, comprises from 5′ to 3′: a first LTR, an HIV-1 psi (^) packaging sequence, a rev response element (RRE), a central polypurine tract with a downstream central termination sequence (cPPT/CTS), a CAG promoter comprising the CMV enhancer, the chicken beta-actin promoter and the chimeric intron, an Ig-kappa leader sequence, a transgene comprising the SORL1 variant, the WPRE, a second LTR, an M13 rev sequence, a lac operator, a lac promoter, a CAP binding site, an origin of replication (ori), an ampicillin resistance gene, an AmpR promoter, and the SV40 poly(A) signal. In some embodiments, the lentiviral vector comprising a SORL1 variant comprises from 5′ to 3′: a first LTR, an HIV-1 psi (^) packaging sequence, a rev response element (RRE), a central polypurine tract with a downstream central termination sequence (cPPT/CTS), a CAG promoter comprising the CMV enhancer, the chicken beta-actin promoter and the chimeric intron, an Ig-kappa leader sequence, a transgene comprising the SORL1 variant (e.g., one encoding a SORL1 variant further comprising the three N-terminal FLAG tags), the WPRE, a second LTR, an M13 rev sequence, a lac operator, a lac promoter, a CAP binding site, an origin of replication (ori), an ampicillin resistance gene, an AmpR promoter, and the SV40 poly(A) signal. [0232] In some embodiments, a lentiviral vector comprises a sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 29, 32, 35-37, 43-55, or 58-59. Further non-limiting examples of lentiviral vectors comprising a SORL1 variant are provided below: > LV-CAG-IG(Kappa)-3xFlag Sorl1mini-WPRE (1) TGGAAGGGCTAATTCACTCCCAAAGAAGACAAGATATCCTTGATCTGTGGATCTACCACACACAA GGCTACTTCCCTGATTAGCAGAACTACACACCAGGGCCAGGGGTCAGATATCCACTGACCTTTGGA TGGTGCTACAAGCTAGTACCAGTTGAGCCAGATAAGGTAGAAGAGGCCAATAAAGGAGAGAACA CCAGCTTGTTACACCCTGTGAGCCTGCATGGGATGGATGACCCGGAGAGAGAAGTGTTAGAGTGG AGGTTTGACAGCCGCCTAGCATTTCATCACGTGGCCCGAGAGCTGCATCCGGAGTACTTCAAGAAC TGCTGATATCGAGCTTGCTACAAGGGACTTTCCGCTGGGGACTTTCCAGGGAGGCGTGGCCTGGGC GGGACTGGGGAGTGGCGAGCCCTCAGATCCTGCATATAAGCAGCTGCTTTTTGCCTGTACTGGGTC TCTCTGGTTAGACCAGATCTGAGCCTGGGAGCTCTCTGGCTAACTAGGGAACCCACTGCTTAAGCC TCAATAAAGCTTGCCTTGAGTGCTTCAAGTAGTGTGTGCCCGTCTGTTGTGTGACTCTGGTAACTA GAGATCCCTCAGACCCTTTTAGTCAGTGTGGAAAATCTCTAGCAGTGGCGCCCGAACAGGGACTTG AAAGCGAAAGGGAAACCAGAGGAGCTCTCTCGACGCAGGACTCGGCTTGCTGAAGCGCGCACGG CAAGAGGCGAGGGGCGGCGACTGGTGAGTACGCCAAAAATTTTGACTAGCGGAGGCTAGAAGGA GAGAGATGGGTGCGAGAGCGTCAGTATTAAGCGGGGGAGAATTAGATCGCGATGGGAAAAAATT CGGTTAAGGCCAGGGGGAAAGAAAAAATATAAATTAAAACATATAGTATGGGCAAGCAGGGAGC TAGAACGATTCGCAGTTAATCCTGGCCTGTTAGAAACATCAGAAGGCTGTAGACAAATACTGGGA CAGCTACAACCATCCCTTCAGACAGGATCAGAAGAACTTAGATCATTATATAATACAGTAGCAAC CCTCTATTGTGTGCATCAAAGGATAGAGATAAAAGACACCAAGGAAGCTTTAGACAAGATAGAGG AAGAGCAAAACAAAAGTAAGACCACCGCACAGCAAGCGGCCGGCCGCTGATCTTCAGACCTGGA GGAGGAGATATGAGGGACAATTGGAGAAGTGAATTATATAAATATAAAGTAGTAAAAATTGAAC CATTAGGAGTAGCACCCACCAAGGCAAAGAGAAGAGTGGTGCAGAGAGAAAAAAGAGCAGTGGG AATAGGAGCTTTGTTCCTTGGGTTCTTGGGAGCAGCAGGAAGCACTATGGGCGCAGCGTCAATGA CGCTGACGGTACAGGCCAGACAATTATTGTCTGGTATAGTGCAGCAGCAGAACAATTTGCTGAGG GCTATTGAGGCGCAACAGCATCTGTTGCAACTCACAGTCTGGGGCATCAAGCAGCTCCAGGCAAG AATCCTGGCTGTGGAAAGATACCTAAAGGATCAACAGCTCCTGGGGATTTGGGGTTGCTCTGGAA AACTCATTTGCACCACTGCTGTGCCTTGGAATGCTAGTTGGAGTAATAAATCTCTGGAACAGATTT GGAATCACACGACCTGGATGGAGTGGGACAGAGAAATTAACAATTACACAAGCTTAATACACTCC TTAATTGAAGAATCGCAAAACCAGCAAGAAAAGAATGAACAAGAATTATTGGAATTAGATAAATG GGCAAGTTTGTGGAATTGGTTTAACATAACAAATTGGCTGTGGTATATAAAATTATTCATAATGAT AGTAGGAGGCTTGGTAGGTTTAAGAATAGTTTTTGCTGTACTTTCTATAGTGAATAGAGTTAGGCA GGGATATTCACCATTATCGTTTCAGACCCACCTCCCAACCCCGAGGGGACCCGACAGGCCCGAAG GAATAGAAGAAGAAGGTGGAGAGAGAGACAGAGACAGATCCATTCGATTAGTGAACGGATCTCG ACGGTATCGCCTTTAAAAGAAAAGGGGGGATTGGGGGGTACAGTGCAGGGGAAAGAATAGTAGA CATAATAGCAACAGACATACAAACTAAAGAATTACAAAAACAAATTACAAAAATTCAAAATTTTC GGGTTTATTACAGGGACAGCAGAGATCCAGTTTATCGATATTAATAGTAATCAATTACGGGGTCAT TAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGAC CGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGG ACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTG TATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCC CAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCA TGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCCCACCCCCAATTT TGTATTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGCGCGCGCCA GGCGGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAAT CAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAAAA GCGAAGCGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGCCTC GCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCGGGACGGCCCTT CTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCTTTTCTGTGGCTGCGTGAAAG CCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGGGAGCGGCTCGGGGGGTGCGTGCGTGTGT GTGTGCGTGGGGAGCGCCGCGTGCGGCCCGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGC GCGGGGCTTTGTGCGCTCCGCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGC GGGGGGGCTGCGAGGGGAACAAAGGCTGCGTGCGGGGTGTGTGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTGAGCACGGCC CGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCCGTGCCGGGCGGGGGGTGG CGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGCCTCGGGCCGGGGAGGGCTCGGGGGAGGGGC GCGGCGGCCCCGGAGCGCCGGCGGCTGTCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGT AATCGTGCGAGAGGGCGCAGGGACTTCCTTTGTCCCAAATCTGGCGGAGCCGAAATCTGGGAGGC GCCGCCGCACCCCCTCTAGCGGGCGCGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATGGGC GGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCTCCATCTCCAGCCTCGGGGCTGCCGC AGGGGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTCGGCTTCTGGCGTGTGACCGGC GGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTCTTCTTTTTCCTACAGCTCCTGGGCAACGTGC TGGTTATTGTGCTGTCTCATCATTTTGGCAAAGaattctgcagatatcctcgaggggcccgtttaagcccgctggccaccatggaga cagacacactcctgctatgggtactgctgctctgggttccaggttccactggtgacgcggcccagccggccaggcgcgcgcgccgtacgaagcttggtaccgag ctcggatccgactacaaggaccacgacggcgactacaaggaccacgacatcgactacaaggacgacgacgacaaggagttgactgtgtacaaagtacagaatc ttcagtggacagctgacttctctggggatgtgactttgacctggatgaggcccaaaaaaatgccctctgcttcttgtgtatataatgtctactacagggtggttggagag agcatatggaagactctggagacccacagcaataagacaaacactgtattaaaagtcttgaaaccagataccacgtatcaggttaaagtacaggttcagtgtctcag caaggcacacaacaccaatgactttgtgaccctgaggaccccagagggattgccagatgcccctcgaaatctccagctgtcactccccagggaagcagaaggtg tgattgtaggccactgggctcctcccatccacacccatggcctcatccgtgagtacattgtagaatacagcaggagtggttccaagatgtgggcctcccagagggc tgctagtaactttacagaaatcaagaacttattggtcaacactctatacaccgtcagagtggctgcggtgactagtcgtggaataggaaactggagcgattctaaatc cattaccaccataaaaggaaaagtgatcccaccaccagatatccacattgacagctatggtgaaaattatctaagcttcaccctgaccatggagagtgatatcaaggt gaatggctatgtggtgaaccttttctgggcatttgacacccacaagcaagagaggagaactttgaacttccgaggaagcatattgtcacacaaagttggcaatctga cagctcatacatcctatgagatttctgcctgggccaagactgacttgggggatagccctctggcatttgagcatgttatgaccagaggggttcgcccacctgcaccta gcctcaaggccaaagccatcaaccagactgcagtggaatgtacctggaccggcccccggaatgtggtttatggtattttctatgccacgtcctttcttgacctctatcg caacccgaagagcttgactacttcactccacaacaagacggtcattgtcagtaaggatgagcagtatttgtttctggtccgtgtagtggtaccctaccaggggccatc ctctgactacgttgtagtgaagatgatcccggacagcaggcttccaccccgtcacctgcatgtggttcatacgggcaaaacctccgtggtcatcaagtgggaatcac cgtatgactctcctgaccaggacttgttgtatgcaattgcagtcaaagatctcataagaaagactgacaggagctacaaagtaaaatcccgtaacagcactgtggaat acacccttaacaagttggagcctggcgggaaataccacatcattgtccaactggggaacatgagcaaagattccagcataaaaattaccacagtttcattatcagca cctgatgccttaaaaatcataacagaaaatgatcatgttcttctgttttggaaaagcctggctttaaaggaaaagcattttaatgaaagcaggggctatgagatacacat gtttgatagtgccatgaatatcacagcttaccttgggaatactactgacaatttctttaaaatttccaacctgaagatgggtcataattacacgttcaccgtccaagcaag atgcctttttggcaaccagatctgtggggagcctgccatcctgctgtacgatgagctggggtctggtgcagatgcatctgcaacgcaggctgccagatctacggatg ttgctgctgtggtggtgcccatcttattcctgatactgctgagcctgggggtggggtttgccatcctgtacacgaagcaccggaggctgcagagcagcttcaccgcc ttcgccaacagccactacagctccaggctggggtccgcaatcttctcctctggggatgacctgggggaagatgatgaagatgcccctatgataactggattttcaga tgacgtccccatggtgatagcctgaggatccgatatcggtaccaagcttagcttagcttatcgataatcaacctctggattacaaaatttgtgaaagattgactggtatt cttaactatgttgctccttttacgctatgtggatacgctgctttaatgcctttgtatcatgctattgcttcccgtatggctttcattttctcctccttgtataaatcctggttgctgt ctctttatgaggagttgtggcccgttgtcaggcaacgtggcgtggtgtgcactgtgtttgctgacgcaacccccactggttggggcattgccaccacctgtcagctcc tttccgggactttcgctttccccctccctattgccacggcggaactcatcgccgcctgccttgcccgctgctggacaggggctcggctgttgggcactgacaattccg tggtgttgtcggggaagctgacgtcctttccatggctgctcgcctgtgttgccacctggattctgcgcgggacgtccttctgctacgtcccttcggccctcaatccagc ggaccttccttcccgcggcctgctgccggctctgcggcctcttccgcgtcttcgccttcgccctcagacgagtcggatctccctttgggccgcctccccgcctgatc gataccgtcgactagagctcgctgatcagcctcgatccggagacccagctttcttgtacaaagttttaattaaCCTCAGGTACCTTTAAGACCAA TGACTTACAAGGCAGCTGTAGATCTTAGCCACTTTTTAAAAGAAAAGAGGGGACTGGAAGGGCTA ATTCACTCCCAACGAAGACAAGATATCCTTGATCTGTGGATCTACCACACACAAGGCTACTTCCCT GATTAGCAGAACTACACACCAGGGCCAGGGGTCAGATATCCACTGACCTTTGGATGGTGCTACAA GCTAGTACCAGTTGAGCCAGATAAGGTAGAAGAGGCCAATAAAGGAGAGAACACCAGCTTGTTAC ACCCTGTGAGCCTGCATGGGATGGATGACCCGGAGAGAGAAGTGTTAGAGTGGAGGTTTGACAGC CGCCTAGCATTTCATCACGTGGCCCGAGAGCTGCATCCGGAGTACTTCAAGAACTGCTGATATCGA GCTTGCTACAAGGGACTTTCCGCTGGGGACTTTCCAGGGAGGCGTGGCCTGGGCGGGACTGGGGA GTGGCGAGCCCTCAGATCCTGCATATAAGCAGCTGCTTTTTGCCTGTACTGGGTCTCTCTGGTTAG ACCAGATCTGAGCCTGGGAGCTCTCTGGCTAACTAGGGAACCCACTGCTTAAGCCTCAATAAAGCT TGCCTTGAGTGCTTCAAGTAGTGTGTGCCCGTCTGTTGTGTGACTCTGGTAACTAGAGATCCCTCA GACCCTTTTAGTCAGTGTGGAAAATCTCTAGCAGTAGTAGTTCATGTCATCTTATTATTCAGTATTT ATAACTTGCAAAGAAATGAATATCAGAGAGTGAGAGGCCTTGACATTGCTAGCGTTTACCGTCGA CCTCTAGCTAGAGCTTGGCGTAATCATGGTCATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCAC AATTCCACACAACATACGAGCCGGAAGCATAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCT AACTCACATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGC ATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGC TCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAA TACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAA GGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGC ATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGC GTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCC ı43 GCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGT AGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTAT CCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTG GTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAAC TACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAA AGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAG CAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGA CGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCA CCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGT CTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCAT AGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGC TGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCG GAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATTGTTGCC GGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCA TCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAG TTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAA GTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCC ATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCG GCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAA AAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGAT CCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTC TGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGT TGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGCG GATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAA GTGCCACCTGACGTCGACGGATCGGGAGATCAACTTGTTTATTGCAGCTTATAATGGTTACAAATA AAGCAATAGCATCACAAATTTCACAAATAAAGCATTTTTTTCACTGCATTCTAGTTGTGGTTTGTCC AAACTCATCAATGTATCTTATCATGTCTGGATCAACTGGATAACTCAAGCTAACCAAAATCATCCC AAACTTCCCACCCCATACCCTATTACCACTGCCAATTACCTGTGGTTTCATTTACTCTAAACCTGTG ATTCCTCTGAATTATTTTCATTTTAAAGAAATTGTATTTGTTAAATATGTACTACAAACTTAGTAGT (SEQ ID NO: 29) >LV-CAG-Sorl1mini FANSHY mut (4.0) TGGAAGGGCTAATTCACTCCCAAAGAAGACAAGATATCCTTGATCTGTGGATCTACCACACACAA GGCTACTTCCCTGATTAGCAGAACTACACACCAGGGCCAGGGGTCAGATATCCACTGACCTTTGGA TGGTGCTACAAGCTAGTACCAGTTGAGCCAGATAAGGTAGAAGAGGCCAATAAAGGAGAGAACA CCAGCTTGTTACACCCTGTGAGCCTGCATGGGATGGATGACCCGGAGAGAGAAGTGTTAGAGTGG AGGTTTGACAGCCGCCTAGCATTTCATCACGTGGCCCGAGAGCTGCATCCGGAGTACTTCAAGAAC TGCTGATATCGAGCTTGCTACAAGGGACTTTCCGCTGGGGACTTTCCAGGGAGGCGTGGCCTGGGC GGGACTGGGGAGTGGCGAGCCCTCAGATCCTGCATATAAGCAGCTGCTTTTTGCCTGTACTGGGTC TCTCTGGTTAGACCAGATCTGAGCCTGGGAGCTCTCTGGCTAACTAGGGAACCCACTGCTTAAGCC TCAATAAAGCTTGCCTTGAGTGCTTCAAGTAGTGTGTGCCCGTCTGTTGTGTGACTCTGGTAACTA GAGATCCCTCAGACCCTTTTAGTCAGTGTGGAAAATCTCTAGCAGTGGCGCCCGAACAGGGACTTG AAAGCGAAAGGGAAACCAGAGGAGCTCTCTCGACGCAGGACTCGGCTTGCTGAAGCGCGCACGG CAAGAGGCGAGGGGCGGCGACTGGTGAGTACGCCAAAAATTTTGACTAGCGGAGGCTAGAAGGA GAGAGATGGGTGCGAGAGCGTCAGTATTAAGCGGGGGAGAATTAGATCGCGATGGGAAAAAATT CGGTTAAGGCCAGGGGGAAAGAAAAAATATAAATTAAAACATATAGTATGGGCAAGCAGGGAGC TAGAACGATTCGCAGTTAATCCTGGCCTGTTAGAAACATCAGAAGGCTGTAGACAAATACTGGGA CAGCTACAACCATCCCTTCAGACAGGATCAGAAGAACTTAGATCATTATATAATACAGTAGCAAC CCTCTATTGTGTGCATCAAAGGATAGAGATAAAAGACACCAAGGAAGCTTTAGACAAGATAGAGG AAGAGCAAAACAAAAGTAAGACCACCGCACAGCAAGCGGCCGGCCGCTGATCTTCAGACCTGGA GGAGGAGATATGAGGGACAATTGGAGAAGTGAATTATATAAATATAAAGTAGTAAAAATTGAAC CATTAGGAGTAGCACCCACCAAGGCAAAGAGAAGAGTGGTGCAGAGAGAAAAAAGAGCAGTGGG AATAGGAGCTTTGTTCCTTGGGTTCTTGGGAGCAGCAGGAAGCACTATGGGCGCAGCGTCAATGA CGCTGACGGTACAGGCCAGACAATTATTGTCTGGTATAGTGCAGCAGCAGAACAATTTGCTGAGG GCTATTGAGGCGCAACAGCATCTGTTGCAACTCACAGTCTGGGGCATCAAGCAGCTCCAGGCAAG AATCCTGGCTGTGGAAAGATACCTAAAGGATCAACAGCTCCTGGGGATTTGGGGTTGCTCTGGAA AACTCATTTGCACCACTGCTGTGCCTTGGAATGCTAGTTGGAGTAATAAATCTCTGGAACAGATTT GGAATCACACGACCTGGATGGAGTGGGACAGAGAAATTAACAATTACACAAGCTTAATACACTCC TTAATTGAAGAATCGCAAAACCAGCAAGAAAAGAATGAACAAGAATTATTGGAATTAGATAAATG GGCAAGTTTGTGGAATTGGTTTAACATAACAAATTGGCTGTGGTATATAAAATTATTCATAATGAT AGTAGGAGGCTTGGTAGGTTTAAGAATAGTTTTTGCTGTACTTTCTATAGTGAATAGAGTTAGGCA GGGATATTCACCATTATCGTTTCAGACCCACCTCCCAACCCCGAGGGGACCCGACAGGCCCGAAG GAATAGAAGAAGAAGGTGGAGAGAGAGACAGAGACAGATCCATTCGATTAGTGAACGGATCTCG ACGGTATCGCCTTTAAAAGAAAAGGGGGGATTGGGGGGTACAGTGCAGGGGAAAGAATAGTAGA CATAATAGCAACAGACATACAAACTAAAGAATTACAAAAACAAATTACAAAAATTCAAAATTTTC GGGTTTATTACAGGGACAGCAGAGATCCAGTTTATCGATATTAATAGTAATCAATTACGGGGTCAT TAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGAC CGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGG ACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTG TATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCC CAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCA TGGGTCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCCCACCCCCAATTT TGTATTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGCGCGCGCCA GGCGGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAAT CAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAAAA GCGAAGCGCGCGGCGGGCGGGAGTCGCTGCGTTGCCTTCGCCCCGTGCCCCGCTCCGCGCCGCCTC GCGCCGCCCGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCGGGACGGCCCTT CTCCTCCGGGCTGTAATTAGCGCTTGGTTTAATGACGGCTCGTTTCTTTTCTGTGGCTGCGTGAAAG CCTTAAAGGGCTCCGGGAGGGCCCTTTGTGCGGGGGGGAGCGGCTCGGGGGGTGCGTGCGTGTGT GTGTGCGTGGGGAGCGCCGCGTGCGGCCCGCGCTGCCCGGCGGCTGTGAGCGCTGCGGGCGCGGC GCGGGGCTTTGTGCGCTCCGCGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGTGCCCCGCGGTGC GGGGGGGCTGCGAGGGGAACAAAGGCTGCGTGCGGGGTGTGTGCGTGGGGGGGTGAGCAGGGGG TGTGGGCGCGGCGGTCGGGCTGTAACCCCCCCCTGCACCCCCCTCCCCGAGTTGCTGAGCACGGCC CGGCTTCGGGTGCGGGGCTCCGTGCGGGGCGTGGCGCGGGGCTCGCCGTGCCGGGCGGGGGGTGG CGGCAGGTGGGGGTGCCGGGCGGGGCGGGGCCGCCTCGGGCCGGGGAGGGCTCGGGGGAGGGGC GCGGCGGCCCCGGAGCGCCGGCGGCTGTCGAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGT AATCGTGCGAGAGGGCGCAGGGACTTCCTTTGTCCCAAATCTGGCGGAGCCGAAATCTGGGAGGC GCCGCCGCACCCCCTCTAGCGGGCGCGGGCGAAGCGGTGCGGCGCCGGCAGGAAGGAAATGGGC GGGGAGGGCCTTCGTGCGTCGCCGCGCCGCCGTCCCCTTCTCCATCTCCAGCCTCGGGGCTGCCGC AGGGGGACGGCTGCCTTCGGGGGGGACGGGGCAGGGCGGGGTTCGGCTTCTGGCGTGTGACCGGC GGCTCTAGAGCCTCTGCTAACCATGTTCATGCCTTCTTCTTTTTCCTACAGCTCCTGGGCAACGTGC TGGTTATTGTGCTGTCTCATCATTTTGGCAAAGaattctgcagatatcctcgaggggcccgtttaagcccgctggccaccatggaga cagacacactcctgctatgggtactgctgctctgggttccaggttccactggtgacgcggcccagccggccaggcgcgcgcgccgtacgaagcttggtaccgag ctcggatccgactacaaggaccacgacggcgactacaaggaccacgacatcgactacaaggacgacgacgacaaggagttgactgtgtacaaagtacagaatc ttcagtggacagctgacttctctggggatgtgactttgacctggatgaggcccaaaaaaatgccctctgcttcttgtgtatataatgtctactacagggtggttggagag agcatatggaagactctggagacccacagcaataagacaaacactgtattaaaagtcttgaaaccagataccacgtatcaggttaaagtacaggttcagtgtctcag caaggcacacaacaccaatgactttgtgaccctgaggaccccagagggattgccagatgcccctcgaaatctccagctgtcactccccagggaagcagaaggtg tgattgtaggccactgggctcctcccatccacacccatggcctcatccgtgagtacattgtagaatacagcaggagtggttccaagatgtgggcctcccagagggc tgctagtaactttacagaaatcaagaacttattggtcaacactctatacaccgtcagagtggctgcggtgactagtcgtggaataggaaactggagcgattctaaatc cattaccaccataaaaggaaaagtgatcccaccaccagatatccacattgacagctatggtgaaaattatctaagcttcaccctgaccatggagagtgatatcaaggt gaatggctatgtggtgaaccttttctgggcatttgacacccacaagcaagagaggagaactttgaacttccgaggaagcatattgtcacacaaagttggcaatctga cagctcatacatcctatgagatttctgcctgggccaagactgacttgggggatagccctctggcatttgagcatgttatgaccagaggggttcgcccacctgcaccta gcctcaaggccaaagccatcaaccagactgcagtggaatgtacctggaccggcccccggaatgtggtttatggtattttctatgccacgtcctttcttgacctctatcg caacccgaagagcttgactacttcactccacaacaagacggtcattgtcagtaaggatgagcagtatttgtttctggtccgtgtagtggtaccctaccaggggccatc ctctgactacgttgtagtgaagatgatcccggacagcaggcttccaccccgtcacctgcatgtggttcatacgggcaaaacctccgtggtcatcaagtgggaatcac cgtatgactctcctgaccaggacttgttgtatgcaattgcagtcaaagatctcataagaaagactgacaggagctacaaagtaaaatcccgtaacagcactgtggaat acacccttaacaagttggagcctggcgggaaataccacatcattgtccaactggggaacatgagcaaagattccagcataaaaattaccacagtttcattatcagca cctgatgccttaaaaatcataacagaaaatgatcatgttcttctgttttggaaaagcctggctttaaaggaaaagcattttaatgaaagcaggggctatgagatacacat gtttgatagtgccatgaatatcacagcttaccttgggaatactactgacaatttctttaaaatttccaacctgaagatgggtcataattacacgttcaccgtccaagcaag atgcctttttggcaaccagatctgtggggagcctgccatcctgctgtacgatgagctggggtctggtgcagatgcatctgcaacgcaggctgccagatctacggatg ttgctgctgtggtggtgcccatcttattcctgatactgctgagcctgggggtggggtttgccatcctgtacacgaagcaccggaggctgcagagcagcttcaccgcc gcTgcAgcGgcAgcTgccagctccaggctggggtccgcaatcttctcctctggggatgacctgggggaagatgatgaagatgcccctatgataactggatttt cagatgacgtccccatggtgatagcctgagtttaaacAATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTA TTCTTAACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATT GCTTCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTT GTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTG GGGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCG GAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCC GTGGTGTTGTCGGGGAAATCATCGTCCTTTCCTTGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGC ıĴĵ GCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCT GCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCC GCCTCCCCGCttaattaaCCTCAGGTACCTTTAAGACCAATGACTTACAAGGCAGCTGTAGATCTTAGCC ACTTTTTAAAAGAAAAGAGGGGACTGGAAGGGCTAATTCACTCCCAACGAAGACAAGATATCCTT GATCTGTGGATCTACCACACACAAGGCTACTTCCCTGATTAGCAGAACTACACACCAGGGCCAGG GGTCAGATATCCACTGACCTTTGGATGGTGCTACAAGCTAGTACCAGTTGAGCCAGATAAGGTAG AAGAGGCCAATAAAGGAGAGAACACCAGCTTGTTACACCCTGTGAGCCTGCATGGGATGGATGAC CCGGAGAGAGAAGTGTTAGAGTGGAGGTTTGACAGCCGCCTAGCATTTCATCACGTGGCCCGAGA GCTGCATCCGGAGTACTTCAAGAACTGCTGATATCGAGCTTGCTACAAGGGACTTTCCGCTGGGGA CTTTCCAGGGAGGCGTGGCCTGGGCGGGACTGGGGAGTGGCGAGCCCTCAGATCCTGCATATAAG CAGCTGCTTTTTGCCTGTACTGGGTCTCTCTGGTTAGACCAGATCTGAGCCTGGGAGCTCTCTGGCT AACTAGGGAACCCACTGCTTAAGCCTCAATAAAGCTTGCCTTGAGTGCTTCAAGTAGTGTGTGCCC GTCTGTTGTGTGACTCTGGTAACTAGAGATCCCTCAGACCCTTTTAGTCAGTGTGGAAAATCTCTA GCAGTAGTAGTTCATGTCATCTTATTATTCAGTATTTATAACTTGCAAAGAAATGAATATCAGAGA GTGAGAGGCCTTGACATTGCTAGCGTTTACCGTCGACCTCTAGCTAGAGCTTGGCGTAATCATGGT CATAGCTGTTTCCTGTGTGAAATTGTTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCA TAAAGTGTAAAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCTCACTGC CCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGA GGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGC TGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAAC GCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGC TGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGT GGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTC CTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTC TCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCA CGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGT AAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAG GCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGT ATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAA ACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCT CAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGG ATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTT AAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCA CCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTA CGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCG GCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAAC TTTATCCGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAA TAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCT TCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCG GTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTA TGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTA CTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACG GGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGC GAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACT GATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCG CAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATT GAAGCATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAAC AAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTGACGTCGACGGATCGGGAGATCAA CTTGTTTATTGCAGCTTATAATGGTTACAAATAAAGCAATAGCATCACAAATTTCACAAATAAAGC ATTTTTTTCACTGCATTCTAGTTGTGGTTTGTCCAAACTCATCAATGTATCTTATCATGTCTGGATCA ACTGGATAACTCAAGCTAACCAAAATCATCCCAAACTTCCCACCCCATACCCTATTACCACTGCCA ATTACCTGTGGTTTCATTTACTCTAAACCTGTGATTCCTCTGAATTATTTTCATTTTAAAGAAATTGT ATTTGTTAAATATGTACTACAAACTTAGTAGT (SEQ ID NO: 32) [0233] In some embodiments, a transgene comprising a SORL1 variant is provided in a lentiviral vector comprising a polynucleotide that is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% sequence identical to any one of SEQ ID NOs: 1-12, 25-26, 29, 32, 35-37, 43-55, or 58-59. In some embodiments, a transgene comprising a SORL1 variant is provided in a lentiviral vector comprising a polynucleotide sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 29, 32, 35-37, 43-55, or 58-59. [0234] A transgene comprising a SORL1 variant may be provided in virtually any rAAV vector. In some embodiments, a transgene comprising a SORL1 variant is provided in a rAAV vector, wherein the transgene is flanked by ITRs. In some embodiments, the rAAV vector comprising a SORL1 variant comprises from 5′ to 3′ a first ITR, a CAG promoter comprising the CMV enhancer, the chicken beta-actin promoter and the chimeric intron, an Ig-kappa leader sequence, a transgene comprising the SORL1 variant (e.g., one encoding a SORL1 variant comprising the N-terminal hemagglutinin HA tag), WPRE3, the bovine growth hormone (bGH) poly(A) signal, a second ITR, an origin of replication (ori), a neomycin/kanamycin resistance gene, an AmpR promoter, and a f1 ori. In some embodiments, the rAAV vector comprising a SORL1 variant comprises from 5′ to 3′ a first ITR, a CAG promoter comprising the CMV enhancer, the chicken beta-actin promoter and the chimeric intron, an Ig-kappa leader sequence, the SORL1 variant, the WPRE3, the bovine growth hormone (bGH) poly(A) signal, a second ITR, an origin of replication (ori), a neomycin/kanamycin resistance gene, an AmpR promoter, and a f1 ori. [0235] In some embodiments, an rAAV vector comprises a sequence of any one of SEQ ID NOs: 1-12, 25-26, 30, 31, 35-37, 43-53, or 56-59. Further non-limiting examples of rAAV vectors comprising a SORL1 variant are provided below: >pAAV CAG HA-Sorl1mini WPRE3 (2.1) ggggggggggggggggggttggccactccctctctgcgcgctcgctcgctcactgaggccgggcgaccaaaggtcgcccgacgcccgggctttgcccgggc ggcctcagtgagcgagcgagcgcgcagagagggagtggccaactccatcactaggggttcctagatctgaattccgttacataacttacggtaaatggcccgcct ggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttccattgacgtcaatgggtggactatttacg gtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctattgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgac cttatgggactttcctacttggcagtacatctacgtattagtcatcgctattaccatggtcgaggtgagccccacgttctgcttcactctccccatctcccccccctcccc acccccaattttgtatttatttattttttaattattttgtgcagcgatgggggcggggggggggggggggcgcgcgccaggcggggcggggcggggcgaggggc ggggcggggcgaggcggagaggtgcggcggcagccaatcagagcggcgcgctccgaaagtttccttttatggcgaggcggcggcggcggcggccctataa aaagcgaagcgcgcggcgggcgggagtcgctgcgacgctgccttcgccccgtgccccgctccgccgccgcctcgcgccgcccgccccggctctgactgacc gcgttactcccacaggtgagcgggcgggacggcccttctcctccgggctgtaattagcgcttggtttaatgacggcttgtttcttttctgtggctgcgtgaaagccttg aggggctccgggagggccctttgtgcgggggggagcggctcggggggtgcgtgcgtgtgtgtgtgcgtggggagcgccgcgtgcggcccgcgctgcccgg cggctgtgagcgctgcgggcgcggcgcggggctttgtgcgctccgcagtgtgcgcgaggggagcgcggccgggggcggtgccccgcggtgcgggggggg ctgcgaggggaacaaaggctgcgtgcggggtgtgtgcgtgggggggtgagcagggggtgtgggcgcggcggtcgggctgtaacccccccctgcacccccct ccccgagttgctgagcacggcccggcttcgggtgcggggctccgtacggggcgtggcgcggggctcgccgtgccgggcggggggtggcggcaggtgggg gtgccgggcggggcggggccgcctcgggccggggagggctcgggggaggggcgcggcggcccccggagcgccggcggctgtcgaggcgcggcgagc cgcagccattgccttttatggtaatcgtgcgagagggcgcagggacttcctttgtcccaaatctgtgcggagccgaaatctgggaggcgccgccgcaccccctcta gcgggcgcggggcgaagcggtgcggcgccggcaggaaggaaatgggcggggagggccttcgtgcgtcgccgcgccgccgtccccttctccctctccagcct cggggctgtccgcggggggacggctgccttcgggggggacggggcagggcggggttcggcttctggcgtgtgaccggcggctctagagcctctgctaaccat gttcatgccttcttctttttcctacaggttaacgtcgacggccaccatggagacagacacactcctgctatgggtactgctgctctgggttccaggttccactggtgact acccatacgatgttccagattacgctgagttgactgtgtacaaagtacagaatcttcagtggacagctgacttctctggggatgtgactttgacctggatgaggccca aaaaaatgccctctgcttcttgtgtatataatgtctactacagggtggttggagagagcatatggaagactctggagacccacagcaataagacaaacactgtattaa aagtcttgaaaccagataccacgtatcaggttaaagtacaggttcagtgtctcagcaaggcacacaacaccaatgactttgtgaccctgaggaccccagagggatt gccagatgcccctcgaaatctccagctgtcactccccagggaagcagaaggtgtgattgtaggccactgggctcctcccatccacacccatggcctcatccgtga gtacattgtagaatacagcaggagtggttccaagatgtgggcctcccagagggctgctagtaactttacagaaatcaagaacttattggtcaacactctatacaccgt cagagtggctgcggtgactagtcgtggaataggaaactggagcgattctaaatccattaccaccataaaaggaaaagtgatcccaccaccagatatccacattgac agctatggtgaaaattatctaagcttcaccctgaccatggagagtgatatcaaggtgaatggctatgtggtgaaccttttctgggcatttgacacccacaagcaagag aggagaactttgaacttccgaggaagcatattgtcacacaaagttggcaatctgacagctcatacatcctatgagatttctgcctgggccaagactgacttgggggat agccctctggcatttgagcatgttatgaccagaggggttcgcccacctgcacctagcctcaaggccaaagccatcaaccagactgcagtggaatgtacctggacc ggcccccggaatgtggtttatggtattttctatgccacgtcctttcttgacctctatcgcaacccgaagagcttgactacttcactccacaacaagacggtcattgtcagt aaggatgagcagtatttgtttctggtccgtgtagtggtaccctaccaggggccatcctctgactacgttgtagtgaagatgatcccggacagcaggcttccaccccgt cacctgcatgtggttcatacgggcaaaacctccgtggtcatcaagtgggaatcaccgtatgactctcctgaccaggacttgttgtatgcaattgcagtcaaagatctc ataagaaagactgacaggagctacaaagtaaaatcccgtaacagcactgtggaatacacccttaacaagttggagcctggcgggaaataccacatcattgtccaa ctggggaacatgagcaaagattccagcataaaaattaccacagtttcattatcagcacctgatgccttaaaaatcataacagaaaatgatcatgttcttctgttttggaa aagcctggctttaaaggaaaagcattttaatgaaagcaggggctatgagatacacatgtttgatagtgccatgaatatcacagcttaccttgggaatactactgacaat ttctttaaaatttccaacctgaagatgggtcataattacacgttcaccgtccaagcaagatgcctttttggcaaccagatctgtggggagcctgccatcctgctgtacga tgagctggggtctggtgcagatgcatctgcaacgcaggctgccagatctacggatgttgctgctgtggtggtgcccatcttattcctgatactgctgagcctgggggt ggggtttgccatcctgtacacgaagcaccggaggctgcagagcagcttcaccgccttcgccaacagccactacagctccaggctggggtccgcaatcttctcctct ggggatgacctgggggaagatgatgaagatgcccctatgataactggattttcagatgacgtccccatggtgatagcctgaggatccatcgataatcaacctctgga ttacaaaatttgtgaaagattgactggtattcttaactatgttgctccttttacgctatgtggatacgctgctttaatgcctttgtatcatgctattgcttcccgtatggctttcat tttctcctccttgtataaatcctggttagttcttgccacggcggaactcatcgccgcctgccttgcccgctgctggacaggggctcggctgttgggcactgacaattcc gtggtgttgagctcgcctgtgccttctagttgccagccatctgttgtttgcccctcccccgtgccttccttgaccctggaaggtgccactcccactgtcctttcctaataa aatgaggaaattgcatcgcattgtctgagtaggtgtcattctattctggggggtggggtggggcaggacagcaagggggaggattgggaagacaatagcaggca tgctggggagagatctaggaacccctagtgatggagttggccactccctctctgcgcgctcgctcgctcactgaggccgcccgggcaaagcccgggcgtcggg cgacctttggtcgcccggcctcagtgagcgagcgagcgcgcagagagggagtggccaacccccccccccccccccctgcagcccagctgcattaatgaatcg gccaacgcgcggggagaggcggtttgcgtattgggcgctcttccgcttcctcgctcactgactcgctgcgctcggtcgttcggctgcggcgagcggtatcagctc actcaaaggcggtaatacggttatccacagaatcaggggataacgcaggaaagaacatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccg cgttgctggcgtttttccataggctccgcccccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactataaagataccagg cgtttccccctggaagctccctcgtgcgctctcctgttccgaccctgccgcttaccggatacctgtccgcctttctcccttcgggaagcgtggcgctttctcaatgctca cgctgtaggtatctcagttcggtgtaggtcgttcgctccaagctgggctgtgtgcacgaaccccccgttcagcccgaccgctgcgccttatccggtaactatcgtctt gagtccaacccggtaagacacgacttatcgccactggcagcagccactggtaacaggattagcagagcgaggtatgtaggcggtgctacagagttcttgaagtg gtggcctaactacggctacactagaaggacagtatttggtatctgcgctctgctgaagccagttaccttcggaaaaagagttggtagctcttgatccggcaaacaaa ccaccgctggtagcggtggtttttttgtttgcaagcagcagattacgcgcagaaaaaaaggatctcaagaagatcctttgatcttttctacggggtctgacgctcagtg gaacgaaaactcacgttaagggattttggtcatgagattatcaaaaaggatcttcacctagatccttttaaattaaaaatgaagttttaaatcaatctaaagtatatatgag taaacttggtctgacagttagaaaaattcatccagcagacgataaaacgcaatacgctggctatccggtgccgcaatgccatacagcaccagaaaacgatccgccc attcgccgcccagttcttccgcaatatcacgggtggccagcgcaatatcctgataacgatccgccacgcccagacggccgcaatcaataaagccgctaaaacggc cattttccaccataatgttcggcaggcacgcatcaccatgggtcaccaccagatcttcgccatccggcatgctcgctttcagacgcgcaaacagctctgccggtgcc aggccctgatgttcttcatccagatcatcctgatccaccaggcccgcttccatacgggtacgcgcacgttcaatacgatgtttcgcctgatgatcaaacggacaggtc gccgggtccagggtatgcagacgacgcatggcatccgccataatgctcactttttctgccggcgccagatggctagacagcagatcctgacccggcacttcgccc agcagcagccaatcacggcccgcttcggtcaccacatccagcaccgccgcacacggaacaccggtggtggccagccagctcagacgcgccgcttcatcctgc agctcgttcagcgcaccgctcagatcggttttcacaaacagcaccggacgaccctgcgcgctcagacgaaacaccgccgcatcagagcagccaatggtctgctg cgcccaatcatagccaaacagacgttccacccacgctgccgggctacccgcatgcaggccatcctgttcaatcatactcttcctttttcaatattattgaagcatttatc agggttattgtctcatgagcggatacatatttgaatgtatttagaaaaataaacaaataggggttccgcgcacatttccccgaaaagtgccacctgacgtctaagaaac cattattatcatgacattaacctataaaaataggcgtatcacgaggccctttcgtctcgcgcgtttcggtgatgacggtgaaaacctctgacacatgcagctcccggag acggtcacagcttgtctgtaagcggatgccgggagcagacaagcccgtcagggcgcgtcagcgggtgttggcgggtgtcggggctggcttaactatgcggcat cagagcagattgtactgagagtgcaccatatgcggtgtgaaataccgcacagatgcgtaaggagaaaataccgcatcaggaaattgtaaacgttaatattttgttaaa attcgcgttaaatttttgttaaatcagctcattttttaaccaataggccgaaatcggcaaaatcccttataaatcaaaagaatagaccgagatagggttgagtgttgttcca gtttggaacaagagtccactattaaagaacgtggactccaacgtcaaagggcgaaaaaccgtctatcagggcgatggcccactacgtgaaccatcaccctaatca agttttttggggtcgaggtgccgtaaagcactaaatcggaaccctaaagggagcccccgatttagagcttgacggggaaagccggcgaacgtggcgagaaagg aagggaagaaagcgaaaggagcgggcgctagggcgctggcaagtgtagcggtcacgctgcgcgtaaccaccacacccgccgcgcttaatgcgccgctacag ggcgcgtcgcgccattcgccattcaggctacgcaactgttgggaagggcgatcggtgcgggcctcttcgctattacgccagctggctgca (SEQ ID NO: 30) >pAAV CAG Sorl1mini WPRE3 (2.2) ggggggggggggggggggttggccactccctctctgcgcgctcgctcgctcactgaggccgggcgaccaaaggtcgcccgacgcccgggctttgcccgggc ggcctcagtgagcgagcgagcgcgcagagagggagtggccaactccatcactaggggttcctagatctgaattccgttacataacttacggtaaatggcccgcct ggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttccattgacgtcaatgggtggactatttacg gtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctattgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgac cttatgggactttcctacttggcagtacatctacgtattagtcatcgctattaccatggtcgaggtgagccccacgttctgcttcactctccccatctcccccccctcccc acccccaattttgtatttatttattttttaattattttgtgcagcgatgggggcggggggggggggggggcgcgcgccaggcggggcggggcggggcgaggggc ggggcggggcgaggcggagaggtgcggcggcagccaatcagagcggcgcgctccgaaagtttccttttatggcgaggcggcggcggcggcggccctataa aaagcgaagcgcgcggcgggcgggagtcgctgcgacgctgccttcgccccgtgccccgctccgccgccgcctcgcgccgcccgccccggctctgactgacc gcgttactcccacaggtgagcgggcgggacggcccttctcctccgggctgtaattagcgcttggtttaatgacggcttgtttcttttctgtggctgcgtgaaagccttg aggggctccgggagggccctttgtgcgggggggagcggctcggggggtgcgtgcgtgtgtgtgtgcgtggggagcgccgcgtgcggcccgcgctgcccgg cggctgtgagcgctgcgggcgcggcgcggggctttgtgcgctccgcagtgtgcgcgaggggagcgcggccgggggcggtgccccgcggtgcgggggggg ctgcgaggggaacaaaggctgcgtgcggggtgtgtgcgtgggggggtgagcagggggtgtgggcgcggcggtcgggctgtaacccccccctgcacccccct ccccgagttgctgagcacggcccggcttcgggtgcggggctccgtacggggcgtggcgcggggctcgccgtgccgggcggggggtggcggcaggtgggg gtgccgggcggggcggggccgcctcgggccggggagggctcgggggaggggcgcggcggcccccggagcgccggcggctgtcgaggcgcggcgagc cgcagccattgccttttatggtaatcgtgcgagagggcgcagggacttcctttgtcccaaatctgtgcggagccgaaatctgggaggcgccgccgcaccccctcta gcgggcgcggggcgaagcggtgcggcgccggcaggaaggaaatgggcggggagggccttcgtgcgtcgccgcgccgccgtccccttctccctctccagcct cggggctgtccgcggggggacggctgccttcgggggggacggggcagggcggggttcggcttctggcgtgtgaccggcggctctagagcctctgctaaccat gttcatgccttcttctttttcctacaggttaacgtcgacggccaccatggagacagacacactcctgctatgggtactgctgctctgggttccaggttccactggtgacg agttgactgtgtacaaagtacagaatcttcagtggacagctgacttctctggggatgtgactttgacctggatgaggcccaaaaaaatgccctctgcttcttgtgtatat aatgtctactacagggtggttggagagagcatatggaagactctggagacccacagcaataagacaaacactgtattaaaagtcttgaaaccagataccacgtatc aggttaaagtacaggttcagtgtctcagcaaggcacacaacaccaatgactttgtgaccctgaggaccccagagggattgccagatgcccctcgaaatctccagct gtcactccccagggaagcagaaggtgtgattgtaggccactgggctcctcccatccacacccatggcctcatccgtgagtacattgtagaatacagcaggagtggt tccaagatgtgggcctcccagagggctgctagtaactttacagaaatcaagaacttattggtcaacactctatacaccgtcagagtggctgcggtgactagtcgtgg aataggaaactggagcgattctaaatccattaccaccataaaaggaaaagtgatcccaccaccagatatccacattgacagctatggtgaaaattatctaagcttcac cctgaccatggagagtgatatcaaggtgaatggctatgtggtgaaccttttctgggcatttgacacccacaagcaagagaggagaactttgaacttccgaggaagc atattgtcacacaaagttggcaatctgacagctcatacatcctatgagatttctgcctgggccaagactgacttgggggatagccctctggcatttgagcatgttatga ccagaggggttcgcccacctgcacctagcctcaaggccaaagccatcaaccagactgcagtggaatgtacctggaccggcccccggaatgtggtttatggtatttt ctatgccacgtcctttcttgacctctatcgcaacccgaagagcttgactacttcactccacaacaagacggtcattgtcagtaaggatgagcagtatttgtttctggtcc gtgtagtggtaccctaccaggggccatcctctgactacgttgtagtgaagatgatcccggacagcaggcttccaccccgtcacctgcatgtggttcatacgggcaa aacctccgtggtcatcaagtgggaatcaccgtatgactctcctgaccaggacttgttgtatgcaattgcagtcaaagatctcataagaaagactgacaggagctaca aagtaaaatcccgtaacagcactgtggaatacacccttaacaagttggagcctggcgggaaataccacatcattgtccaactggggaacatgagcaaagattccag cataaaaattaccacagtttcattatcagcacctgatgccttaaaaatcataacagaaaatgatcatgttcttctgttttggaaaagcctggctttaaaggaaaagcatttt aatgaaagcaggggctatgagatacacatgtttgatagtgccatgaatatcacagcttaccttgggaatactactgacaatttctttaaaatttccaacctgaagatggg tcataattacacgttcaccgtccaagcaagatgcctttttggcaaccagatctgtggggagcctgccatcctgctgtacgatgagctggggtctggtgcagatgcatc tgcaacgcaggctgccagatctacggatgttgctgctgtggtggtgcccatcttattcctgatactgctgagcctgggggtggggtttgccatcctgtacacgaagca ccggaggctgcagagcagcttcaccgccttcgccaacagccactacagctccaggctggggtccgcaatcttctcctctggggatgacctgggggaagatgatg aagatgcccctatgataactggattttcagatgacgtccccatggtgatagcctgaggatccatcgataatcaacctctggattacaaaatttgtgaaagattgactggt attcttaactatgttgctccttttacgctatgtggatacgctgctttaatgcctttgtatcatgctattgcttcccgtatggctttcattttctcctccttgtataaatcctggttagt tcttgccacggcggaactcatcgccgcctgccttgcccgctgctggacaggggctcggctgttgggcactgacaattccgtggtgttgagctcgcctgtgccttcta gttgccagccatctgttgtttgcccctcccccgtgccttccttgaccctggaaggtgccactcccactgtcctttcctaataaaatgaggaaattgcatcgcattgtctga gtaggtgtcattctattctggggggtggggtggggcaggacagcaagggggaggattgggaagacaatagcaggcatgctggggagagatctaggaaccccta gtgatggagttggccactccctctctgcgcgctcgctcgctcactgaggccgcccgggcaaagcccgggcgtcgggcgacctttggtcgcccggcctcagtgag cgagcgagcgcgcagagagggagtggccaacccccccccccccccccctgcagcccagctgcattaatgaatcggccaacgcgcggggagaggcggtttgc gtattgggcgctcttccgcttcctcgctcactgactcgctgcgctcggtcgttcggctgcggcgagcggtatcagctcactcaaaggcggtaatacggttatccaca gaatcaggggataacgcaggaaagaacatgtgagcaaaaggccagcaaaaggccaggaaccgtaaaaaggccgcgttgctggcgtttttccataggctccgcc cccctgacgagcatcacaaaaatcgacgctcaagtcagaggtggcgaaacccgacaggactataaagataccaggcgtttccccctggaagctccctcgtgcgc tctcctgttccgaccctgccgcttaccggatacctgtccgcctttctcccttcgggaagcgtggcgctttctcaatgctcacgctgtaggtatctcagttcggtgtaggt cgttcgctccaagctgggctgtgtgcacgaaccccccgttcagcccgaccgctgcgccttatccggtaactatcgtcttgagtccaacccggtaagacacgacttat cgccactggcagcagccactggtaacaggattagcagagcgaggtatgtaggcggtgctacagagttcttgaagtggtggcctaactacggctacactagaagg acagtatttggtatctgcgctctgctgaagccagttaccttcggaaaaagagttggtagctcttgatccggcaaacaaaccaccgctggtagcggtggtttttttgtttg caagcagcagattacgcgcagaaaaaaaggatctcaagaagatcctttgatcttttctacggggtctgacgctcagtggaacgaaaactcacgttaagggattttgg tcatgagattatcaaaaaggatcttcacctagatccttttaaattaaaaatgaagttttaaatcaatctaaagtatatatgagtaaacttggtctgacagttagaaaaattca tccagcagacgataaaacgcaatacgctggctatccggtgccgcaatgccatacagcaccagaaaacgatccgcccattcgccgcccagttcttccgcaatatca cgggtggccagcgcaatatcctgataacgatccgccacgcccagacggccgcaatcaataaagccgctaaaacggccattttccaccataatgttcggcaggca cgcatcaccatgggtcaccaccagatcttcgccatccggcatgctcgctttcagacgcgcaaacagctctgccggtgccaggccctgatgttcttcatccagatcat cctgatccaccaggcccgcttccatacgggtacgcgcacgttcaatacgatgtttcgcctgatgatcaaacggacaggtcgccgggtccagggtatgcagacgac gcatggcatccgccataatgctcactttttctgccggcgccagatggctagacagcagatcctgacccggcacttcgcccagcagcagccaatcacggcccgctt cggtcaccacatccagcaccgccgcacacggaacaccggtggtggccagccagctcagacgcgccgcttcatcctgcagctcgttcagcgcaccgctcagatc ggttttcacaaacagcaccggacgaccctgcgcgctcagacgaaacaccgccgcatcagagcagccaatggtctgctgcgcccaatcatagccaaacagacgtt ccacccacgctgccgggctacccgcatgcaggccatcctgttcaatcatactcttcctttttcaatattattgaagcatttatcagggttattgtctcatgagcggatacat atttgaatgtatttagaaaaataaacaaataggggttccgcgcacatttccccgaaaagtgccacctgacgtctaagaaaccattattatcatgacattaacctataaaa ataggcgtatcacgaggccctttcgtctcgcgcgtttcggtgatgacggtgaaaacctctgacacatgcagctcccggagacggtcacagcttgtctgtaagcggat gccgggagcagacaagcccgtcagggcgcgtcagcgggtgttggcgggtgtcggggctggcttaactatgcggcatcagagcagattgtactgagagtgcacc atatgcggtgtgaaataccgcacagatgcgtaaggagaaaataccgcatcaggaaattgtaaacgttaatattttgttaaaattcgcgttaaatttttgttaaatcagctc attttttaaccaataggccgaaatcggcaaaatcccttataaatcaaaagaatagaccgagatagggttgagtgttgttccagtttggaacaagagtccactattaaag aacgtggactccaacgtcaaagggcgaaaaaccgtctatcagggcgatggcccactacgtgaaccatcaccctaatcaagttttttggggtcgaggtgccgtaaa gcactaaatcggaaccctaaagggagcccccgatttagagcttgacggggaaagccggcgaacgtggcgagaaaggaagggaagaaagcgaaaggagcgg ıĴĹ gcgctagggcgctggcaagtgtagcggtcacgctgcgcgtaaccaccacacccgccgcgcttaatgcgccgctacagggcgcgtcgcgccattcgccattcag gctacgcaactgttgggaagggcgatcggtgcgggcctcttcgctattacgccagctggctgca (SEQ ID NO: 31) [0236] In some embodiments, a transgene comprising a SORL1 variant is provided in a rAAV vector comprising a polynucleotide that is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% sequence identical to any one of SEQ ID NOs: 1-12, 25-26, 30, 31, 35-37, 43-53, or 56-59. In some embodiments, a transgene comprising a SORL1 variant is provided in a rAAV vector comprising a polynucleotide sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 30, 31, 35-37, 43-53, or 56-59. Recombinant Viral Genomes [0237] Aspects of the present disclosure relate to recombinant viral genomes comprising any of the therapeutic agents described herein. Examples of genetic sequences that may be found in recombinant viral genomes include, but are not limited to, engineered nucleic acids comprising a sequence encoding a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid), ITRs, LTRs, promoters, enhancers, WPREs, Ig-kappa leader sequences, introns, transcription initiation, termination, efficient RNA processing signals, such as splicing and polyadenylation (poly(A)) signals, sequences that stabilize cytoplasmic mRNA, sequences that enhance translation efficiency (e.g., Kozak consensus sequence), sequences that enhance protein stability, and when desired, sequences that enhance secretion of the encoded product. [0238] In some embodiments, recombinant viral genomes comprise deoxyribonucleotides. In some embodiments, recombinant viral genomes comprise ribonucleotides. In some embodiments, recombinant viral genomes comprise both deoxyribonucleotides and ribonucleotides. In some embodiments, recombinant viral genomes are single-stranded. In some embodiments, recombinant viral genomes are double-stranded. In some embodiments, recombinant viral genomes are circular. In some embodiments, recombinant viral genomes are linear. In some embodiments, a recombinant viral genome comprise an engineered nucleic acid or a vector comprising an engineered nucleic acid, such as a transgene. In some embodiments, a recombinant viral genome sequence encoding an engineered nucleic acid comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) can comprise a lentivirus sequence. In some embodiments, a recombinant viral genome sequence encoding an engineered nucleic acid comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) can comprise an rAAV sequence. In some embodiments, a recombinant viral genome comprising an engineered nucleic acid comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) is provided within a virus particle (e.g., a lentiviral or rAAV particle). [0239] In some embodiments, a recombinant viral genome comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) is sufficiently small to be effectively packaged in an AAV viral particle (e.g., the vector has a packaging capacity from 1 to 40 kb, for example from 1 to 30 kb, such as from 1 to 20 kb, for example from 1 to 15 kb, such as from 1 to 10, for example from 1 to 8 kb, such as from 2 to 7 kb, for example from 3 to 6 kb, such as from 4 to 5 kb). In order to fit into the AAV viral particle, in some embodiments an engineered nucleic acid comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) comprises one or more truncated and/or recombinant sequences, as described elsewhere herein. Accordingly, a truncated and/or recombinant sequence is typically shorter than 4 kb but can be between around 20 bases long and around 2,000 bases long to provide space for other components (e.g., exons, regulatory sequences, other introns, viral packaging sequences) in the nucleic acid (e.g., recombinant gene) construct. In some embodiments, a truncated and/or recombinant sequence is shorter than 4 kb, shorter than 3 kb, or shorter than 2 kb. [0240] In some embodiments, a recombinant viral genome comprises a sequence which is at least 75% (e.g., 75-80%, 80-85%, 85-90%, 90-95%, 95-99%, or more) identical to a sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43-59. In some embodiments, a recombinant viral genome comprises a sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43-59. [0241] In some embodiments, a recombinant viral genome comprises a sequence which is at least 75% (e.g., 75-80%, 80-85%, 85-90%, 90-95%, 95-99%, or more) identical to a sequence set forth in Table 6. In some embodiments, a recombinant viral genome comprising at least 75% identity to any one of SEQ ID NOs: 54-57 will comprise one or more of: a different set of ITRs or LTRs, a different promoter, enhancer, and/or other regulatory element, or a different SORL1 variant sequence. In some embodiments, a recombinant viral genome comprises a sequence set forth in any one of SEQ ID NOs: 54-57 (see Table 6). Table 6. Examples of Recombinant Viral Genomes Comprising SORL1 Variants

Lentiviruses [0242] In some embodiments, a transgene (or vector thereof) comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) is provided in a lentivirus or a lentivirus particle. In some embodiments, a viral vector comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) of the present disclosure comprises a recombinant lentivirus genome (e.g., a recombinant genome in a lentivirus particle). [0243] Lentiviruses are the only type of virus that are diploid; they have two strands of RNA. The lentivirus is a retrovirus, meaning it has a single stranded RNA genome with a reverse transcriptase enzyme, which functions to perform transcription of the viral genetic material upon entering the cell. Lentiviruses also have a viral envelope with protruding glycoproteins that aid in attachment to the outer membrane of a host cell. [0244] Within the lentivirus genome are RNA sequences that code for specific proteins that facilitate the incorporation of the viral sequences into genome of a host cell. The ends of the genome are flanked with long terminal repeats (LTRs). LTRs are necessary for integration of the dsDNA into the host chromosome. LTRs also serve as part of the promoter for transcription of the viral genes. [0245] Additionally, the “gag” gene codes for the structural components of the viral nucleocapsid proteins: the matrix (MA/p17), the capsid (CA/p24), and the nucleocapsid (NC/p7) proteins. The “pol” domain codes for the reverse transcriptase and integrase enzymes. The “env” domain of the viral genome encodes the glycoproteins of the envelope found on the surface of the virus. [0246] In some embodiments, the gag and/or pol vector(s) encoding components of the particle comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) do not contain a nucleic acid sequence from the lentiviral genome that expresses an Env protein. In some embodiments, a separate vector containing a nucleic acid sequence encoding an Env protein operably linked to a promoter is used (e.g., an env vector). In some embodiments, such env vector also does not contain a lentiviral packaging sequence. In some embodiments, the env nucleic acid sequence encodes a lentiviral envelope protein. [0247] In some embodiments, the lentivirus particle comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) is expressed by a vector system encoding the necessary viral proteins to produce a lentivirus particle comprising the therapeutic agent. In some embodiments, there is at least one vector containing a nucleic acid sequence encoding the lentiviral Pol proteins necessary for reverse transcription and integration operably linked to a promoter. In some embodiments, the Pol proteins are expressed by multiple vectors. In some embodiments, there is also a vector containing a nucleic acid sequence encoding the lentiviral gag proteins necessary for forming a viral capsid operably linked to a promoter. In some embodiments, the gag-pol genes are on the same vector. In some embodiments, the gag nucleic acid sequence is on a separate vector than at least some of the pol nucleic acid sequence. In some embodiments, the gag nucleic acid sequence is on a separate vector from all the pol nucleic acid sequences that encode Pol proteins. [0248] In some embodiments, the lentiviral vector comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) does not contain nucleic acid sequence from the lentiviral genome that packages lentiviral RNA, referred to as the lentiviral packaging sequence. [0249] It will be understood that selective inclusion of envelopes could result in changes in infectivity, such that the lentiviral vector could infect many different types of cells and could be targeted to specific cell types of interest. Accordingly, in some embodiments, the envelope protein is not from the lentivirus, but from a different virus. The resultant lentivirus particle is referred to as a pseudotyped particle. In some embodiments, env gene that encodes an envelope protein that targets an endocytic compartment, such as that of the influenza virus, VSV-G, alpha viruses (Semliki forest virus, Sindbis virus), arenaviruses (lymphocytic choriomeningitis virus), flaviviruses (tick-borne encephalitis virus, Dengue virus), rhabdoviruses (vesicular stomatitis virus, rabies virus), and orthomyxoviruses (influenza virus) is used. [0250] In some embodiments, the lentivirus or lentivirus particle comprising a therapeutic agent (e.g. a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) is a human immunodeficiency virus (HIV1 or HIV2), a feline immunodeficiency virus (FIV), a bovine immunodeficiency virus (BIV), a caprine arthritis encephalitis virus, an equine infectious anemia virus, a Jembrana disease virus, a puma lentivirus, Simian immunodeficiency virus, or a Visna-maedi virus. [0251] In some embodiments, a nucleic acid sequence encoding a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including transgenes thereof) is inserted into the empty lentiviral particles by use of a plurality of vectors each containing a nucleic acid segment of interest (e.g., a transgene encoding a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) and a lentiviral packaging sequence necessary to package lentiviral RNA into the lentiviral particles (the packaging vector). In some embodiments, the packaging vector contains a 5′ and 3′ lentiviral LTR with the desired nucleic acid segment (e.g., a transgene encoding a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) inserted between them. [0252] In some embodiments, the packaging vector contains a selectable marker gene. Such marker genes are well known in the art and include such genes as green fluorescent protein (GFP), mNeonGreen, GFP, EGFP, Superfold GFP, Azami Green, mWasabi, TagGFP, TurboGFP, acGFP, zsGreen, T-sapphire, EBFP, EBFP2, Azurite, TagBFP, ECFP, mECFP, Cerulean, mTurquoise, CyPet, AmCyan1, TagCFP, mTFP1, EYFP, mCitrine, TagYFP, phiYFP, zsYellow1, mBanana, Kusabira Orange, mOrange, dTomato, DsRed, mTangerine, mRuby, mApple, mStrawberry, AsRed2, mRFP1, mCherry, HcRed1, iRFP720, and AQ143, blue fluorescent protein (BFP), luciferase, β-galactosidase, and LacZ,. [0253] Additional examples of lentiviruses, lentiviral vectors, and methods of use thereof are described in U.S. Patent No.: 8,420,104 B2, U.S. Patent No.: 5,994,136, U.S. Patent No.: 6,207,455 B1, WO2006/089001 A2, Merten et al., Methods Clin. Dev., 3:16017 (2016), Sakuma et al., Biochem. J., 443(3):603-618 (2012), Tiscornia et al., Nature Prot., 1:241-245 (2006) which are incorporated by reference herein for disclosures related to producing lentiviruses and administering lentiviruses. Recombinant Adeno-Associated Viruses (rAAVs) [0254] In other aspects, the present disclosure provides a recombinant adeno-associated virus genome comprising a viral vector comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid). Accordingly, engineered nucleic acids comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) of this disclosure may be recombinant adeno-associated virus (rAAV) vectors. [0255] “Recombinant AAV (rAAV) vectors” typically comprise, at a minimum, a transgene including its regulatory sequences, and 5' and 3' AAV inverted terminal repeats (ITRs). In some embodiments, the 5' and 3' ITRs may be alternatively referred to as “first” and “second” ITRs, respectively. The rAAVs of the present disclosure may comprise a transgene comprising a sequence encoding a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) region in addition to expression control sequences (e.g., a promoter, an enhancer, a poly(A) signal, etc.) as described elsewhere in this disclosure. [0256] In some embodiments, the rAAV vectors comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) of the present disclosure comprise at least, in order from 5’ to 3’, a first adeno-associated virus (AAV) inverted terminal repeat (ITR) sequence, a promoter operably linked to the sequence of the transgene a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid), a polyadenylation signal, and a second AAV inverted terminal repeat (ITR) sequence. In some embodiments, the rAAV vector genome comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) is circular. In some embodiments, the rAAV vector genome comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) is linear. In some embodiments, the rAAV vector genome comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) is single-stranded. In some embodiments, the rAAV vector genome comprising a SORL1 variant or retromer complex subunit is double-stranded. In some embodiments, the rAAV genome vector genome comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) is a self-complementary rAAV vector. [0257] Inverted terminal repeat (ITR) sequences are about 145 bp in length. While the entire sequences encoding the ITRs are commonly used in engineering rAAVs, some degree of minor modification of these sequences is permissible. The ability to modify these ITR sequences is within the capabilities of one of ordinary skill in the pertinent the art. (See, e.g., texts such as Sambrook et al., Molecular Cloning. A Laboratory Manual, 2d ed., Cold Spring Harbor Laboratory, New York (1989); and K. Fisher et al., J Virol., 70:520532 (1996) which are incorporated by reference for disclosures related to rAAV production). [0258] The rAAV particles comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) or particles within an rAAV preparation comprising a therapeutic agent disclosed herein, may be of any AAV serotype, including any derivative or pseudotype (e.g., AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV2/1, AAV2/5, AAV2/8, AAV2/9, AAV3/1, AAV3/5, AAV3/8, or AAV3/9). As used herein, the serotype of an rAAV refers to the serotype of the capsid proteins of the recombinant virus. Non-limiting examples of derivatives, pseudotypes, and/or other vector types include, but are not limited to, AAVrh.10, AAVrh.74, AAV2/1, AAV2/5, AAV2/6, AAV2/8, AAV2/9, AAV2-AAV3 hybrid, AAVhu.14, AAV3a/3b, AAVrh32.33, AAV-HSC15, AAV- HSC17, AAVhu.37, AAVrh.8, CHt-P6, AAV2.5, AAV6.2, AAV2i8, AAV-HSC15/17, AAVM41, AAV9.45, AAV6(Y445F/Y731F), AAV2.5T, AAV-HAE1/2, AAV clone 32/83, AAVShHIO, AAV2 (Y->F), AAV8 (Y733F), AAV2.15, AAV2.4, AAVM41, and AAVr3.45. Such AAV serotypes and derivatives/pseudotypes, and methods of producing such derivatives/pseudotypes are known in the art (see, e.g., Mol. Ther.2012 Apr;20(4):699- 708. doi: 10.1038/mt.2011.287. Epub 2012 Jan 24. The AAV vector toolkit: poised at the clinical crossroads. Asokan Al, Schaffer DV, Samulski RJ.). Methods for producing and using pseudotyped rAAV vectors are known in the art (see, e.g., Duan et al, J. Virol., 75:7662-7671, 2001; Halbert et al, J. Virol., 74:1524-1532, 2000; Zolotukhin et al, Methods, 28:158-167, 2002; and Auricchio et al., Hum. Molec. Genet., 10:3075-3081, 2001). In some embodiments, the rAAV comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) is pseudotyped. In some embodiments, the rAAV comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) is of serotype AAV9. [0259] The components to be cultured in the host cell to package a rAAV vector comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) in an AAV capsid may be provided to the host cell in trans. Alternatively, any one or more of the required components (e.g., recombinant AAV vector, rep sequences, cap sequences, and/or helper functions, such as an E1 gene, E2A gene, E4 gene, and/or VA gene) can be provided by a stable host cell which has been engineered to contain one or more of the required components using methods known to those of skill in the art. Such a stable host cell will contain the required component(s) under the control of either an inducible promoter or a constitutive promoter. Examples of suitable inducible and constitutive promoters are provided herein in the discussion of regulatory elements suitable for use with the transgene. [0260] The recombinant AAV vector(s) comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid), rep sequences, cap sequences, and helper functions required for producing the rAAV comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) of this disclosure may be delivered to the packaging host cell using any appropriate genetic element (e.g., a vector). The selected genetic element may be delivered by any suitable method including those described herein. The methods used to construct any embodiment of this disclosure are known to those with skill in nucleic acid manipulation and include genetic engineering, recombinant engineering, and synthetic techniques. See, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. Similarly, methods of generating rAAV virions comprising a SORL1 variant or retromer complex subunit are well known and the selection of a suitable method is not a limitation on this disclosure. See, e.g., K. Fisher et al., J. Virol., 70:520-532 (1993) and U.S. Pat. No.5,478,745. [0261] In some embodiments, recombinant AAVs comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) can be produced using the triple transfection method (described in detail in U.S. Pat. No.6,001,650). Typically, the recombinant AAVs are produced by transfecting a host cell with an AAV vector (comprising a transgene flanked by ITR elements) to be packaged into AAV particles, an AAV helper function vector, and an accessory function vector. An AAV helper function vector encodes the “AAV helper function” sequences (e.g., rep and cap), which function in trans for productive AAV replication and encapsidation. Preferably, the AAV helper function vector supports efficient AAV vector production without generating any detectable wild-type AAV virions (e.g., AAV virions containing functional rep and cap genes). The accessory function vector encodes nucleotide sequences for non-AAV derived viral and/or cellular functions upon which AAV is dependent for replication (e.g., “accessory functions”). The accessory functions include those functions required for AAV replication, including, without limitation, those moieties involved in activation of AAV gene transcription, stage specific AAV mRNA splicing, AAV DNA replication, synthesis of cap expression products, and AAV capsid assembly. Viral-based accessory functions can be derived from any of the known helper viruses, such as adenovirus, herpes virus (other than herpes simplex virus type-1), and vaccinia virus. [0262] The rAAV vectors and rAAV particles comprising a therapeutic agent (e.g., a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid) as described herein may be used for therapy (e.g., gene therapy and/or gene-editing therapy) in a subject in need thereof. In some embodiments, the subject has been diagnosed with or is susceptible to developing a disease, disorder, or condition associated with abnormal endosomal trafficking, increased amyloid plaque levels, and/or increased intracellular fibrillary tangles comprised of hyperphosphorylated tau proteins. In some embodiments, the subject is an experimental/research animal. In some embodiments, the subject is a human. In some embodiments, the human subject has been diagnosed or is susceptible to developing a neurological disease, disorder, or condition (i.e., one that effects tissues of the central nervous system and/or the peripheral nervous system). In some embodiments, the neurological disease, disorder, or condition is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is selected from the group consisting of Parkinson’s Disease, Dementia, Pick’s Disease, Lewy Body Dementia, Huntington’s Disease, Alzheimer’s disease, Early-Onset Alzheimer’s disease, Late-Onset Alzheimer’s disease, Sporadic late-onset Alzheimer’s disease, SORL1-positive Alzheimer’s disease, APOE4-positive Alzheimer’s disease, Familial Alzheimer’s disease, frontotemporal disorders associated with neurodegeneration, Niemann Pick Type I, Neuronal Ceroid Lipofuscinosis, Hereditary Spastic Paraparesis, Amyotrophic Lateral Sclerosis, tauopathies, such as progressive supranuclear palsy, and Steele-Richardson-Olszewski Syndrome, and diseases that are associated with TDP-43 pathologies. In some embodiments, the human subject is characterized as having or suspected of having a disease-associated mutation in SORL1 described herein. Compositions [0263] In some aspects, the present disclosure provides a variety of compositions (e.g., pharmaceutical compositions) comprising a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein. [0264] In some embodiments, a composition comprises a SORL1 variant polypeptide or retromer complex subunit. In some embodiments, the composition comprises a SORL1 variant polypeptide wherein the polypeptide comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 13-24, 27-28, or 127. In some embodiments, the composition comprises a SORL1 variant polypeptide set forth in any one of SEQ ID NOs: 13-24, 27-28, or 127. [0265] In some embodiments, the composition comprises an engineered nucleic acid encoding a SORL1 variant, retromer complex subunit, inhibitory nucleic acid, Cas molecule, gRNA, and/or repair template. In some embodiments, the composition comprises an engineered nucleic acid comprising a SORL1 variant, wherein the engineered nucleic acid comprises a sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43-59. In some embodiments, the composition comprises an engineered nucleic acid comprising a SORL1 variant, wherein the engineered nucleic acid comprises the sequence set forth in SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43-59. [0266] In some embodiments, the composition comprises a transgene comprising a SORL1 variant, retromer complex subunit, inhibitory nucleic acid, Cas molecule, gRNA, and/or repair template. In some embodiments, the composition comprises a transgene comprising a SORL1 variant, wherein the transgene comprises a sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43-59. In some embodiments, the composition comprises a transgene comprising a SORL1 variant, wherein the transgene comprises a sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43- 59. [0267] In some embodiments, the composition comprises a vector comprising a SORL1 variant or retromer complex subunit. In some embodiments, the composition comprises a vector comprising a SORL1 variant, wherein the vector comprises a sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43-59. In some embodiments, the composition comprises a vector comprising a SORL1 variant, wherein the vector comprises the sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35- 37, or 43-59. [0268] In some embodiments, the composition comprises a lentiviral vector comprising a SORL1 variant or retromer complex subunit. In some embodiments, the composition comprises a lentiviral vector comprising a SORL1 variant, wherein the lentiviral vector comprises a sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 1-12, 25-26, 29, 32, 35-37, or 43-55. In some embodiments, the composition comprises a lentiviral vector comprising a SORL1 variant, wherein the lentiviral vector comprises the sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 29, 32, 35-37, or 43-55. [0269] In some embodiments, the composition comprises a rAAV vector comprising a SORL1 variant or retromer complex subunit. In some embodiments, the composition comprises a rAAV vector comprising a SORL1 variant, wherein the rAAV vector comprises a sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 1-12, 25-26, 30, 31, 35-37, 43-53, or 56- 59. In some embodiments, the composition comprises a rAAV vector comprising a SORL1 variant, wherein the rAAV vector comprises the sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 30, 31, 35-37, 43-53, or 56-59. [0270] In some embodiments, the composition comprises a recombinant viral genome comprising a SORL1 variant or retromer complex subunit. In some embodiments, the composition comprises a recombinant viral genome comprising a SORL1 variant. In some embodiments, the composition comprises a recombinant viral genome comprising a SORL1 variant, wherein the recombinant viral genome comprises a sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 1-12, 25-26, 29, 32, 35-37, 43-55, or 58-59. In some embodiments, the composition comprises a recombinant viral genome comprising a SORL1 variant, wherein the recombinant viral genome comprises the sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 29, 32, 35-37, 43-55, or 58-59. [0271] In some embodiments, the composition comprises a lentivirus comprising a SORL1 variant or retromer complex subunit. In some embodiments, the composition comprises a lentivirus comprising a SORL1 variant, wherein the composition further comprises an envelope vector and at least one packaging plasmid described herein. In some embodiments, the composition comprises a lentivirus, wherein the lentivirus comprises a SORL1 variant, an envelope vector, and at least one packaging plasmid described herein. In some embodiments, the composition comprises a lentivirus comprising lentiviral vector comprising a SORL1 variant, wherein the lentiviral vector comprises a sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 1-12, 25-26, 29, 32, 35-37, 43-55, or 58-59. In some embodiments, the composition comprises a lentivirus comprising a lentiviral vector comprising a SORL1 variant, wherein the lentiviral vector comprises the sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 29, 32, 35-37, 43-55, or 58-59. In some embodiments, the composition comprises a lentivirus comprising a recombinant viral genome comprising a SORL1 variant, wherein the recombinant viral genome comprises a sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 1-12, 25-26, 29, 32, 35-37, 43-55, or 58-59. In some embodiments, the composition comprises a lentivirus comprising a recombinant viral genome comprising a SORL1 variant, wherein the recombinant viral genome comprises the sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 29, 32, 35-37, 43-55, or 58-59. In some embodiments, the composition comprises a lentivirus comprising a lentiviral vector or a recombinant viral genome comprising a SORL1 variant, wherein the lentiviral vector or recombinant viral genome comprises a sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 1-12, 25-26, 29, 32, 35-37, 43- 55, or 58-59, wherein the composition further comprises an envelope vector, and at least one packaging plasmid described herein. In some embodiments, the composition comprises a lentivirus comprising a lentiviral vector or a recombinant viral genome comprising a SORL1 variant, wherein the lentiviral vector or recombinant viral genome comprises the sequence set forth in SEQ ID NO: 1-12, 25-26, 29, 32, 35-37, 43-55, or 58-59, wherein the composition further comprises an envelope vector, and at least one packaging plasmid described herein. In some embodiments, the composition comprises a lentivirus comprising a lentiviral vector or a recombinant viral genome comprising a SORL1 variant, wherein the lentiviral vector or recombinant viral genome comprises a sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 1- 12, 25-26, 29, 32, 35-37, 43-55, or 58-59, wherein the lentivirus further comprises an envelope vector, and at least one packaging plasmid described herein. In some embodiments, the composition comprises a lentivirus comprising a lentiviral vector or a recombinant viral genome comprising a SORL1 variant, wherein the lentiviral vector or recombinant viral genome comprises the sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 29, 32, 35- 37, 43-55, or 58-59, wherein the lentivirus further comprises an envelope vector, and at least one packaging plasmid described herein. [0272] In some embodiments, the composition comprises an rAAV comprising a SORL1 variant or retromer complex subunit. In some embodiments, the composition comprises an rAAV comprising a SORL1 variant or retromer complex subunit, wherein the composition further comprises at least one helper plasmid described herein. In some embodiments, the composition comprises an rAAV comprising a SORL1 variant or retromer complex subunit, wherein the composition further comprises at least one helper plasmid, wherein the helper plasmid comprises a rep gene and a cap gene described herein. In some embodiments, the composition comprises an rAAV, wherein the rAAV comprises a SORL1 variant or retromer complex subunit and at least one helper plasmid described herein. In some embodiments, the composition comprises an rAAV, wherein the rAAV comprises a SORL1 variant or retromer complex subunit and at least one helper plasmid, wherein the helper plasmid comprises a rep gene and a cap gene described herein. In some embodiments, the composition comprises an rAAV comprising an rAAV vector comprising a SORL1 variant, wherein the rAAV vector comprises a sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 1- 12, 25-26, 30, 31, 35-37, 43-53, or 56-59. In some embodiments, the composition comprises an rAAV comprising a rAAV vector comprising a SORL1 variant, wherein the rAAV vector comprises the sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 30, 31, 35-37, 43- 53, or 56-59. In some embodiments, the composition comprises an rAAV comprising a recombinant viral genome comprising a SORL1 variant, wherein the recombinant viral genome comprises a sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 1-12, 25-26, 30, 31, 35-37, 43-53, or 56-59. In some embodiments, the composition comprises an rAAV comprising a recombinant viral genome comprising a SORL1 variant, wherein the recombinant viral genome comprises the sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 30, 31, 35-37, 43-53, or 56-59. In some embodiments, the composition comprises an rAAV comprising an rAAV vector or a recombinant viral genome comprising a SORL1 variant, wherein the rAAV vector or recombinant viral genome comprises a sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 1-12, 25-26, 30, 31, 35-37, 43-53, or 56-59, wherein the composition further comprises at least one helper plasmid described herein. In some embodiments, the composition comprises an rAAV comprising an rAAV vector or a recombinant viral genome comprising a SORL1 variant, wherein the rAAV vector or recombinant viral genome comprises a sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 1- 12, 25-26, 30, 31, 35-37, 43-53, or 56-59, wherein the composition further comprises at least one helper plasmid, wherein the helper plasmid comprises a rep gene and a cap gene described herein. In some embodiments, the composition comprises an rAAV comprising an rAAV vector or a recombinant viral genome comprising a SORL1 variant, wherein the rAAV vector or recombinant viral genome comprises the sequence set forth in SEQ ID NO: 1-12, 25-26, 30, 31, 35-37, 43-53, or 56-59, wherein the composition further comprises at least one helper plasmid. In some embodiments, the composition comprises an rAAV comprising an rAAV vector or a recombinant viral genome comprising a SORL1 variant, wherein the rAAV vector or recombinant viral genome comprises the sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 30, 31, 35-37, 43-53, or 56-59, wherein the composition further comprises at least one helper plasmid, wherein the helper plasmid comprises a rep gene and a cap gene described herein. In some embodiments, the composition comprises an rAAV comprising a rAAV vector or a recombinant viral genome comprising a SORL1 variant, wherein the rAAV vector or recombinant viral genome comprises a sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 1-12, 25-26, 30, 31, 35-37, 43-53, or 56-59, wherein the rAAV further comprises at least one helper plasmid described herein. In some embodiments, the composition comprises an rAAV comprising a rAAV vector or a recombinant viral genome comprising a SORL1 variant, wherein the rAAV vector or recombinant viral genome comprises a sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 1-12, 25-26, 30, 31, 35-37, 43-53, or 56-59, wherein the rAAV further comprises at least one helper plasmid, wherein the helper plasmid comprises a rep gene and a cap gene described herein. In some embodiments, the composition comprises an rAAV comprising a rAAV vector or a recombinant viral genome comprising a SORL1 variant, wherein the rAAV vector or recombinant viral genome comprises the sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 30, 31, 35-37, 43-53, or 56-59, wherein the rAAV further comprises at least one helper plasmid described herein. In some embodiments, the composition comprises an rAAV comprising a rAAV vector or a recombinant viral genome comprising a SORL1 variant, wherein the rAAV vector or recombinant viral genome comprises the sequence set forth in any one of SEQ ID NOs: 1-12, 25-26, 30, 31, 35-37, 43- 53, or 56-59, wherein the rAAV further comprises at least one helper plasmid, wherein the helper plasmid comprises a rep gene and a cap gene described herein. [0273] In some embodiments, compositions comprising a therapeutic agent is stable under the conditions of manufacture and storage, and is preserved against the contaminating action of microorganisms and pathogens, such as bacteria, fungi and viruses. In some embodiments, the composition is sterilized prior to storage. In some embodiments, the composition is manufactured and stored as a dried or dehydrated powder or as a lyophilized (i.e., partially or fully dehydrated following freezing and placed under a vacuum) substance. In some embodiments, the composition is manufactured and stored as a liquid. In some embodiments, the composition is manufactured and stored as a sterile liquid. In some embodiments, the composition is prepared from a powder or lyophilized substance by solvation and sterile-filtered prior to use. [0274] Compositions comprising a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) may further optionally comprise a liposome, a lipid, a lipid complex, a lipid nanoparticle, a microsphere, a microparticle, a nanosphere, or a nanoparticle, or may be otherwise formulated for administration to the cells, biological samples, tissues, organs, or body of a subject in need thereof. [0275] Compositions comprising a therapeutic agent described herein may further comprise a pharmaceutical excipient. Pharmaceutically acceptable excipients (excipients) are substances other than the therapeutic agent (i.e., a small molecule such as an aminoguanidine hydrazone or a retromer chaperone, a biologic, a SORL1 variant polypeptide or retromer complex subunit, an engineered nucleic acid encoding a SORL1 variant or retromer complex subunit, a lentivirus comprising a SORL1 variant or retromer complex subunit, or an rAAV comprising a SORL1 variant or retromer complex subunit, an ASO targeting a SORL1 encoding a disease-associated mutation, or a ribonucleoprotein complex capable of correcting a disease-associated mutation in SORL1) that are intentionally included in the drug delivery system. Excipients do not exert or are not intended to exert a therapeutic effect at the intended dosage. Excipients may act to a) aid in processing of the drug delivery system during manufacture, b) protect, support or enhance stability, bioavailability or patient acceptability of the API, c) assist in product identification, and/or d) enhance any other attribute of the overall safety, effectiveness, or delivery of the therapeutic agent during storage or use. A pharmaceutically acceptable excipient may or may not be an inert substance. Excipients include, but are not limited to, absorption enhancers, anti-adherents, anti-foaming agents, anti-oxidants, binders, buffering agents, carriers, coating agents, colors, delivery enhancers, delivery polymers, dextran, dextrose, diluents, disintegrants, emulsifiers, extenders, fillers, flavors, glidants, humectants, lubricants, oils, polymers, preservatives, saline, salts, solvents, sugars, suspending agents, sustained release matrices, sweeteners, thickening agents, tonicity agents, vehicles, water-repelling agents, and wetting agents. [0276] The pharmaceutical compositions comprising a therapeutic agent can contain other additional components commonly found in pharmaceutical compositions. Such additional components can include, but are not limited to: anti-pruritics, astringents, local anesthetics, or anti-inflammatory agents (e.g., antihistamine, diphenhydramine). In fact, there is virtually no limit to the components of a composition comprising a therapeutic agent and may also include any of those that are Generally Recognized as Safe (GRAS) by the United States Food and Drug Administration [0277] Compositions comprising a therapeutic agent may be suitable for treatment regimens and thereby administered to a subject via a variety of methods described herein. Such compositions may be formulated for use in a variety of therapies, such as, for example, in the amelioration, prevention, and/or treatment of conditions, such as those related to the expression of a SORL1 mutant. Accordingly, the compositions comprising a therapeutic agent described herein may be administered to a subject, such as human or non-human subjects, a host cell in situ in a subject, a host cell ex vivo, a host cell derived from a subject, or a biological sample (e.g., one derived from a subject). Methods of Administration [0278] Aspects of the disclosure also relate to methods comprising the administration of therapeutic agents (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein. In some embodiments, a method comprises administering a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein to a subject in need thereof. In some embodiments, a method described herein is useful for treating a subject in need thereof (e.g., a human subject who is characterized as having or suspected of having a neurological disease, such as a neurodegenerative disease, such as a subject who is characterized as having or suspected of having a disease-associated mutation in SORL1). In some embodiments, a method of administration described herein (e.g., a method of treating a subject in need thereof) comprises administering a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein in an amount which is effective (alternatively referred to as an effective amount) of reducing, preventing, and/or reversing one or more symptoms of a disease, disorder, or condition (e.g., a disease, disorder, or condition of the nervous system, such as a neurological disease). [0279] Administration of combination therapies is also provided by the disclosure. A combination therapy will typically involve administration of two more therapeutic agents to a subject. The two more therapeutic agents can comprise any combination of a small molecule therapy, a gene therapy, or a gene-editing therapy described herein. [0280] In some embodiments, administration of a composition comprising a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) achieves one, two, three, four, or more of the following effects, including, for example: (i) reduction or amelioration the severity of disease, disorder, or condition or symptom associated therewith; (ii) reduction in the duration of a symptom associated with a disease, disorder, or condition; (iii) protection against the progression of a disease or disorder or symptom associated therewith; (iv) regression of a disease, disorder, or condition or symptom associated therewith; (v) protection against the development or onset of a symptom associated with a disease, disorder, or condition; (vi) protection against the recurrence of a symptom associated with a disease; (vii) reduction in the hospitalization of a subject; (viii) reduction in the hospitalization length; (ix) an increase in the survival of a subject with a disease; (x) a reduction in the number of symptoms associated with a disease, disorder, or condition; (xi) an enhancement, improvement, supplementation, complementation, or augmentation of the prophylactic or therapeutic effect(s) of another therapy. [0281] Administering a combination therapy can be used to achieve more than one therapeutic effect in a subject. For example, inhibiting expression of a SORL1 protein comprising a disease-associated mutation can be achieved by administration of an inhibitory nucleic acid that binds to a nucleic acid (e.g., an RNA transcript) encoding the SORL1 protein comprising a disease-associated mutation while a SORL1 variant protein can be expressed to replace the function of the SORL1 protein comprising the disease-associated mutation. As a further example, expression of a SORL1 protein comprising a disease- associated mutation can be decreased by using a gene-editing therapy while a SORL1 variant protein can be expressed to replace the function of the SORL1 protein comprising the disease-associated mutation. Further, aminoguanidine hydrazone or retromer chaperone small molecule therapies can be administered to stabilize and/or increase retromer activity while inhibition of a SORL1 protein comprising a disease-associated mutation (e.g., via administration of an inhibitory nucleic acid and/or a gene editing therapy) and/or expression of a SORL1 variant is used to modulate SORL1-dependent functions. [0282] Administration of an agent to a subject (e.g., a human subject) can be performed once the subject is known to have or when the subject is suspected of having a disease, disorder, or condition. In some embodiments, the disease, disorder, or condition is associated with a mutation in the VPS10p domain, 10CC domain, YWTD domain, EGF domain, the CR domain, the FnIII domain, the transmembrane domain, or the cytoplasmic tail domain. In some embodiments, the disease, disorder, or condition is associated with a pathogenic mutation as set forth in Table 13. [0283] In some embodiments, the disease, disorder, or condition is associated with a mutation in any one of positions: R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹,

L³⁷², Y³⁷³, I³⁷⁴, V⁴⁴¹, I⁴⁴², V⁵²⁰, Y⁵²¹, I⁵²², L⁵⁶¹, Y⁵⁶³, L⁶¹³, V⁶¹⁵, S¹³⁸, D¹⁴⁰, G¹⁴², S¹⁴⁴, F¹⁴⁵, T¹⁹⁰, D¹⁹², T¹⁹⁶, S²³⁴, D²³⁶, G²³⁸, T²⁴⁰, W²⁴¹, S²⁸⁰, D²⁸², S²⁸⁶, S³²⁹, S³⁷⁵, G³⁷⁹, F³⁸², T⁴⁴³, D⁴⁴⁵, G⁴⁴⁷, T⁴⁴⁹, W⁴⁵⁰, S⁵²³, G⁵²⁷, W⁵³⁰, S⁵⁶⁴, N⁵⁶⁶, G⁵⁶⁸, T⁵⁷⁰, W⁵⁷¹, C⁴⁶⁷, or C⁴⁷³ in the VPS10p domain; C⁶²⁵, C⁶⁴³, C⁶⁶⁰, C⁶⁷⁵, C⁶⁷⁷, C⁶⁸⁴, C⁶⁹⁹, C⁷¹⁶, C⁷³⁶, or C⁷⁵² in the 10CC domain; L⁷⁹³, F⁷⁹⁵, L⁸⁰², L⁸³⁷, F⁸³⁹, L⁸⁴⁶, L⁸⁸¹, L⁸⁸³, M⁸⁹⁰, I⁹²⁶, V⁹²⁸, I⁹³³, I⁹⁶⁶, V⁹⁶⁸, I⁹⁷³, M¹⁰⁰⁷, I¹⁰⁰⁹, L⁷⁸², V⁸²⁵, I⁸²⁶, I⁸⁶⁹, V⁸⁷⁰, L⁹¹⁵, V⁹¹⁶, I⁹⁵⁶, L⁹⁵⁷, I⁹⁹⁶, L⁹⁹⁷, L⁷⁸⁷, L⁸³¹, L⁸⁷⁵, V⁹²⁰, L⁹⁶⁰, L¹⁰⁰¹, R⁸⁷⁹, W⁸⁹⁵, N⁹²⁴, Y⁹⁶⁴, W⁹⁷⁸, Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶, Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, T⁹³⁶, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³, I⁹⁸³, R⁷⁷¹, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, G⁷⁷⁷, G⁸¹⁹, G⁸⁶³, G⁹⁰⁹, G⁹⁵⁰, G⁹⁹¹, R⁸⁶⁶, R⁹⁵³, C⁸⁰¹, or C⁸¹⁶ in the YWTD doman; C¹⁰²¹, C¹⁰²⁶, C¹⁰³⁰, C¹⁰⁴⁰, C¹⁰⁴², C¹⁰⁵⁸, C¹⁰⁶⁰, or C¹⁰⁷¹ in the EGF domain; S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹²⁹⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁴⁰, G¹⁴⁹³, G¹⁵³⁶, D¹⁰⁹⁸, D¹¹⁰², D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸², D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, D¹²⁶⁷, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁴⁹, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁴⁴, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁵³, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁰, C¹⁵⁴⁹, D¹¹⁰⁵, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴, D¹³⁵², D¹³⁹⁶, D¹⁴⁴⁶, D¹⁴⁹⁹, or D¹⁵⁴² in the

V¹⁵⁷¹, L¹⁵⁷³, I¹⁶⁶⁹, L¹⁷⁶³, F¹⁷⁶⁵, V¹⁸⁵⁸, C¹⁸⁶⁰, V¹⁹⁴⁸, I¹⁹⁵⁰, V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², W¹⁷³⁵, P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, P¹⁹⁵⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹, P¹⁹⁹⁸, R¹⁹¹⁰, C¹⁵⁸⁶, C¹⁶³¹, C²¹⁰¹, or C²¹⁰⁸ in the FnIII domain; or F²¹⁷², A²¹⁷³, N²¹⁷⁴, S²¹⁷⁵, H²¹⁷⁶, Y²¹⁷⁷, D²¹⁹⁰, D²¹⁹¹, L²¹⁹², G²¹⁹³, E²¹⁹⁴, D²¹⁹⁵, D²¹⁹⁶, E²¹⁹⁷, D²¹⁹⁸, D²²⁰⁷, D²²⁰⁸, V²²⁰⁹, P²²¹⁰, M²²¹¹, V²²¹², I²²¹³, or A²²¹⁴ in the cytoplasmic tail domain; or any combination thereof. In some embodiments, the disease, disorder, or condition is associated with a mutation in any one of positions: R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹, F⁴¹⁴, L⁴⁹⁵, Y⁵³⁹, Y⁵⁴⁰, V⁵⁸³, Y⁵⁸⁴, I¹¹⁷, V¹¹⁸, A¹¹⁹, Y¹⁷⁷, I¹⁷⁸, F¹⁷⁹, L²¹⁸, L²¹⁹, L²²⁰, I²⁶⁴, Y²⁶⁵, I²⁶⁶, Y³⁰⁶, F³⁰⁸, V³⁵⁹, F³⁶⁰, V³⁶¹,

YWTD domain; C¹⁰²¹, C¹⁰²⁶, C¹⁰³⁰, C¹⁰⁴⁰, C¹⁰⁴², C¹⁰⁵⁸, C¹⁰⁶⁰, or C¹⁰⁷¹ in the EGF domain; S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁹³, G¹⁵³⁶, D¹⁰⁹⁸, D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁹, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴,

V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², W¹⁷³⁵, P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³,

Y²¹⁷⁷, D²¹⁹⁰, D²¹⁹¹, L²¹⁹², G²¹⁹³, E²¹⁹⁴, D²¹⁹⁵, D²¹⁹⁶, E²¹⁹⁷, D²¹⁹⁸, D²²⁰⁷, D²²⁰⁸, V²²⁰⁹, P²²¹⁰, M²²¹¹, V²²¹², I²²¹³, or A²²¹⁴ in the cytoplasmic tail domain; or any combination thereof. [0284] In some embodiments, the disease, disorder, or condition is associated with a mutation in the VPS10p domain of SORL1. In some embodiments, the mutation in the VPS10p domain confers a moderate risk of developing Alzheimer’s disease. In some embodiments, the mutation in the VPS10p domain of SORL1 which confers a moderate risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹, Y³⁵⁰, F⁴¹⁴, L⁴⁹⁵, Y⁵³⁹, Y⁵⁴⁰, V⁵⁸³,

V³⁶¹, Y⁴²⁴, I⁴²⁵, A⁴²⁶,I⁵⁰⁴, I⁵⁰⁵, A⁵⁰⁶, I⁵⁴⁸, I⁵⁴⁹, V⁵⁹⁶, F⁵⁹⁷, V¹³⁵, Y¹³⁶, V¹³⁷, L¹⁸⁷, W¹⁸⁸, I¹⁸⁹, L²³¹, W²³², V²⁷⁷, F²⁷⁸, L³²⁶, W³²⁷, V³²⁸, L³⁷², Y³⁷³, I³⁷⁴, V⁴⁴¹, I⁴⁴², V⁵²⁰, Y⁵²¹, I⁵²², L⁵⁶¹, Y⁵⁶³, L⁶¹³, and V⁶¹⁵. In some embodiments, the mutation in the VPS10p domain of SORL1 which confers a moderate risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹, F⁴¹⁴, L⁴⁹⁵, Y⁵³⁹, Y⁵⁴⁰, V⁵⁸³, Y⁵⁸⁴, I¹¹⁷, V¹¹⁸, A¹¹⁹, Y¹⁷⁷, I¹⁷⁸, F¹⁷⁹, L²¹⁸, L²¹⁹, L²²⁰, I²⁶⁴, Y²⁶⁵, I²⁶⁶, Y³⁰⁶, F³⁰⁸, V³⁵⁹, F³⁶⁰, V³⁶¹, Y⁴²⁴, I⁴²⁵, A⁴²⁶,I⁵⁰⁴, I⁵⁰⁵, A⁵⁰⁶, I⁵⁴⁸, I⁵⁴⁹, V⁵⁹⁶, F⁵⁹⁷, V¹³⁵, Y¹³⁶, V¹³⁷, L¹⁸⁷, W¹⁸⁸, I¹⁸⁹, L²³¹, W²³², V²⁷⁷, F²⁷⁸, L³²⁶, W³²⁷, V³²⁸, L³⁷², Y³⁷³, I³⁷⁴, V⁴⁴¹, I⁴⁴², V⁵²⁰, Y⁵²¹, I⁵²², L⁵⁶¹, Y⁵⁶³, L⁶¹³, and V⁶¹⁵. In some embodiments, the mutation in the VPS10p domain confers a high risk of developing Alzheimer’s disease. In some embodiments, the mutation in the VPS10p domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of S¹³⁸, D¹⁴⁰, G¹⁴², S¹⁴⁴, F¹⁴⁵, T¹⁹⁰, D¹⁹², T¹⁹⁶, S²³⁴, D²³⁶, G²³⁸, T²⁴⁰, W²⁴¹, S²⁸⁰, D²⁸², S²⁸⁶, S³²⁹, S³⁷⁵, G³⁷⁹, F³⁸², T⁴⁴³, D⁴⁴⁵, G⁴⁴⁷, T⁴⁴⁹, W⁴⁵⁰, S⁵²³, G⁵²⁷, W⁵³⁰, S⁵⁶⁴, N⁵⁶⁶, G⁵⁶⁸, T⁵⁷⁰, W⁵⁷¹, C⁴⁶⁷, and C⁴⁷³. In some embodiments, the mutation in the VPS10p domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of S¹³⁸, G¹⁴², S¹⁴⁴, F¹⁴⁵, T¹⁹⁰, D¹⁹², T¹⁹⁶, S²³⁴, D²³⁶, G²³⁸, T²⁴⁰, W²⁴¹, S²⁸⁰, D²⁸², S²⁸⁶, S³²⁹, S³⁷⁵, G³⁷⁹, F³⁸², T⁴⁴³, D⁴⁴⁵, G⁴⁴⁷, T⁴⁴⁹, W⁴⁵⁰, S⁵²³, G⁵²⁷, W⁵³⁰, S⁵⁶⁴, N⁵⁶⁶, G⁵⁶⁸, T⁵⁷⁰, W⁵⁷¹, C⁴⁶⁷, and C⁴⁷³. In some embodiments, the mutation in the VPS10p domain which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease, such as Alzheimer’s disease) occurs at any position between 391 – 411 and 457 – 493. [0285] In some embodiments, the mutation occurs in the 10CC domain of SORL1. In some embodiments, the mutation in the 10CC domain confers a high risk of developing Alzheimer’s disease. In some embodiments, the mutation in the 10CC domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of C⁶²⁵, C⁶⁴³, C⁶⁶⁰, C⁶⁷⁵, C⁶⁷⁷, C⁶⁸⁴, C⁶⁹⁹, C⁷¹⁶, C⁷³⁶, and C⁷⁵². [0286] In some embodiments, the disease, disorder, or condition is associated with a mutation in the YWTD domain of SORL1. In some embodiments, the mutation in the YWTD domain confers a moderate risk of developing Alzheimer’s disease. In some embodiments, the mutation in the YWTD domain of SORL1 which confers a moderate risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of L⁷⁹³, F⁷⁹⁵, L⁸⁰², L⁸³⁷, F⁸³⁹, L⁸⁴⁶, L⁸⁸¹, L⁸⁸³, M⁸⁹⁰, I⁹²⁶, V⁹²⁸, I⁹³³, I⁹⁶⁶, V⁹⁶⁸, I⁹⁷³, M¹⁰⁰⁷, I¹⁰⁰⁹, L⁷⁸², V⁸²⁵, I⁸²⁶, I⁸⁶⁹, V⁸⁷⁰, L⁹¹⁵, V⁹¹⁶, I⁹⁵⁶, L⁹⁵⁷, I⁹⁹⁶, L⁹⁹⁷, L⁷⁸⁷, L⁸³¹, L⁸⁷⁵, V⁹²⁰, L⁹⁶⁰, L¹⁰⁰¹, R⁸⁷⁹, W⁸⁹⁵, N⁹²⁴, Y⁹⁶⁴, and W⁹⁷⁸. In some embodiments, the mutation in the YWTD domain confers a high risk of developing Alzheimer’s disease. In some embodiments, the mutation in the YWTD domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶, Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, T⁹³⁶, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³, I⁹⁸³, R⁷⁷¹, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, G⁷⁷⁷, G⁸¹⁹, G⁸⁶³, G⁹⁰⁹, G⁹⁵⁰, G⁹⁹¹, R⁸⁶⁶, R⁹⁵³, C⁸⁰¹, and C⁸¹⁶. In some embodiments, the mutation in the YWTD domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶, Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³, I⁹⁸³, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, G⁷⁷⁷, G⁸¹⁹, G⁸⁶³, G⁹⁰⁹, G⁹⁵⁰, G⁹⁹¹, R⁸⁶⁶, R⁹⁵³, C⁸⁰¹, and C⁸¹⁶. [0287] In some embodiments, the mutation occurs in the EGF domain of SORL1. In some embodiments, a fragment of the EGF domain is deleted. In some embodiments, the entire EGF domain is deleted. In some embodiments, the mutation comprises an insertion of on or more cysteine residues into the EGF domain. In some embodiments, the mutation in the EGF domain confers a high risk of developing Alzheimer’s disease. In some embodiments, the mutation in the EGF domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of C¹⁰²¹, C¹⁰²⁶, C¹⁰³⁰, C¹⁰⁴⁰, C¹⁰⁴², C¹⁰⁵⁸, C¹⁰⁶⁰, and C¹⁰⁷¹. [0288] In some embodiments, the mutation occurs in the CR domain of SORL1. In some embodiments, the mutation in the CR domain confers a moderate risk of developing Alzheimer’s disease. In some embodiments, the mutation in the CR domain of SORL1 which confers a moderate risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹²⁹⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁴⁰, G¹⁴⁹³, and G¹⁵³⁶. In some embodiments, the mutation in the CR domain of SORL1 which confers a moderate risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁹³, and G¹⁵³⁶. [0289] In some embodiments, the mutation in the CR domain confers a high risk of developing Alzheimer’s disease. In some embodiments, the mutation in the CR domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of D¹⁰⁹⁸, D¹¹⁰², D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸², D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, D¹²⁶⁷, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁴⁹, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁴⁴, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁵³, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁰, C¹⁵⁴⁹, D¹¹⁰⁵, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴, D¹³⁵², D¹³⁹⁶, D¹⁴⁴⁶, D¹⁴⁹⁹, and D¹⁵⁴². In some embodiments, the mutation in the CR domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of D¹⁰⁹⁸, D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁹, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴, D¹³⁵², D¹³⁹⁶, D¹⁴⁴⁶, D¹⁴⁹⁹, and D¹⁵⁴². [0290] In some embodiments, the mutation occurs in the FnIII domain of SORL1. In some embodiments, the mutation in the FnIII domain confers a moderate risk of developing Alzheimer’s disease. In some embodiments, the mutation in the FnIII domain of SORL1 which confers a moderate risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of L¹⁵⁶¹, W¹⁵⁶³, L¹⁶⁵⁹, L¹⁶⁶¹, I¹⁷⁵³, I¹⁷⁵⁵, L¹⁸⁴⁸, A¹⁸⁵⁰, L¹⁹³⁸, V¹⁹⁴⁰, L²⁰³⁰, I²⁰³², V¹⁵⁷¹, L¹⁵⁷³, I¹⁶⁶⁹, L¹⁷⁶³, F¹⁷⁶⁵, V¹⁸⁵⁸, C¹⁸⁶⁰, V¹⁹⁴⁸, I¹⁹⁵⁰, V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², and W¹⁷³⁵. In some embodiments, the mutation in the FnIII domain confers a high risk of developing Alzheimer’s disease. In some embodiments, the mutation in the FnIII domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, P¹⁹⁵⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹, P¹⁹⁹⁸, R¹⁹¹⁰, C¹⁵⁸⁶, C¹⁶³¹, C²¹⁰¹, and C²¹⁰⁸. In some embodiments, the mutation in the FnIII domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹, P¹⁹⁹⁸, R¹⁹¹⁰, C¹⁵⁸⁶, C¹⁶³¹, C²¹⁰¹, and C²¹⁰⁸. [0291] In some embodiments, the mutation occurs in the tail domain of SORL1. In some embodiments, the ed mutation in the tail domain confers a high risk of developing Alzheimer’s disease. In some embodiments, the mutation in the tail domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of F²¹⁷², A²¹⁷³, N²¹⁷⁴, S²¹⁷⁵, H²¹⁷⁶, Y²¹⁷⁷, D²¹⁹⁰, D²¹⁹¹, L²¹⁹², G²¹⁹³, E²¹⁹⁴, D²¹⁹⁵, D²¹⁹⁶, E²¹⁹⁷, D²¹⁹⁸, D²²⁰⁷, D²²⁰⁸, V²²⁰⁹, P²²¹⁰, M²²¹¹, V²²¹², I²²¹³, and A²²¹⁴. In some embodiments, the mutation occurs in the tail domain of SORL1. In some embodiments, the mutation in the tail domain confers a high risk of developing Alzheimer’s disease. In some embodiments, the mutation in the tail domain of SORL1 which confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s disease) occurs at any position selected from the group consisting of F²¹⁷², A²¹⁷³, S²¹⁷⁵, H²¹⁷⁶, Y²¹⁷⁷, D²¹⁹⁰, D²¹⁹¹, L²¹⁹², G²¹⁹³, E²¹⁹⁴, D²¹⁹⁵, D²¹⁹⁶, E²¹⁹⁷, D²¹⁹⁸, D²²⁰⁷, D²²⁰⁸, V²²⁰⁹, P²²¹⁰, M²²¹¹, V²²¹², I²²¹³, and A²²¹⁴. [0292] In some embodiments, the mutation does not occur at a position in SORL1 selected from the group consisting of 101, 115, 140, 146, 191, 205, 269, 270, 303, 332, 371, 391, 416, 446, 459, 474, 480, 508, 528, 552, 560, 577, 581, 583, 636, 639, 642, 656, 674, 679, 695, 729, 734, 743744, 762, 786, 807, 818, 833, 852, 870, 884, 885, 942, 961, 980, 1000, 1002, 1074, 1080, 1081, 1084, 1094, 1099, 1113, 1116, 1156, 1167, 1181, 1187, 1207, 1222, 1222, 1246, 1258, 1276, 1276, 1279, 1291, 1304, 1310, 1311, 1322, 1379, 1383, 1392, 1409, 1435, 1442, 1447, 1454, 1470, 1481, 1483, 1490, 1501, 1504, 1522, 1526, 1535, 1543, 1548, 1563, 1584, 1594, 1620, 1657, 1668, 1675, 1680, 1697, 1697, 1729, 1732, 1747, 1809, 1813, 1816, 1866, 1873, 1885, 1895, 1910, 1958, 1967, 2000, 2007, 2014, 2038, 2065, 2079, 2083, 2090, 2097, 2106, 2134, 2147, 2158, and 2160. [0293] In some embodiments, the disease, disorder or condition, is associated with abnormal endosomal trafficking, increased amyloid plaque levels, and/or increased intracellular fibrillary tangles comprised of hyperphosphorylated tau proteins. In some embodiments, the disease, disorder, or condition is associated with dysregulated levels and/or activity of at least one of SORL1 comprising a disease-associated mutation, sAPPα, APP at the cell surface, AMPA receptor at the cell surface, Aβ38, Aβ40, Aβ42, VPS26 (e.g., VPS26a and/or VPS26b), and/or VPS35. In some embodiments, the disease, disorder, or condition is associated with increased levels and/or activity of sAPPβ, tau aggregation, tau phosphorylation, Aβ38, Aβ40, and/or Aβ42. In some embodiments, the disease, disorder, or condition is associated with decreased levels and/or activity of at least one of SORL1, APP at the cell surface, AMPA receptor at the cell surface, sAPPα, VPS26, (e.g., VPS26a and/or VPS26b), and/or VPS35. In some embodiments, the disease, disorder, or condition is a neurological disease or a neurodegenerative disease including, but not limited to, Parkinson’s Disease, Dementia, Pick’s Disease, Lewy Body Dementia, Huntington’s Disease, Alzheimer’s disease, Early-Onset Alzheimer’s disease, Late-Onset Alzheimer’s disease, Sporadic late-onset Alzheimer’s disease, SORL1-positive Alzheimer’s disease, APOE4- positive Alzheimer’s disease, Familial Alzheimer’s disease, frontotemporal disorders associated with neurodegeneration, Niemann Pick Type I, Neuronal Ceroid Lipofuscinosis, Hereditary Spastic Paraparesis, Amyotrophic Lateral Sclerosis, tauopathies, such as progressive supranuclear palsy, and Steele-Richardson-Olszewski Syndrome, and diseases that are associated with TDP-43 pathologies. In some embodiments, a symptom which is treated using a method described herein is a symptom associated with one of the said diseases. [0294] In some embodiments, modulating the activity and/or levels of at least one of SORL1 comprising a disease-associated mutation, sAPPα, sAPPβ, tau aggregation, tau phosphorylation, APP at the cell surface, AMPA receptor at the cell surface, Aβ38, Aβ40, Aβ42, VPS26 (e.g., VPS26a and/or VPS26b), and/or VPS35 by administering a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein is useful for treating a subject in need thereof (e.g., a subject who is characterized as having or suspected of having a neurological disease, such as a neurodegenerating disease). In some embodiments, a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein can contacted with or administered to a cell, biological sample, or subject in order to increase sAPPα levels in the cell, biological sample, or subject. In some embodiments, a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein can contacted with or administered to a cell, biological sample, or subject in order to increase APP cell surface levels in the cell, biological sample, or subject. In some embodiments, a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein can contacted with or administered to a cell, biological sample, or subject in order to increase AMPA receptor levels in the cell, biological sample, or subject. In some embodiments, a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein can contacted with or administered to a cell, biological sample, or subject in order to decrease sAPPβ, tau aggregation, tau phosphorylation, Aβ30, Aβ40, and/or Aβ42 levels in the cell, biological sample, cell, or subject. In some embodiments, a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein can contacted with or administered to a cell, biological sample, or subject in order to increase VPS35 levels and/or activity in the cell, biological sample, or subject. In some embodiments, a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein can contacted with or administered to a cell, biological sample, or subject in order to increase VPS26 (e.g., VPS26a and/or VPS26b) levels and/or activity in the cell, biological sample, or subject. In some embodiments, a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein can be contacted with or administered to a cell, biological sample, or subject in order to increase AMPA receptor cell surface levels and/or activity in the cell, biological sample, or subject. In some embodiments, a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein can be contacted with or administered to a cell, biological sample, or subject in order to increase levels and/or activity of SORL1 comprising a disease-associated mutation in the cell, biological sample, or subject. In some embodiments, a therapeutic agent or a composition thereof can be contacted with a cell, biological sample, or subject in order to decrease activity or levels of SORL1 protein comprising a disease-associated mutation in the cell, biological sample, or subject. In some embodiments, a therapeutic agent or a composition thereof can be contacted with a cell, biological sample, or subject in order to correct a mutation in a SORL1 gene comprising a disease-associated mutation in the cell, biological sample, or subject. [0295] During the course of treatment, administration of the therapeutic agent or composition thereof may be altered or adjusted accordingly. For example, effects associated with administration of a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) can be monitored to inform therapeutic methods. Administration of a combination therapy and the timing of administration for such combination therapies can be determined by biological samples analysis methods described herein. In some embodiments, such analyses can be used to determine the efficacy of a combination therapy or a dose thereof in a subject. Expression information may be obtained, for example, through measuring changes in the levels and/or activity of the endogenous SORL1, the SORL1 variant provided by a gene therapy, sAPPα, APP at the cell surface, AMPA receptor at the cell surface, sAPPβ, tau aggregation, tau phosphorylation, Aβ30, Aβ40, Aβ42, (e.g., VPS26a and/or VPS26b), and/or VPS35 in a cell, biological sample, or subject through methods described herein and/or any other suitable methods known in the art. [0296] In some embodiments, a method comprises measuring the levels and/or activity of the endogenous SORL1, sAPPα, APP at the cell surface, AMPA receptor at the cells surface, sAPPβ, tau aggregation, tau phosphorylation, Aβ30, Aβ40, Aβ42, (e.g., VPS26a and/or VPS26b), and/or VPS35 in a biological sample obtained from a subject. In some embodiments, a method comprises obtaining or having obtained a biological sample from a subject, measuring or having measured the levels and/or activity of the endogenous SORL1, sAPPα, APP at the cell surface, AMPA receptor at the cell surface, sAPPβ, tau aggregation, tau phosphorylation, Aβ30, Aβ40, Aβ42, VPS26a, VPS26b, and/or VPS35 in the biological sample, and administering or having administered a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein to the subject when dysregulated levels and/or activity of the endogenous SORL1, sAPPα, sAPPβ, tau aggregation, tau phosphorylation, APP at the cell surface, AMPA receptor at the cell surface, Aβ30, Aβ40, Aβ42, VPS26a, VPS26b, and/or VPS35 are detected in the biological sample relative to a control sample. In some embodiments, a method comprising measuring or having measured the levels and/or activity of the endogenous SORL1, sAPPα, APP at the cell surface, AMPA receptor at the cell surface, sAPPβ, tau aggregation, tau phosphorylation, Aβ30, Aβ40, Aβ42, VPS26a, VPS26b, and/or VPS35 in a biological sample comprises a method described herein (e.g., an immunoassay, such as western blot, ELISA, or a method of assaying SORL1 shedding, such as one involving an eGluc-SORL1 reporter). [0297] In some embodiments, a method comprises administering or having administered a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein when increased levels of Aβ30, Aβ40, and/or Aβ42 are detected in a biological sample obtained from the subject relative to a control sample are detected. In some embodiments, a method comprises administering or having administered a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein when levels of sAPPβ, tau aggregation, tau phosphorylation, Aβ30, Aβ40, and/or Aβ42 in a biological sample obtained from the subject are increased relative to a control sample by at least 1.1 fold. In some embodiments, a method comprises administering or having administered a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein when levels of sAPPβ, tau aggregation, tau phosphorylation, Aβ30, Aβ40, and/or Aβ42 in a biological sample obtained from the subject are increased relative to a control sample by at least 1.25 fold, 1.5 fold, 1.75 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, or more. In some embodiments, a method comprises administering or having administered a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein when levels of sAPPβ, tau aggregation, tau phosphorylation, Aβ30, Aβ40, and/or Aβ42 in a biological sample obtained from the subject are increased relative to a control sample by 1-1.5 fold, 1.5-2 fold, 2-3 fold, 3-4 fold, 4-5 fold, 5-6 fold, 6-7 fold, 7-8 fold, 8-9 fold, 9-10 fold, or more. [0298] In some embodiments, a method comprises administering or having administered a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein when decreased levels and/or activity of SORL1, sAPPα, APP at the cell surface, AMPA receptor at the cell surface, VPS26 (e.g., VPS26a and/or VPS26b), and/or VPS35 are detected in a biological sample obtained from the subject relative to a control sample are detected. In some embodiments, a method comprises administering or having administered a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein when levels and/or activity of SORL1, sAPPα, APP at the cell surface, AMPA receptor at the cell surface, VPS26 (e.g., VPS26a and/or VPS26b), and/or VPS35 in a biological sample obtained from the subject are decreased relative to a control sample by at least 1.1 fold. In some embodiments, a method comprises administering or having administered a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein when levels and/or activity of SORL1, sAPPα, APP at the cell surface, AMPA receptor at the cell surface, VPS26 (e.g., VPS26a and/or VPS26b), and/or VPS35 in a biological sample obtained from the subject are decreased relative to a control sample by at least 1.25 fold, 1.5 fold, 1.75 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, or more. In some embodiments, a method comprises administering or having administered a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein when levels and/or activity of SORL1, sAPPα, APP at the cell surface, AMPA receptor at the cell surface, VPS26 (e.g., VPS26a and/or VPS26b), and/or VPS35 in a biological sample obtained from the subject are decreased relative to a control sample by 1-1.5 fold, 1.5-2 fold, 2-3 fold, 3-4 fold, 4-5 fold, 5-6 fold, 6-7 fold, 7-8 fold, 8-9 fold, 9-10 fold, or more. [0299] In some embodiments, a method comprises obtaining or having obtained a first biological sample and a second biological sample from a subject. In some embodiments, the first or the second biological sample is obtained prior to being treated with a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof). In some embodiments, the first or the second biological sample is obtained during the course of treatment with a therapeutic agent. In some embodiments, the first or the second biological sample is obtained after being treated with a therapeutic agent. In some embodiments, the therapeutic agent is therapeutic for a neurological disease, such as a neurodegenerative disease. In some embodiments, the first or the second biological sample is obtained at a time point when the subject has been diagnosed with a neurological disease, is suspected of having a neurological disease, is at risk of developing a neurological disease, is suspected of experiencing an increase in the severity of one or more symptoms of a neurological disease, or is at risk of experiencing an increase in the severity of neurological disease. [0300] In some embodiments, a method comprises obtaining or having obtained a first biological sample and a second biological sample from a subject, measuring or having measured the levels and/or activity of the endogenous SORL1, the SORL1 variant, sAPPα, sAPPβ, tau aggregation, tau phosphorylation, APP at the cell surface, AMPA receptor at the cell surface, Aβ30, Aβ40, Aβ42, VPS26a, VPS26b, and/or VPS35 in the first and second biological sample, and administering or having administered a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein. In some embodiments, a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein is administered when a difference in the levels and/or activity of the endogenous SORL1, sAPPα, sAPPβ, tau aggregation, tau phosphorylation, APP at the cell surface, AMPA receptor at the cell surface, Aβ30, Aβ40, Aβ42, VPS26a, VPS26b, and/or VPS35 is detected in the first biological sample relative to the second biological sample. In some embodiments, a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein is administered when an increase in the levels (e.g., by at least 1.1 fold, 1.25 fold, 1.5 fold, 1.75 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold, such as 1-1.5 fold, 1.5-2 fold, 2-3 fold, 3- 4 fold, 4-5 fold, 5-6 fold, 6-7 fold, 7-8 fold, 8-9 fold, 9-10 fold, or more) of sAPPβ, tau aggregation, tau phosphorylation, Aβ30, Aβ40, and/or Aβ42 are detected in the second biological sample relative to the first biological sample. In some embodiments a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein is administered when a decrease (e.g., by at least 1.1 fold, 1.25 fold, 1.5 fold, 1.75 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold, such as 1-1.5 fold, 1.5-2 fold, 2-3 fold, 3-4 fold, 4-5 fold, 5-6 fold, 6-7 fold, 7-8 fold, 8-9 fold, 9-10 fold, or more) in the levels and/or activity of the endogenous SORL1, sAPPα, sAPPβ, tau aggregation, tau phosphorylation, APP at the cell surface, AMPA receptor at the cell surface, Aβ30, Aβ40, Aβ42, VPS26 (e.g., VPS26a and/or VPS26b), and/or VPS35 are detected in the second biological sample relative to the first biological sample. In some embodiments, the subject has been administered a therapeutic agent (e.g., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone and/or a biologic, a SORL1 variant, a retromer complex subunit, a gRNA, a Cas molecule, a repair template, and/or an inhibitory nucleic acid, including engineered nucleic acids, transgenes, lentiviruses, rAAVs, and compositions thereof) described herein one or more times (e.g., before the first biological sample was obtained) and is administered one or more additional doses (e.g., of the same amount or a different amount) when a decrease (e.g., by at least 1.1 fold, 1.25 fold, 1.5 fold, 1.75 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold, such as 1-1.5 fold, 1.5-2 fold, 2-3 fold, 3-4 fold, 4-5 fold, 5-6 fold, 6-7 fold, 7-8 fold, 8-9 fold, 9-10 fold, or more) in the levels and/or activity of the endogenous SORL1, the SORL1 variant, sAPPα, APP at the cell surface, AMPA receptor at the cell surface, VPS26 (e.g., VPS26a and/or VPS26b), and/or VPS35 and/or an increase in the levels (e.g., by at least 1.1 fold, 1.25 fold, 1.5 fold, 1.75 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, or 10 fold, such as 1-1.5 fold, 1.5-2 fold, 2-3 fold, 3-4 fold, 4-5 fold, 5-6 fold, 6-7 fold, 7-8 fold, 8-9 fold, 9-10 fold, or more) of sAPPβ, tau aggregation, tau phosphorylation, Aβ30, Aβ40, and/or Aβ42 are detected in the second biological sample relative to the first biological sample. [0301] Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration of the therapeutic agent will, in any event, determine the appropriate dose for the individual subject. Moreover, for human administration, preparations should meet sterility, pyrogenicity, and the general safety and purity standards as required by, e.g., FDA Office of Biologics standards. [0302] Typically, these compositions may contain at least about 0.1% of the therapeutic agent or active ingredient (i.e., a small molecule, such as an aminoguanidine hydrazone or a retromer chaperone, a biologic, a SORL1 variant polypeptide or retromer complex subunit, an engineered nucleic acid encoding a SORL1 variant or retromer complex subunit, a lentivirus comprising a SORL1 variant or retromer complex subunit, or an rAAV comprising a SORL1 variant or retromer complex subunit, an ASO targeting a SORL1 encoding a disease-associated mutation, or a ribonucleoprotein complex capable of correcting a disease-associated mutation in SORL1). The percentage of the active ingredient(s) may, of course, be varied and may conveniently be between about 1-2%, 1-5%, 5-10%, 10-20%, 20- 30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% of the weight or volume of the total formulation. Naturally, the amount of therapeutic agent(s) in each therapeutically useful composition may be prepared in such a way that a suitable dosage will be obtained in any given unit dose of the composition. Factors such as solubility, bioavailability, biological half-life, route of administration, product shelf life, as well as other pharmacological considerations will be contemplated by one skilled in the art when preparing such pharmaceutical formulations. Additionally, a variety of dosages and treatment regimens may be desirable. [0303] In certain embodiments, the desired dosage is delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). [0304] Two more therapeutic agents can be administered at the same time or at different times. Simultaneous administration of two or more therapeutic agents will typically comprise administration of the two or more agents to the subject on the same day (e.g., less than 24 hours apart, such as less than 1 hour, less than 2 hours, less than 4 hours, less than 6 hours, less than 12 hours, or less than 18 hours apart) by either providing separate compositions that are administered either via the same route or different routes or by providing a single composition comprising the two or more therapeutic agents. Administration of two or more therapeutic agents can also be achieved, for example, by separating the administration of a first therapeutic agent and a second therapeutic agent by 1 day or more, such as 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11-14 days, 14-21 days, 21-28 days, more than 1 month, more than 2 months, more than 3 months, more than 4 months, more than 5 months, more than 6 months, or more than 1 year. In some embodiments, when a gene editing therapy and/or an inhibitory nucleic acid is administered in combination with a SORL1 variant, the administrations of the therapeutic agents are temporally separated to prevent editing and/or knockdown of the SORL1 variant. In some embodiments, when a gene editing therapy is administered in combination with a SORL1 variant and/or an inhibitory nucleic acid, the gene editing therapy is designed to not be able to target the SORL1 variant and/or the inhibitory nucleic acid (e.g., by using a gRNA that cannot bind to the SORL1 variant or the inhibitory nucleic acid and/or performing editing at a PAM sequence in SORL1 that is not comprised in the SORL1 variant or the inhibitory nucleic acid). In some embodiments, when a SORL1 variant is administered in combination with a gene editing therapy or an inhibitory nucleic acid, the SORL1 variant is designed to comprise a sequence which is resistant to the gRNA or the inhibitory nucleic acid and/or the SORL1 variant will be designed to lack a PAM recognized by the Cas molecule used in the gene-editing therapy. The two or more therapeutic agents can be administered an equal or non-equal number of times. Administering two or more therapeutic agents a non-equal number of times can involve administering a first therapeutic agent more regularly (e.g., every 2 weeks, or every 4 weeks) than a second therapeutic agent (e.g., an agent that is administered once every three months, once every six months, or once per year). In some embodiments, a subject is administered a combination therapy at the beginning of treatment. In some embodiments, a combination therapy is administered once a subject has received a single therapeutic agent one or more times. In some embodiments, a subject is administered a combination therapy at the beginning of treatment and then continues to be administered a single therapeutic agent after administration of the combination therapy is discontinued. [0305] In certain embodiments, an effective amount of a composition comprising a therapeutic agent for administration one or more times per day to a 70 kg adult human comprises about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a composition per unit dosage form and may be administered through any route. [0306] In certain embodiments, the compositions comprising a therapeutic agent may be administered through any route to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. [0307] In some embodiments, a composition comprising a lentivirus or an rAAV described herein may comprise at least 1 x 10² (e.g., 1 x 10², 1 x 10³, 1 x 10⁴, 1 x 10⁵, 1 x 10⁶, 1 x 10⁷, 1 x 10⁸, 1 x 10⁹, 1 x 10¹⁰, 1 x 10¹¹, 1 x 10¹², 1 x 10¹³, 1 x 10¹⁴, 1 x 10¹⁵, 1 x 101⁶, 1 x 10¹⁷, 1 x 10¹⁸, 1 x 10¹⁹, or more) vector genomes (vg). In some embodiments, a composition comprising a lentivirus or an rAAV described herein may comprise at least 1 x 10² vector genomes per kilogram of the subject to which administration is contemplated (vg/kg). In some embodiments, a composition comprising a lentivirus or an rAAV described herein may comprise a dose of at least 1 x 10¹⁰ vg/kg, 2 x 10¹⁰ vg/kg, 3 x 10¹⁰ vg/kg, 4 x 10¹⁰ vg/kg, 5 x 10¹⁰ vg/kg, 6 x 10¹⁰ vg/kg, 7 x 10¹⁰ vg/kg, 8 x 10¹⁰ vg/kg, 9 x 10¹⁰ vg/kg, or more. In some embodiments, a composition comprising a lentivirus or an rAAV described herein may comprise a dose of at least 1 x 10¹¹ vg/kg, 2 x 10¹¹ vg/kg, 3 x 10¹¹ vg/kg, 4 x 10¹¹ vg/kg, 5 x 10¹¹ vg/kg, 6 x 10¹¹ vg/kg, 7 x 10¹¹ vg/kg, 8 x 10¹¹ vg/kg, 9 x 10¹¹ vg/kg, or more. In some embodiments, a composition comprising a lentivirus or an rAAV described herein may comprise a dose of at least 1 x 10¹² vg/kg, 2 x 10¹² vg/kg, 3 x 10¹² vg/kg, 4 x 10¹² vg/kg, 5 x 10¹² vg/kg, 6 x 10¹² vg/kg, 7 x 10¹² vg/kg, 8 x 10¹² vg/kg, 9 x 10¹² vg/kg, or more. In some embodiments, a composition comprising a lentivirus or an rAAV described herein may comprise a dose of at least 1 x 10¹³ vg/kg, 2 x 10¹³ vg/kg, 3 x 10¹³ vg/kg, 4 x 10¹³ vg/kg, 5 x 10¹³ vg/kg, 6 x 10¹³ vg/kg, 7 x 10¹³ vg/kg, 8 x 10¹³ vg/kg, 9 x 10¹³ vg/kg, or more. In some embodiments, a composition comprising a lentivirus or an rAAV described herein may comprise a dose of about 1 x 10¹⁰ vg/kg to 1 x 10¹¹ vg/kg, 1 x 10¹¹ vg/kg to 1 x 10¹² vg/kg, 1 x 10¹² vg/kg to 1 x 10¹³ vg/kg, or 1 x 10¹³ vg/kg to 1 x 10¹⁴ vg/kg. In some embodiments, a composition comprising a lentivirus or an rAAV described herein may comprise a dose of about 1 x 10¹⁰ vg/kg, 2 x 10¹⁰ vg/kg, 3 x 10¹⁰ vg/kg, 4 x 10¹⁰ vg/kg, 5 x 10¹⁰ vg/kg, 6 x 10¹⁰ vg/kg, 7 x 10¹⁰ vg/kg, 8 x 10¹⁰ vg/kg, 9 x 10¹⁰ vg/kg, 1 x 10¹¹ vg/kg, 2 x 10¹¹ vg/kg, 3 x 10¹¹ vg/kg, 4 x 10¹¹ vg/kg, 5 x 10¹¹ vg/kg, 6 x 10¹¹ vg/kg, 7 x 10¹¹ vg/kg, 8 x 10¹¹ vg/kg, 9 x 10¹¹ vg/kg, 1 x 10¹² vg/kg, 2 x 10¹² vg/kg, 3 x 10¹² vg/kg, 4 x 10¹² vg/kg, 5 x 10¹² vg/kg, 6 x 10¹² vg/kg, 7 x 10¹² vg/kg, 8 x 10¹² vg/kg, 9 x 10¹² vg/kg, 1 x 10¹³ vg/kg, 2 x 10¹³ vg/kg, 3 x 10¹³ vg/kg, 4 x 10¹³ vg/kg, 5 x 10¹³ vg/kg, 6 x 10¹³ vg/kg, 7 x 10¹³ vg/kg, 8 x 10¹³ vg/kg, or 9 x 10¹³ vg/kg. In some embodiments, an amount of a lentivirus or an rAAV described herein for treating a subject in need thereof is about 1 x 10¹⁰ vg/kg to 1 x 10¹¹ vg/kg, 1 x 10¹¹ vg/kg to 1 x 10¹² vg/kg, 1 x 10¹² vg/kg to 1 x 10¹³ vg/kg, 1 x 10¹³ vg/kg to 1 x 10¹⁴ vg/kg, 1 x 10¹⁴ vg/kg to 1 x 10¹⁵ vg/kg, or 1 x 10¹⁵ vg/kg to 1 x 10¹⁶ vg/kg. [0308] It will be appreciated that dose ranges described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. Methods of determining the most effective means and dosages of administration are well known to those of skill in the art and will vary with the composition of the therapy, the target cell (e.g., a cell of the nervous system), and the subject being treated. Single and multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. [0309] Toxicity and efficacy of the compositions utilized in methods of the present disclosure may be determined by standard pharmaceutical procedures, using either cells in culture or experimental animals to determine the LD50 (the dose lethal to 50% of the population). The dose of the composition used for a therapeutic purpose may be chosen based on the ratio between toxicity and efficacy, and thus may be expressed as the ratio LD50/ED50 (where ED50 means the dose which is effective in 50% of the population). Those compositions that exhibit large therapeutic indices are preferred. While compositions that exhibit toxic side effects may be used, care should be taken to design a delivery system that minimizes the potential damage of such side effects. The dosage of compositions as described herein lies generally within a range that includes an ED50 or IC50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. [0310] Sterile injectable solutions comprising the therapeutic agent (i.e., a small molecule such as an aminoguanidine hydrazone or a retromer chaperone, a biologic, a SORL1 variant polypeptide or retromer complex subunit, an engineered nucleic acid encoding a SORL1 variant or retromer complex subunit, a lentivirus comprising a SORL1 variant or retromer complex subunit, or an rAAV comprising a SORL1 variant or retromer complex subunit, an ASO targeting a SORL1 encoding a disease-associated mutation, or a ribonucleoprotein complex capable of correcting a disease-associated mutation in SORL1) are prepared by solvation in the required amount of appropriate solvent in addition to any of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized ingredients into a sterile vehicle that contains the basic dispersion medium and the other ingredients from those enumerated above. [0311] For administration of an injectable aqueous solution, the composition comprising a therapeutic agent and the liquid diluent first rendered isotonic with sufficient saline, polyalcohols, or glucose. For example, one dosage of a therapeutic agent (i.e., a small molecule such as an aminoguanidine hydrazone or a retromer chaperone, a biologic, a SORL1 variant polypeptide or retromer complex subunit, an engineered nucleic acid encoding a SORL1 variant or retromer complex subunit, a lentivirus comprising a SORL1 variant or retromer complex subunit, or an rAAV comprising a SORL1 variant or retromer complex subunit, an ASO targeting a SORL1 encoding a disease-associated mutation, or a ribonucleoprotein complex capable of correcting a disease-associated mutation in SORL1) may be dissolved in an isotonic NaCl solution and optionally added to a larger volume of hypodermoclysis fluid prior to being injected at the proposed site of infusion. In some embodiments, the composition comprising a therapeutic agent is provided in a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. A composition may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Proper fluidity may be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. [0312] In certain circumstances, it will be desirable to deliver the therapeutic agent or suitably formulated pharmaceutical compositions thereof disclosed herein either subcutaneously, intraocularly, intravitreally, parenterally, subcutaneously, intravenously, intracerebro-ventricularly, intramuscularly, intracranially, intrathecally, orally, intraperitoneally, or by oral or nasal inhalation, or by direct injection to one or more cells, tissues, or organs. In some embodiments, a therapeutic agent or composition thereof is delivered via intrathecal or intracranial injection, particularly in those for treating a human. In some embodiments, a therapeutic agent or composition thereof is administered to one or more brain regions (e.g., a brain region effected by a neurodegenerative disease described herein, such as the hippocampus, the cortex, etc.) of a subject. In some embodiments, the administration to the one or more brain regions comprises direct injection into the one or more brain regions. In some embodiments, the administration to the one or more brain regions comprises administering the therapeutic agent into the cerebrospinal fluid. In some embodiments, a therapeutic agent or composition thereof is administered to the hippocampus of a subject. In some embodiments, administration to the hippocampus comprises direct injection to the hippocampus or injection into a different site (e.g., into the cerebrospinal fluid which promotes subsequent delivery of the agent to the hippocampal tissue). In some embodiments, administration to the hippocampus comprises direct injection to parenchyma of the hippocampus. In some embodiments, a therapeutic agent or composition thereof is injected directly into the cerebrospinal fluid of the subject. In some embodiments, direct injection of a therapeutic agent or composition thereof to human CNS is preferred, for example, delivery is performed concurrently with a surgical procedure or interventional procedure whereby access to the central nervous system tissue is provided. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration, injection, etc.). In some embodiments, compositions are administered to a subject through only one administration route. In some embodiments, multiple administration routes may be exploited (e.g., serially, or simultaneously) for administration of the composition to a subject. [0313] The administration of therapeutically effective amounts of the compositions of the present disclosure which comprise a therapeutic agent may be achieved by a single administration. For example, a single injection of a sufficient amount of the therapeutic agent (i.e., a small molecule such as an aminoguanidine hydrazone or a retromer chaperone, a biologic, a SORL1 variant polypeptide or retromer complex subunit, an engineered nucleic acid encoding a SORL1 variant or retromer complex subunit, a lentivirus comprising a SORL1 variant or retromer complex subunit, or an rAAV comprising a SORL1 variant or retromer complex subunit, an ASO targeting a SORL1 encoding a disease-associated mutation, or a ribonucleoprotein complex capable of correcting a disease-associated mutation in SORL1) or composition thereof may be performed to provide therapeutic benefit to the patient undergoing such treatment. In some circumstances, it may be desirable to provide multiple or successive administrations of the therapeutic agent or composition thereof, either over a relatively short, or a relatively prolonged period of time, as may be determined by the medical practitioner responsible for treatment. In some embodiments, administration of the therapeutic agent or composition thereof to a subject occurs at least one time. In some embodiments, administration of the therapeutic agent or composition thereof to a subject occurs 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more times over the course of treatment. [0314] If desired the therapeutic agent or composition thereof may be administered in combination with other agents as well, such as, e.g., proteins or polypeptides or various pharmaceutically active agents, including one or more administrations of therapeutic polypeptides, biologically active fragments, or variants thereof. In fact, there is virtually no limit to other components that may also be included, as long as the additional agents do not cause a significant adverse effect upon contact with the target cells (e.g., a cell of the nervous system) or host tissues. The therapeutic agent or composition thereof may thus be delivered along with various other pharmaceutically acceptable agents as required in the particular instance. Such agents may be purified from host cells or other biological sources, or alternatively may be chemically synthesized as described herein. EXAMPLES Example 1 [0315] This example describes analyses of the relationship between known disease- causing variants in homologous proteins to predict pathogenicity of SORL1 variants in Alzheimer’s disease. Together, the findings represent a comprehensive compendium on SORL1 protein variation and functional effects, which allowed for the prioritization of SORL1 genetic variants into high or moderate priority mutations. This compendium may be used by clinical geneticists for assessing variants they identify in patients, allowing further development of diagnostic procedures and patient counseling strategies. Ultimately, this compendium will inform investigations into the molecular mechanisms of endosomal recycling which will support the development of therapeutic treatment strategies for SORL1 variant-carrying patients. [0316] The VPS10p-domain (residues 1-753) 1.a Sequence details [0317] Signal peptide (residues 1-28) The most N-terminal part encoded by the SORL1 gene is a signal peptide (SP) (residues 1-28) that directs the polypeptide into the endoplasmatic reticulum (ER), and is lost by signal peptidase cleavage upon translocation into the ER, similar to other transmembrane proteins. Accordingly, functional SORL1 protein in cells does not contain this initial part of the polypeptide. [0318] Propeptide (residues 29-81) Residues 29-81 of SORL1 is a propeptide (ProP), that can be removed from the remaining part of the receptor by enzymatic cleavage by the prohormone convertase furin that is active in secretory vesicles in the late Golgi/TGN¹. The⁷⁸RRKR⁸¹ (SEQ ID NO: 144) tetrapeptide serves as a recognition site for furin binding and cleavage between residues 81-82². The ProP also contains a⁶³RGD⁶⁵ tripeptide motif, which serves as an interaction site for adhesive proteins, including integrins in other proteins. This suggests that SORL1 proteins that escape cleavage by furin still include a ProP and may have a unique function in cell adhesion and integrin binding. The presence of ProP is also suggested to block binding of small ligands to the VPS10p-domain (see next section), which is speculated to prevent binding of certain ligands to the VPS10p-domain in the ER of cells where receptor and ligand are co-expressed 2. [0319] 10-bladed β-propeller (residues 82-617) After the ProP there follows the VPS10p-domain: with its 536 residues, this domain is one of the largest protein domains known. There is only modest sequence conservation between domains across the five members of the VPS10p family (SORL1, sortilin, SorCS1, SorCS2, SorCS3)³. The crystal structure of the VPS10p-domain of sortilin was solved in 2009⁴, and in 2015 for the SORL1 domain⁵, making it the only full SORL1-domain for which the three- dimensional conformation is currently determined. Both sortilin and SORL1 VPS10p-domain structures are organized in a ten-bladed β-propeller, each blade composed of four antiparallel beta-strands (A-D) arranged around a central conical tunnel. C-terminal to both VPS10p- domains is a small domain, corresponding to 136 amino acids of SORL1 including ten conserved cysteine residues with a stringent spacing, known as the 10CC region. This domain (residues 618-753 in SORL1) interacts extensively with the β-propeller (see below) (FIG.1A). The overall dimensions of the β-propeller resemble a 94 Å x 72 Å x 56 Å ellipsoid, and for SORL1 the central cavity narrows toward the bottom face with a maximum width of ~25 Å⁵. The β-propeller is further characterized by a defined and almost flat bottom and top face, demarcated by the loops between strands A-B and C-D, and strands B-C and D-A, respectively (FIGs. 1B-1C). Interestingly, the solved structures of both sortilin and SORL1 were determined in the presence of complexed ligands, which indicated that small (peptide) ligands can bind inside the tunnel. [0320] Alignment of the ten sequences that define each blade, β1-β10 (residues 82- 617) (FIG. 1C), revealed several conserved and functional motifs. The presence of two stretches of hydrophobic amino acids in the inner strands (A: positions 5, 6, and B: positions 19, 20, 21) of each blade is important for domain stability. Similarly, 2-3 hydrophobic residues in strand C (positions 39, 40, 41) establish hydrophobic interactions among the blades that enable the formation of the large central tunnel. Additionally, they partake in the generation of a hydrophobic surface that allows the interaction of small lipophilic ligands with the propeller cavity, as demonstrated for the binding of the Amyloid-β peptide to SORL1⁵. [0321] Asp-boxes (part of β-propeller) The motif with consensus sequence S(or T)-X-D(or N)-X-G-X-T(or S)-W(or F/Y) (spanning positions 42-49 of each blade) is known as the Asp-box⁶, which folds as a conserved β-hairpin 7. The SORL1 VPS10p-domain contains Asp-boxes in the loops located (at the bottom of the domain) between the third (C) and fourth (D) strands of the blades (FIGs.1B-1C). The exact function of this motif has not been clarified. However, the Asp-boxes of the SORL1 domain are unlikely to be directly involved in ligand recognition, since only the top face of propellers appears to be used for this purpose⁸. Rather, the conserved amino acids of the Asp-box motif likely stabilize the propeller, forming blade-to-blade interactions, contacts with preceding loops, or with the nearby 10CC-domains. [0322] L1-L2 Loops (part of the β-propeller) The two sequences connecting β6 with β7 and β7 with β8 are longer than the sequences connecting other blades. Part of these two longer protrusions (residues Y391-F411 and A457- P493, respectively) include the two “loop structures” termed L1 (residues Y391-A412) and L2 (residues L481-P493), respectively⁵ (FIG.1C; loop residues underligned). L2 is located close to the upper entrance of the tunnel, and seems to push bound ligand against the tunnel wall at neutral pH. The L1 segment occupies a more central position, blocking part of the pore. Interestingly, L1 is not present in VPS10p-domains in other proteins, which suggests that the VPS10p-domain in SORL1 has a unique ligand binding profile. Indeed, both L1 and L2 appear to be essential for peptide binding since removal of either of these two protrusions completely abolishes binding activity⁵. Both loops are flexible and undergo conformational changes at different pH, assuming a more stable conformation at pH 6.5 than at pH 4.5. The disordering of the loops at low pH was suggested as important for ligand release at acidic pH, providing a molecular mechanism for dissociating ligands from this SORL1 domain in lysosomes, when SORL1 encounters the low pH in this organelle. [0323] 10CC region (residues 618-753) The VPS10p β-propeller fold is stabilized by the neighboring 10CC region, which is split into two shorter domains named 10CCa (residues 618-675) and 10CCb (residues 676- 753). While rather similar to each other, these domains show neither sequence nor structural resemblance to other known domains. The ten conserved cysteines form five intrachain disulfide bridges with connectivity between cysteines as Cys^I-Cys^III and Cys^II-Cys^IV (in 10CCa), and Cys^V-Cys^IX, Cys^VI-Cys^VII, and Cys^VIII-Cys^X (in 10CCb)^5,9. Structurally, the two domains wrap around the bottom face of the propeller, and form strong contacts with the propeller through numerous hydrogen and ionic bonds. Attempts to express either the propeller or the 10CC regions alone were not successful, which suggests that these interactions between propeller and the 10CC region ensure a compact structure and provide stability to the entire unit. However, the 10CC region is mobile and undergoes a pH-dependent conformational change as evidenced for both sortilin and SORL1^4,5. For SORL1 the 10CCb-domain exhibits the largest rearrangement, with a “lever-like” motion when the pH increases from acidic conditions with the 10CCb-domain is tightly associated with the propeller, to more neutral conditions with the 10CCb-domain forming almost no contacts. Keeping in mind that full- length SORL1 is a modular multi-domain protein, such a movement may affect the overall receptor conformation and is likely relevant for ligand binding activity and possibly receptor dimerization as it traffics between cellular compartments with different pH conditions. [0324] 1.c SORL1 variants in VPS10p-domain The VPS10p-domain is found only in the 5 proteins of the VPS10p-receptor family, with too little pathological information such that there are no orthologous proteins suitable for evaluation of disease-associated variants. In many cases pathogenicity may be inferred from interrogation of the available crystal structure⁵. This has been done for the p.G511R variant (conservation 40/40; “likely pathogenic”), which was previously reported to segregate with AD across 2 generations¹¹. While the residue is located outside the L1/L2 regions, it maps to a position that fixes one end of the L2 loop that is directly involved in Aβbinding. This suggests that conversion of the small glycine to a large amino acid (i.e. like arginine) could cause a severe disturbance in the conformation (or stability) of L2 with possibly the loss of Aβ-binding ability⁵. In line with this reasoning, functional studies suggested that this mutation impairs binding of Aβ to the VPS10p-domain, leading to decreased lysosomal delivery of Aβ and a consequential increase of secreted Aβ¹². Taken together, this variant may, at least in part, explain the observed AD in the family¹¹. Despite the very small (A528T) or absence (E270K) of a variant effect on AD-risk observed in GWAS studies, functional assays using cells transfected with these variants indicated an impaired ability of mutant SORL1 to decrease APP processing¹³. Inspection of the VPS10p crystal structure and the sequence alignment (FIG. 10) is in agreement with neither of these variants being located at very dangerous positions. [0325] 2 The YWTD-repeated β-propeller (residues 754-1013) [0326] 2.a Sequence details Immediately following the VPS10p- and 10CC-domains, SORL1 contains a region spanning 260 amino acids containing five incomplete copies of a characteristic YWTD-tetrapeptide (SEQ ID NO: 145) (FIG. 2C, strand B). In general, a YWTD-repeat region folds into a compact 6-bladed β-propeller, and each blade contains four antiparallel β-strands that are organized around a central pseudo symmetrical axis, forming an internal tunnel. The dimensions of this β-propeller type mimic a 68 Å x 58 Å x 40 Å ellipsoid. Accordingly, this domain is significantly smaller than the 10-bladed VPS10p β-ropeller, and there are no reports describing ligands being able to bind inside these narrow tunnels, that often are so tight they appear closed. YWTD-repeated β-propellers are found in all core members of the LDLR family (FIG.2A) as well as in the physiologically unrelated proteins Nidogen, Osteonidogen, and the precursor of EGF¹⁴. [0327] Crystal structures of homologous domains from LDLR¹⁵, LRP4¹⁶, LRP6^17-20, ApoER2²¹ and Nidogen²² have all been solved, showing how only 5 Å separates the N- and C-terminal residues of the domain in space although they are separated by 260 amino acids in the primary structure (FIGs.2A-2E). [0328] Alignment – unique residues As in homologous YWTD-propellers, the YWTD-motif is absent from the β1 blade where the tetrapeptide is represented by the⁷⁶⁰FILY⁷⁶³ sequence (FIG. 2C). For blades β2-β6, the YWTD-motifs are located in the second (B) strand (FIG.2C). The conserved aromatic residues at the tyrosine and tryptophan positions (16 and 17 of each blade) are embedded inside the domain and contribute to an apparent hydrophobic core. The aspartate residues at position 19 participate in extensive hydrogen bonding with residues in strand A and C of the same blade and strand A of the adjacent blade, thereby maintaining the structural integrity of the β- propeller fold¹⁵ (FIG. 2B). Hydrophobic residues within strand A (positions 6 and 8), B (position 15), and D (positions 41 and 42) are present in blades β2-β6 and add further to a hydrophobic core (FIGs. 2B-2C). A conserved isoleucine (position 27) also contributes to stabilization of the hydrophobic contacts. An arginine is frequently located at position 29 in strand C, where it also functions in domain stabilization through interactions with the tyrosine of the YWTD-motif. Three of the six β-propeller blades include a conserved proline residue at position 3, which supports the loop-structure between blades. Furthermore, a glycine (position 35) and leucine (position 47) represent conserved positions in most YWTD-domain sequences including that of SORL1 (FIG.11, FIG.7). Together, the conserved residues in the YWTD- domain of SORL1 point towards an essential role in maintaining the rigidity of the propeller. [0329] A SBiN-type YWTD-domain in SORL1 [0330] To understand how YWTD-domains interact with binding partners, several studies have analyzed the structures of ligand-bounded YWTD-domains²². The ligand often contains an asparagine-isoleucine pair (the NXI-pair, with the N and I residues separated by a variable residue) that binds a motif called the Shutter Binding NXI (SBiN)-motif, found in several YWTD-domain sequences^{16 23}. The asparagine side chain of the ligand NXI-pair interacts with a tryptophan (pos 20), a phenylananine (pos 4) and an asparagine (pos 4) of the β-propeller, whereas the isoleucine of the ligand NXI-pair engages with an additional paired tryptophan (pos 20) - arginine (pos 4) of the YWTD-domain²². In aggregate, the residues at these five positions all locate to positions 4 or 20 of the β-blade sequence alignment and make up the SBiN-motif^16,23. The SORL1 YWTD-propeller contains an SBiN-motif composed of residues W895 (β4, pos 20), N924 (β5, pos 4), Y964 (β6, pos 4), and the R879-W978 (β4 pos 4-β6 pos 6) pair (FIG.2C – residues highlighted, black background). All five residues are brought together at the top of the folded domain in line with their position in the sequence either before strand A or at the end of strand B. [0331] The SORL1 sequence contains five internal NXI-pairs, which suggests that other SORL1 domains may also serve as ligand to the β-propeller to form intramolecular (intrinsic) contacts. The five internal NXI-pairs are located in blades β1 and β4 of the VPS10p- domain (¹¹⁵NVI¹¹⁷ and²⁶²NTI²⁶⁴⁾, in the first CR-domain (¹⁰⁸⁹NCI¹⁰⁹¹ and¹⁰⁹²NSI¹⁰⁹⁴), and in the sixth FnIII-domain (²¹⁰⁵NQI²¹⁰⁷). As the two NXI sequences within the VPS10p-domain are situated at the bottom of the large β-propeller (in agreement with their position in the primary sequence between strands A and B), it is unlikely they would be in contact with the YWTD-domain SBiN motif. The recently determined model of the full SORL1 protein ectodomain by AlphaFold²⁴ shows no indication that internal NXI-pairs bind to the YWTD- domain. [0332] Takes two to tangle [0333] Our phylogenetic analysis indicates that in all known SORL1 receptors the single YWTD-propeller coexists with the preceding VPS10p β-propeller, suggesting these two domains form a single rigid unit (FIG.7). This is in agreement with the crystal structure of the extracellular domain of LRP6, which contains four YWTD-propellers that form pairs of two rigid structural blocks, with a short intervening hinge that restrains their relative orientation¹⁸. This pairing is observed in several proteins with multiple YWTD-domains (ie. LRP4 and LRP6): it enables interactions with large ligands including co-receptors in multimeric complexes, or large soluble ligands requiring two adjacent b-propellers for efficient binding¹⁸ 16. It is tempting to speculate that both the VPS10p and YWTD β-propellers of SORL1 exclusively bind ligands to their top faces. The SBiN residues in the YWTD domain locate to the top face (FIG.2C), while an EGF-domain, located to the C-terminal end of the β-propeller, forms intimate domain-domain interactions with the bottom face, making it unavailable for ligand-interactions²⁵. Similarly, the bottom face of the VPS10p-domain is occupied by the 10CC-domains, such that this side is also unavailable for ligand-interactions. [0334] 2.c SORL1 variants in YWTD-domain [0335] YWTD-motif at positions 16-19: [0336] Not surprisingly, all four positions (16-19) of the tetrameric YWTD-sequence are potentially deleterious of protein/domain function (FIG.2D). Tyr (pos 16), was identified to be mutated in LDLR1, LRP2, and twice in LRP5 for different patient/diseases. Intriguingly, for each disease-variant the tyrosine is replaced by a histidine: p.Y442H^LDLR (identified in patients with FHCL1;²⁶), p.Y2522H^LRP2 (considered causal of Donnai-Barrow syndrome (DBS);²⁷), p.Y733H^LRP5 (identified in a patient with OPPG;²⁸), and p.Y1168H^LRP5 (identified in woman with total retinal detachment and retinoschisis (EVR4);²⁹) (Tables 3 and 4). This suggests that introduction of the histidine is particularly damaging for position 16 of the propeller-domain. Trp (pos 17), was frequently mutated in patients with FH (W577S^{LDLR 30}, W577G^{LDLR 31}, W577R^{LDLR 26}, and functional characterization of mutant proteins with either glycine substitution³¹ or serine substitution³² showed that substitutions completely abolish receptor membrane expression and LDL uptake. Thr (pos 18) in β-propellers of LRP5 (p.T390K^LRP5) associates with increased risk for osteoporosis-pseudoglioma syndrome (OPPG)²⁸ or is considered causal (p.T253I^LRP5) of Osteopetrosis, Autosomal Dominant 1 (OPTA1) in two related families on Fyn in Denmark³³, respectively. Asp (pos 19), mutations of this residue in LDLR are linked to familial hypercholesterolaemia (FH) (p.D492N^{LDLR 34}, p.D579N^{LDLR 30,35,36} (for this variant less than 2% of receptor activity is reported) and p.D579Y^{LDLR 37}), while mutations in LRP5 or LRP4 are found in patients with OPPG (p.D434N^{LRP5 28}) or considered causal of Cenani-Lenz syndactyly syndrome (CLSS) (p.D529N^{LRP4 38}, p.D1403H^LRP439), respectively (Tables 3 and 4). Taken together, this suggests that variants at these positions in SORL1 may be risk-increasing or even causative for AD, and should alert the clinical geneticist as variants with high priority when observed in a patient- carrier. In line with this p.D806N occurring at position 19 was observed so far only in AD patients and not controls⁴⁰. [0337] SBiN-motif at positions 4 and 20: [0338] In proteins that contain a YWTD-repeated β-propeller with SBiN-motifs, three of the six blades include residues of the ligand-binding SBiN motifs (i.e. β4-β6) at positions 4 and 20 (FIG. 2D)²³. Variants that map to these positions in blades β4-β6 may be more pathogenic than if they map to β1-β3. This is supported by the pathogenicity of variants listed in Uniprot in LDLR, LRP4, and LRP5 that affect the SBiN-residues: p.N564S^{LDLR 41} and p.N564H^{LDLR 30,34,42-44} (position 4 of β5) in patients with FH. Functional analysis of p.N564H^LDLR found 64-73% reduced uptake and degradation of LDL in fibroblasts from heterozogous and compound carriers^43,44. Variant p.W1186S^LRP4 was identified in patient with Sclerosteosis (SOST2)⁴⁵ and show impaired Wnt-suppressing activity of the mutant receptor 46, and p.W478R^LRP5 (position 20 both in β4) in a family with OPPG where the variant segregate with affected subjects⁴⁷, respectively. Interestingly, SORL1 variant p.N924S (conservation: 40/40) affects the Asn residue in the SBiN-motif (position 4 in β5) has been reported in patients with AD⁴⁰, but there is no functional studies nor genetic statistical support to yet claim this variant to be pathogenic. [0339] Arg at position 29: [0340] In SORL1, 5 of 6 YWTD blades contain an Arg at position 29. Uniprot lists 4 pathogenic variants for this position, corresponding to substitution of an Arg: p.R570W^LRP5 (patients with OPPG^28,48), p.R570Q^LRP5 (patients with EVR^28,49), p.R1277H^LRP4 (patients with CMS17⁴⁵), and p.R473Q^LRP6 (segregate with disease in a family with metabolic syndrome; ADCAD2⁵⁰). This suggests that removal of arginine at position 29 may increase risk of AD. The preference for Arg at this position is not obvious from the logo-web consensus (FIG.2E), but is noticeable in the alignments (Section 2d and YWTD domain alignment). [0341] Asp at position 9: [0342] Position 9 is the top position for mutations in YWTD-propellers (FIG.2D) with 6 disease-associated variants listed in Uniprot: p.D482H^LDLR (in FHCL1 patients, listed as causal genetic variant^51,52), p.D203N^LRP5 (in OPPG patients²⁸), p.D381N^LRP5 (identified in a small family with familial EVR1 and functional analysis showed mutations lead to complete receptor inactivity⁵³), p.D511A^LRP5 (identified in a small family with familial EVR4⁵⁴), p.D683N^LRP5 (identified in patients with OPPG²⁸), and p.T852M^LRP5 (identified in a family with EVR4 and determined as pathogenic because of 95% reduction in LRP5 activity⁵⁵). Notably, there is also preference of Asp at position 9 in the consensus sequence (FIG.2E), and the above listed mutations strongly suggest that substitutions that replace an Asp is very likely disease-associated. In the SORL1 sequence only two of the six β-blades have an Asp at position 9; D794 (β2) and D929 (β5) (FIG.2D), and a variant p.D929Y has been identified in both a control and a case leaving it an open question still whether this is a dangerous position for the SORL1 domain⁴⁰. [0343] We would like to provide an example how to apply the species conservation tool, trying to decide whether the variant leading to p.V884M substitution is dangerous. Based on the identification of this variant in 4 AD cases and not yet in any controls⁴⁰, it could be speculated that this variant is pathogenic. But when using the alignment of multiple SORL1 sequences from 40 different species (FIG.13), it is evident that there is no specific requirement for a valine at this position of SORL1 as other hydrophobic residues as Leu and Ile are present at this position for other species, and several species even carry a Met at this position (e.g. SORL1 from horse, salmon, pike, piranha, and zebrafish). This strongly suggests that the p.V884M is a benign mutation. [0344] Arg at position 38: [0345] Our DMDM analysis based on pathogenic variants listed in Uniprot identified 4 variants for position 38 that associate with four diseases: one in LDLR: p.R595W^LDLR (in FHCL1 patients³⁴), and three in LRP5: p.R494Q^LRP5 (in patients with OPPG^28,48), p.R752G^LRP5 (in a family with EVR4⁴⁹), and p.R1188W^LRP5 (segregate with disease in large family pedigrees with PCLD4⁵⁶). Although no strong preference for an arginine in the SORL1 sequence (FIG.2D), but a slight enrichment in the bigger sequence alignment for the β-blade at this position (Section 2d and YWTD domain alignment), it is interesting that each of the four disease-variants involve the replacement of this positively charged amino acid. In SORL1 two of the YWTD blades have an arginine at position 38: R866 (β3) and R953 (β5) (FIG.2D). It is suggested that variants that affect these two amino acids may be deleterious of SORL1 function and associated with AD. The ADES-ADSP dataset includes p.R953H in three cases with very early ages at onset ranging between 46 and 58 years, and not in controls⁴⁰. [0346] 2.d YWTD-domain alignment [0347] Mapping of naturally occurring variants found in human YWTD-domain containing proteins, and being listed as associated with pathology at Uniport. The alignment follows the SORL1 alignment shown on top, and pathogenic variants are indicated by underline. 1 10 20 30 40 LAEENEFILYAV--RKSIYRYDLASGA--TEQLPLTGL RAAVALDFDYEHNCLYWSDLA--LDVIQRLCL-NGSTGQEVIINSGL ETVEALAFEPLSQLLYWVDAG--FKKIEVANP-DGDFRLTIVNSSVL DRPRALVLVPQEGVMFWTDWGDLKPGIYRSNM-DGSAAYHLVSE-DV KWPNGISVDDQ--WIYWTDAY--LECIERITF-SGQQRSVILD--NL PHPYAIAVFKN--EIYWDDWS--QLSIFRASKYSGS-QMEILAN-QL TGLMDMKIFYKG----------------------------------- (SEQ ID NO: 113) 143623546400021433762--212324232-43105222201-00 (total=102) p Φ Φd ΦYWTD I R dG r ΦΦ L LDLR: KAVGSIAYLFFTN--RHEVRKMTL-DRSEYTSLIPNL RNVVALDTEVASNRIYWSDLS--QRMICSTQLDRAHGVSSYDTVISRDI QAPDGLAVDWIHSNIYWTDSV--LGTVSVADT-KGVKRKTLFRENG SKPRAIVVDPVHGFMYWTDWG-TPAKIKKGGL-NGVDIYSLVTENI QWPNGITLDLLSGRLYWVDSK--LHSISSIDVNGGN-RKTILEDEKRL AHPFSLAVFED--KVFWTDII--NEAIFSANRLTGS-DVNLLAENL LSPEDMVLFHN (SEQ ID NO: 146) LRP2_6: AISTENFLIFALSNSLRSLHLDPENHSPPFQTINVE RTVMSLDYDSVSDRIYFTQNLASGVGQISYATLSSGIHTPTVIASGI GTADGIAFDWITRRIYYSDYL--NQMINSMAE-DGSNRTVIARV PKPRAIVLDPCQGYLYWADWD-THAKIERATL-GGNFRVPIVNSSL VMPSGLTLDYEEDLLYWVDAS--LQRIERSTL-TGVDREVIVNAA VHAFGLTLYGQ--YIYWTDLY--TQRIYRANKYDGSGQIAMTTNLL SQPRGINTVVKNQKQQ (SEQ ID NO: 147) LRP5_1: PAPAAASPLLLFAN---RRDVRLVDAGGVKLESTIVVSGL EDAAAVDFQFSKGAVYWTDVS-EEAIKQTYLNQTGAAVQNVVISGL VSPDGLACDWVGKKLYWTDSE--TNRIEVANL-NGTSRKVLFWQDL DQPRAIALDPAHGYMYWTDWG-ETPRIERAGM-DGSTRKIIVDSDI YWPNGLTIDLEEQKLYWADAK--LSFIHRANL-DGSFRQKVVEGSL THPFALTLSGD--TLYWTDWQ--TRSIHACNKRTGGKRKEILSAL YSPMDIQVLSQERQPFFHTR (SEQ ID NO: 148) LRP5_2: KAGAEEVLLLAR--RTDLRRISL-DTPDFTDIVLQVDDI RHAIAIDYDPLEGYVYWTDDE--VRAIRRAYL-DGSGAQTLVNTEI NDPDGIAVDWVARNLYWTDTG--TDRIEVTRL-NGTSRKILVSEDL DEPRAIALHPVMGLMYWTDWG-ENPKIECANL-DGQERRVLVNASL GWPNGLALDLQEGKLYWGDAK--TDKIEVINV-DGTKRRTLLED KLPHIFGFTLLGDFIYWTDWQ--RRSIERVHK-VKASRDVIID QLPDLMGLKAVNVAKVVGTNP (SEQ ID NO: 149) LRP5_3: IVPEAFLVFTS--RAAIHRISL-ETNNNDVAIPLTGV KEASALDFDVSNNHIYWTDVS--LKTISRAFM-NGSSVEHVVEFGL DYPEGMAVDWMGKNLYWADTG--TNRIEVARL-DGQFRQVLVWRDL DNPRSLALDPTKGYIYWTEWG-GKPRIVRAFM-DGTNCMTLVDKV GRANDLTIDYADQRLYWTDLD--TNMIESSNM-LGQER-VVIAD DLPHPFGLTQYSDYIYWTDWN--LHSIERADKTSGRNR-TLIQGHL DFVMDILVFHSSRQDGLND (SEQ ID NO: 150) LRP5_4: SPPTTFLLFSQ--KSAISRMIPDDQHSPDLILPLHGL RNVKAIDYDPLDKFIYWVDGR---QNIKRAKD-DGTQPFVLTSLSQGQNPD RQPHDLSIDIYSRTLFWTCEA--TNTINVHRL-SGEAMGVVLRGDR DKPRAIVVNAERGYLYFTNMQDRAAKIERAAL-DGTEREVLFTTGL IRPVALVVDNTLGKLFWVDAD--LKRIESCDL-SGANRLTLEDANI VQPLGLTILGK--HLYWIDRQ--QQMIERVEKTTGDKRTRIQGRVAHLTGI HAVEEVSLEEFSAHP (SEQ ID NO: 151) LRP4_1: KALGPEPVLLFAN--RIDIRQVLP-HRSEYTLLLNNL ENAIALDFHHRRELVFWSDVT--LDRILRANL-NGSNVEEVVSTGL ESPGGLAVDWVHDKLYWTDSG--TSRIEVANL-DGAHRKVLLWQNL EKPRAIALHPMEGTIYWTDWG-NTPRIEASSM-DGSGRRIIADTHL FWPNGLTIDYAGRRMYWVDAK--HHVIERANL-DGSHRKAVISQGL PHPFAITVFED--SLYWTDWH--TKSINSANKFTGKNQ-EIIRNKL HFPMDIHTLHPQRQPAGKN (SEQ ID NO: 152) LRP4_2: ISSHACAQSLDKFLLFAR--RMDIRRISF-DTEDLSDDVIPLADV RSAVALDWDSRDDHVYWTDVS--TDTISRAKW-DGTGQEVVVDTSL ESPAGLAIDWVTNKLYWTDAG--TDRIEVANT-DGSMRTVLIWENL DRPRDIVVEPMGGYMYWTDWG-ASPKIERAGM-DASGRQVIISSNL TWPNGLAIDYGSQRLYWADAG--MKTIEFAGL-DGSKRKVLIGSQL PHPFGLTLYGE--RIYWTDWQ-- TKSIQSADRLTGLDRETLQENLENLMDIHVFHRRRP PVSTPCAMEN (SEQ ID NO: 153) LRP4_3: PTGINLLSDGKTCSPGMNSFLIFAR--RIDIRMVSL-DIPYFADVVVPINITM KNTIAIGVDPQEGKVYWSDST--LHRISRANL-DGSQHEDIITTGL QTTDGLAVDAIGRKVYWTDTG--TNRIEVGNL-DGSMRKVLVWQNL DSPRAIVLYHEMGFMYWTDWG-ENAKLERSGM-DGSDRAVLINNNL GWPNGLTVDKASSQLLWADAH--TERIEAADL-NGANRHTLVSPV QHPYGLTLLDS--YIYWTDWQ--TRSIHRADK--GTGSNVILVRS NLPGLMDMQAVDRAQPLGF (SEQ ID NO: 154) LRP4_4: DPSPETYLLFSS--RGSIRRISL-DTSDHTDVHVPVPEL NNVISLDYDSVDGKVYYTDVF--LDVIRRADL-NGSNMETVIGRGL KTTDGLAVDWVARNLYWTDTG--RNTIEASRL-DGSCRKVLINNSL DEPRAIAVFPRKGYLFWTDWG-HIAKIERANL-DGSERKVLINTDL GWPNGLTLDYDTRRIYWVDAH--LDRIESADL-NGKLRQVLVSHV SHPFALTQQDR--WIYWTDWQ--TKSIQRVDKYSGRNKETVLANVEGL MDIIVVSPQRQTGTNA (SEQ ID NO: 155) LRP6_1: VLLRAAPLLLYAN--RRDLRLVDATNGKENATIVVGGL EDAAAVDFVFSHGLIYWSDVS--EEAIKRTEFNKTESVQNVVVSGL LSPDGLACDWLGEKLYWTDSE--TNRIEVSNL-DGSLRKVLFWQEL DQPRAIALDPSSGFMYWTDWG-EVPKIERAGM-DGSSRFIIINSEI YWPNGLTLDYEEQKLYWADAK--LNFIHKSNL-DGTNRQAVVKGSL PHPFALTLFED--ILYWTDWS--THSILACNKYTGEGLREIHSDI FSPMDIHAFSQQRQPNATNP (SEQ ID NO: 156) LRP6_2: KDGATELLLLAR--RTDLRRISL-DTPDFTDIVLQLEDI RHAIAIDYDPVEGYIYWTDDE--VRAIRRSFI-DGSGSQFVVTAQI AHPDGIAVDWVARNLYWTDTG--TDRIEVTRL-NGTMRKILISEDL EEPRAIVLDPMVGYMYWTDWG-EIPKIERAAL-DGSDRVVLVNTSL GWPNGLALDYDEGKIYWGDAK--TDKIEVMNT-DGTGRRVLVED KIPHIFGFTLLGDYVYWTDWQ--RRSIERVHK- RSAEREVIIDQLPDLMGLKATNVHRVIG SNPMGAVLRSLLA (SEQ ID NO: 157) LRP6_3: IVPEAFLLFSR--RADIRRISL-ETNNNNVAIPLTGV KEASALDFDVTDNRIYWTDIS--LKTISRAFM-NGSALEHVVEFGL DYPEGMAVDWLGKNLYWADTG--TNRIEVSKL-DGQHRQVLVWKDL DSPRALALDPAEGFMYWTEWG-GKPKIDRAAM-DGSERTTLVPNV GRANGLTIDYAKRRLYWTDLD--TNLIESSNM-LGLNR-EVIAD DLPHPFGLTQYQDYIYWTDWS--RRSIERANKTSGQNR-TIIQGHL DYVMDILVFHSSRQSGWNE (SEQ ID NO: 158) LRP6_4: SAPTTFLLFSQ--KSAINRMVI-DEQQSPDIILPIHSL RNVRAIDYDPLDKQLYWIDSR--QNMIRKAQE-DGSQGFTVVVSSVPSQNLE IQPYDLSIDIYSRYIYWTCEA--TNVINVTRL-DGRSVGVVLKGEQ DRPRAVVVNPEKGYMYFTNLQERSPKIERAAL-DGTEREVLFFSGL SKPIALALDSRLGKLFWADSD--LRRIESSDL-SGANR-IVLEDSNI LQPVGLTVFEN--WLYWIDKQ--QQMIEKIDM-TGREGRTKVQARI AQLSDIHAVKELNLQEYRQHP (SEQ ID NO: 159) [0348] 2.e Identity of mapped YWTD variants: disease proteins and disease variants [0349] Table 7. Summary of included proteins containing naturally occurring variants associated with diseases in YWTD domains shared with SORL1.

Table 7 cont...

[0350] 2.f YWTD disease variants listed according to domain positions [0351] Disease-mutations domain-mapping analysis with identification of pathogenic variants in other proteins with YWTD-domains (as listed in Table 8). Here variants are mapped onto domain positions following alignment of internally repeated sequences in the SORL1 domain sequences. The number of hits for each position depicted in the bar diagram of FIG. 2D. [0352] Table 8. Pathogenic SORL1 YWTD domain mutations.

[0353] 3 The EGF-domain (residues 1014-1074) [0354] 3.a Sequence details [0355] EGF-domains are widely present in proteins with diverse biological functions 58. This domain typically has ~40 amino acids with several short β-strands containing conserved cysteines invariably forming intradomain disulfide bridges⁵⁸. In the mammalian proteome, EGF-domains are commonly divided into two subgroups: (1) those containing eight cysteines, which often occur in proteins of the extracellular space, (i.e. Laminin, Fibrillin, and the β-subunit of integrins) and (2) those with six cysteines commonly found in LDLRs. Indeed, the YWTD β-propellers in LDLR, LRP4, LRP6, and ApoER2 are most often flanked with 1 or 2 six-cysteine-EGF-domains before, and always by at least one six-cysteine EGF-domain at their C-terminal end^15,59 (FIG. 9). While SORL1 has historically been acknowledged as a member of the LDLR family^10,60,61 it includes only one eight-cysteine EGF-domain C-terminal to the β-propeller and none before (FIGs. 9 and 10). Moreover, the SORL1 EGF-domain contains 61 amino acids (residues 1014-1074; encoded by a single exon 22) such that it is substantially larger than EGF-domains in other LDLR family members. (FIG. 13B). Only a single amino acid separates the fourth and fifth cysteines and there is also only a single residue between the sixth and the seventh cysteines of the SORL1 domain⁶². The disulfide connectivity for integrin-type domains is Cys^I-Cys^V, Cys^II-Cys^IV, Cys^III-Cys^VI, and Cys^VII-Cys^VIII. While, based on the number of the cysteine residues and their spacing in the sequence, the SORL1 EGF-domain might resemble the “integrin-like” type, there is little similarity between the SORL1 EGF-domain and the EGF-domains from integrin β-subunits (FIG.13B). In contrast, several residues from the SORL1-EGF domain can be aligned with the sequence of EGF- domains positioned C-terminal to YWTD β-propellers from the LDLR family with the highest sequence similarity between the two last cysteine residues (FIG.13B). This suggests that the SORL1 EGF-domain is evolutionary related to the LDLR family: the connectivity of the outer six cysteines follows the stereotypic pattern of LDLR EGF-domains, and the two additional central cysteines (Cys^IV and Cys^V) could allow the formation of a loop onto the regular EGF- domain fold (FIG.3B). [0356] The solved structure of the YWTD-EGF domain pair from LDLR indicated that the C-terminal EGF-domain stabilizes the 6-bladed YWTD β-propeller. The EGF-domain forms contacts with the propeller through a series of tight hydrophobic interactions with the linker region and the YWTD-domain that assist to fold the combined two-domain structure, analogous to the association between 10CC- and VPS10p-domain pairs. Indeed, functional studies demonstrated that it was impossible to isolate the propeller without the EGF-domain of LDLR¹⁵. In LDLR, the EGF-A domain forms a protein-protein interaction with the catalytic domain of the protein PCSK9, which assists in the endocytosis and subsequent lysosomal degradation of LDLR in the liver (Jackson et al, 2007). [0357] 3.c SORL1 variants in EGF-domain [0358] The importance of the 61-residue EGF-domain in SORL1 as a whole is underscored by a pedigree for a Swedish AD-family carrying variant 11:121437647, which translates to c.3050-2A>G that leads to loss of adjacent splice acceptor site and exclusion of exon 22 – and thus deletion of the entire EGF-domain (p.Gly1017-Glu1074del)⁶³. It is speculated that lack of the EGF-domain is likely not compatible with folding of a functional receptor, which may also explain the observed co-occurrence of the YWTD-domain with a neighboring EGF-domain at its C-terminal end in LDLRs. Due to the limited sequence similarity between the SORL1 EGF- domain and the EGF-domains in the LDLR proteins it was not possible to accurately assess pathogenic variants in Uniprot that map to the SORL1 EGF-domain. [0359] 3.d EGF-domain alignment [0360] We prepared alignments of the SORL1 EGF-domain sequence with homologous domains from LDLR or from Integrin beta2 and beta4. The SORL1 EGF-domain share overall more similarly to YWTD- than integrin-like EGF-domains, despite the presence of 8 Cys residues in the SORL1 domain and ony 6 Cys in the LDLR-type EGF-domains. The annotations shown by underlining codes indicates partial amino acid conservation across the domain sequence. [0361] Alignment between EGF-domain sequences located C-terminal to YWTD- propellers (see FIG.2) LRP6_1: ATNPCGID---NGGCSHLCLMSPVK----------------- PFYQCACPTGVKLLENGKTCK (SEQ ID NO: 160) LRP6_2: GSNPCAEE---NGGCSHLCLYRPQG-------------------LRCACPIGFELISDMKTCI (SEQ ID NO: 161) LRP6_3: GWNECASS---NGHCSHLCLAVPVG------------------ GFVCGCPAHYSLNADNRTCS (SEQ ID NO: 162) LRP6_4: RQHPCAQD---NGGCSHICLVKGDG------------------ TTRCSCPMHLVLLQDELSCG (SEQ ID NO: 163) LRP4_1: GKNRCGDN---NGGCTHLCLPSGQN-------------------YTCACPTGFR- KISSHACA (SEQ ID NO: 164) LRP4_2: VSTPCAME---NGGCSHLCLRSPNP----------------- SGFSCTCPTGINLLSDGKTCS (SEQ ID NO: 165) LRP4_3: GFNKCGSR---NGGCSHLCLPRPSG------------------- FSCACPTGIQLKGDGKTCD (SEQ ID NO: 166) LRP4_4: GTNACGVN---NGGCTHLCFARASD-------------------FVCACPD----EPDSRPCS (SEQ ID NO: 167) LRP5_1: FHTRCEED---NGGCSHLCLLSPSE----------------- PFYTCACPTGVQLQDNGRTCK (SEQ ID NO: 168) LRP5_2: GTNPCADR---NGGCSHLCFFTPHA-------------------TRCGCPIGLELLSDMKTCI (SEQ ID NO: 169) LRP5_3: GLNDCMHN---NGQCGQLCLAIPGG------------------- HRCGCASHYTLDPSSRNCS (SEQ ID NO: 170) LRP5_4: SAHPCARD---NGGCSHICIAKGDG------------------ TPRCSCPVHLVLLQNLLTCG (SEQ ID NO: 171) LDLR: GVNWCERTTLSNGGCQYLCLPAPQI------------- NPHSPKFTCACPDGMLLARDMRSCL (SEQ ID NO: 172) APOER: PDACELSVQPNGGCEYLCLPAPQI------------- SSHSPKYTCACPDTMWLGPDMKRCY (SEQ ID NO: 173) VLDLR: GKNWCEED-MENGGCEYLCLPAPQI------------- NDHSPKYTCSCPSGYNVEENGRDCQ (SEQ ID NO: 174) SORL1: KNTGSNACV----- PRPCSLLCLPKANNSRSCRCPEDVSSSVLPSGDLMCDCPQGYQLKNNT--CVKQ (SEQ ID NO: 114) Alignment with EGF-domains from integrin beta2 and beta4 following a published alignment of these domains in refs^62,64 Beta2_1: CR---------DQSR----DRSLCHG----KGFLEC-------------GICRCDT----GY-- IGKNCE (SEQ ID NO: 175) Beta2_2: CQTQGRSSQELEGSCRKDNNSIICSG----LGDCVC------------- GQCLCHTSDVPGKLIYGQYCE (SEQ ID NO: 176) Beta2_3: CD---------TINCERY-NGQVCGG--PGRGLCFC-------------GKCRCHP----GF-- EGSACQ (SEQ ID NO: 177) Beta2_4: CER-------TTEGCLNP-RRVECSG----RGRCRC-------------NVCECHS----GY-- QLPLCQ (SEQ ID NO: 178) Beta4_1: CE--------LQKEV----RSARCSF----NGDFVC-------------GQCVCSE----GW-- SGQTCN (SEQ ID NO: 179) Beta4_2: CST-G--SLSDIQPCLREGEDKPCSG----RGECQC-------------GHCVCYGE--- GR-YEGQFCE (SEQ ID NO: 180) Beta4_3: Y---------DNFQCPRT-SGFLCND----RGRCSM-------------GQCVCEP----GW-- TGPSCD (SEQ ID NO: 181) Beta4_4: CPL-------SNATCIDS-NGGICNG----RGHCEC-------------GRCHCHQQ---- SLYTDTICEINYS (SEQ ID NO: 182) SORL1: KNTGSNACV---------PRPCS----- LLCLPKANNSRSCRCPEDVSSSVLPSGDLMCDCPQ----GYQLKNNTCVKQ (SEQ ID NO: 114) [0362] 4 The CR-cluster (residues 1075-1550) [0363] 4.a Sequence details [0364] More than half of all the ligands identified to bind the SORL1 receptor, including APP, interact with the CR-cluster^65-67. In fact, SORL1 that lacks all its eleven CR-domains fails to bind APP⁶⁸, making it unlikely that APP binds to regions outside the CR-cluster. [0365] CR-clusters of LDLR family members all contain 2 to 12 CR-domains (FIG. 9), while proteins that belong to the complement system include single CR-domains (i.e. C6, C7, C8α, C8β, C9, factor 1). This has led to two different definitions of the same module: “LDLR- type A repeats” and “Complement-type repeat (CR)-domains”. One CR-domain sequence contains approximately 40 amino acids with several highly conserved residues, including six cysteines and five conserved acidic residues. The 6 cysteines (positions 15, 23, 29, 36, 42, 55) form three invariable disulfide bridges with the connectivity Cys^I-Cys^III, Cys^II-Cys^V, and Cys^IV- Cys^{VI 69,70} (FIGs. 4A-4E), whereas the 5 conserved acidic residues were originally thought to engage in binding of ligands containing exposed basic residues in their receptor-binding site. In addition, a serine (position 46), together with a pair of hydrophobic residues at positions 21 (phenylalanine) and position 30 (isoleucine) in the more N-terminal part of the sequence are also highly conserved across CR-domains (FIG. 4E). Furthermore, the CR-domains in SORL1 also contain a pair of glycines (positions 27 and 38) that is conserved in eight of the eleven CR-domains (FIG. 4C). With this high sequence conservation for 16 out of 40 positions across CR-domains from several proteins, it is not surprising that they all show a very similar folding (including domains from LDLR, ApoER2, LRP1, and LRP2)^71-79. Structure determination by NMR indicates a very compact folding consisting of a β-hairpin structure with two short strands, followed by a series of β-turns (FIG.11). The glycine at position 27 is at the center of the β-hairpin-turn, which requires a small side chain or none at all. The conserved phenylalanine (position 21) and isoleucine (position 30) pack against each other in a small hydrophobic core of the domain interior, preventing their side chains from engaging in ligand interactions (FIGs.4A-4E). [0366] In members of the LDLR family, the combination of CR-domains plays a key role in ligand binding⁸⁰, outlining a functional consequence of exon skipping in some CR-clusters. This is best exemplified by the human ApoER2 gene (aka LRP8), which can encode a receptor with eight different CR-domains⁸¹. Most of the translated ApoER2 molecules lack three central CR-domains CR4-CR6, producing a receptor that binds efficiently to Reelin but not α₂- macroglobulin. However, when CR4-CR6 is included this longer ApoER2 isoform can also bind α2-macroglobulin⁸². Another ApoER2 isoform, with an unknown effect on ligand binding, lacks the most C-terminal CR-domain due to a second alternative splice event. Similarly, exon 4 skipping of human very low-density lipoprotein receptor VLDLR leads to a receptor isoform that lacks the third CR-domain, which increases VLDLR-affinity for ApoE-lipoproteins compared to VLDLR containing all its eight CR-domains⁸³. Accordingly, alternative splicing of exons encoding CR-domains presents a mechanism to generate receptor variants with unique patho/physiological ligand binding properties. A conserved Calcium cage - and the minimal motif [0367] Ligand-binding to members of the LDLR family is critically dependent on calcium ions, which are coordinated by four of the conserved acidic residues in each CR-domain (at positions 37, 41, 47, and 48) (FIG.4A, grey arrows in FIG.4C). Their acidic side chains form an octahedral calcium cage⁷³, which also stabilizes the folding of the C-terminal part of the domain⁸⁴. The side chain of a fifth conserved acidic residue (aspartate at position 44) forms a structure known as an “Asx-turn”: it makes a hydrogen bond with the backbone amides of two residues: one residue upstream and the conserved serine two residues downstream (position 46) 85. Two additional amino acids (positions 34 and 39) contribute to the calcium coordination with their backbone carbonyl groups (FIG.4A, and black arrows in FIG.4C). This geometry makes the side chains of residues at these two positions (most often a Trp-Asp pair in LDLR family proteins) ideally positioned at the domain’s molecular surface to engage in calcium-dependent ligand interactions^86-88. These two amino acids, at positions 34 and 39, have therefore been named “CR-domain fingerprint residues”²³. APP binding to SORL1 Is also strictly dependent on the presence of calcium⁶⁵. [0368] The side chains of the two fingerprint residues interact most often with a lysine residue of the ligand (often positioned on a helical structure⁸⁹) and a residue containing a hydrophobic side chain. It is intriguing how such a simple motif, called the “the minimal motif” 23,79,90, allows for discrimination of interaction partners^79,91-94. The fingerprint of the SORL1 CR- cluster is strongly conserved among all the 11 CR-domains across evolution, highlighting the importance of the CR-cluster function (FIG.4C). Substitutions at positions of fingerprint residues can impair binding of specific ligands, but do not affect overall folding and stability of CR- domains^86-88,95. [0369] The CR-domain fingerprint residues of five of the eleven CR-modules in SORL1 (CR1, CR2, CR3, CR4, and CR8) are represented by the canonical Trp-Asp pair of amino acids common to the receptor:ligand complexes for the LDLR family (FIG. 4A). The remaining six pairs of fingerprint residues have a hydrophobic residue instead of the aspartate, and three CR- domains (CR5, CR10 and CR11) have a charged residue (Glu or Lys) instead of the Trp, suggesting that the SORL1 CR-cluster may also bind ligands with motifs different from the common lysine-based motif for ligands of LDLR family members. The SORL1 ligand profile of these CR-domains may be more similar to SCO-spondin which contains 10 CR-domains, none of which has a Trp-Asp fingerprint pair⁹⁶. Alternatively, the binding partner for these CR-domains may be another part of a (compact?) SORL1 conformation. [0370] The necklace model and linker length [0371] CR-domains fold independently from neighboring CR-domains, and substitutions that cause local misfolding of one CR-domain (e.g. substitutions of residues in the Calcium cage) still allow for correct folding of its adjacent CR-domain in vitro

This agrees with the observed negligible interdomain interactions^21,100,101, suggesting that CR-clusters are like a necklace with the individual CR-domains behaving as “pearls-on-a-string”¹⁰⁰. This modular organization allows for a high degree of flexibility that seems primarily determined by the length (and eventually the composition) of the interdomain sequence of amino acids; ie.e., the so-called linkers. This flexibility enables different CR-domains to wrap around larger ligands and engage in minimal motif interactions with multiple sites of the ligand. Such avidity, including two or more receptor CR-domains, leads to high-affinity ligand binding^86,102. The linker sequences of CR-clusters are commonly 3 to 4 residues, with 12 amino acids as the longest connective string in LDLR. Many linker sequences in the SORL1 CR-cluster are longer, and the linkers towards the most C-terminal part of the cluster are extremely long. The sequences connecting CR8 with CR9 and CR9 with CR10 contain 15 and 17 amino acids, respectively, suggesting a unique flexibility of the SORL1 CR-cluster. However, as these linker-sequences are also highly conserved among species (FIG. 13), it may be hypothesized that they fulfill an important role in the physiological function of SORL1. Interestingly, some of the SORL1 linkers become modified by O-linked glycans, including residues T1198 and T1508^103,104, but how that relates to receptor activity has not yet been determined. [0372] Odd-numbered cysteines (ONC, positions 15, 23, 29, 36, 42, and 55 + all): [0373] Either removal of one of the six conserved cysteines or introduction of a cysteine residue at another position of the domain sequence may disrupt the disulfide connectivity of CR- domains. There is strong evidence from the DMDM analysis that variants leading to an odd number (5 or 7) of cysteines (ONC) result in dysfunctional folding for other proteins with CR- clusters (FIG.4D). Most prominently, it was found that 21 out of 51 positions in LDLR linked to FH involve the replacement of a cysteine residue within the CR-cluster Table 9. Also the introduction of an extra cysteine, p.R78C^LDLR is considered pathogenic⁵¹. The DMDM analysis also identified disease associated variants that involve replacement of cysteines in other LDLR family members: p.C160Y^LRP4 causal for CLSS³⁸ and p.C1361G^LRP5 in patients with EVR4^28,29. Such ONC mutations are also pathogenic in proteins outside the LDLR family, e.g. the transmembrane proteinase TMPRSS6, (p.C510S^{TMPRSS6 105,106} and p.C510R^{TMPRSS6 105} in patients with IRIDA) or the COP9 protein (p.C119G^{C9 107} in patients with C9D). [0374] Two different ONC variants in SORL1 has lately been reported to segregate with AD in small pedigrees that indicate that such mutations are truly pathogenic. First, a Swedish family (PED.25) with segregating variant p.R1303C in the sixth CR-domain was identified⁶³, and later a family in Saudi Arabia with variant p.R1084C in the first CR-domain was reported¹⁰⁸, both resulting in CR-domains with 7 cysteines. Also, a 59-year-old AD patient with variant p.C1192Y that results in having 5 cysteines in the third CR-domain has been identified¹⁰⁹, supporting that ONC variants in SORL1 is associated with high risk for AD. The variant p.C1344R was reported associated with a possible family history in Finland⁶³, and also variants p.C1453S and p.C1249S were identified exclusively in AD patients¹¹⁰. [0375] Additional analysis of ONC variants in SORL1 from the ADES-ADSP dataset⁴⁰, show how they occur predominantly in AD cases (p.R1080C, p.W1095C, pC1112Y, p.R1124C, p.R1172C, p.C1177Y, p.C1196CY, p.R1243C, p.R1260C, p.C1275S, p.C1286C, p.R1303C, p.Y1371C, p.Y1424C, p.Y1441C, p.C1453F, p.C1478S, p.R1490C, p.C1521R, p.C1540S; n=31) compared to controls (p.Y1196C, p.R1490C, p.C1497Y; n=5). Hence, ONC substitutions associate with a very strong increased risk of AD (OR = 6.3195% CI: 2.45 - 16.24, p=5.1E-6; Fisher Exact test). [0376] We note the similarity between ONC variants in SORL1 associated with AD and variants in NOTCH3 causal of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), where stereotypic causal variants also result in an odd-number of cysteines in EGF-domains of NOTCH3 carrying 32-34 copies of this domain type¹¹¹. Or how 22 of 80 cysteines from the sequence of ten EGF-domains (of the eight-cysteine type) from the Usherin protein (encoded by USH2A are found mutated in patients with retinitis pigmentosa (USH2A LOVD mutation database, ovd.nl/USH2A). This demonstrates a general mechanism how variants in small cysteine-rich protein disulfide-containing domains that affects the number of cysteine residues may associate with a very high disease penetrance, and suggest that also ONC variants in SORL1 should with high confidence be considered pathogenic and causal of AD. [0377] Calcium cage (CaCa, positions 37,41, 47, and 48): [0378] In proteins with CR-domains, residues at positions 37 and 41 and 47 are almost all Asp (in SORL1, there is a single exception; Gln¹³⁰¹ at pos 41 in CR6) and positions 48 are all Glu (FIG.4C). The side chains of these residues coordinate Ca²⁺ establishing an octahedral Ca²⁺ cage (CaCa) that is important for domain folding^99,112. As a consequence, substitutions of these variants may be strongly associated with disease. [0379] Our DMDM analysis showed that in LDLR, substitutions of CaCa residues are associated with FH; position 37: p.D90G⁵¹, p.D90N⁵¹, p.D90Y¹¹³, p.D168A³⁴, p.D168H¹¹⁴, p.D168N^51,115, p.D168Y¹¹⁶, p.D172N^30,115, p.D221G^{26,34,51,52,117,118}, p.D221N^42,52, p.D221Y^117,118; position 41: p.D301G^34,115,119, p.D301A¹²⁰; position 47: p.D139H, p.D227E^51,121, p.D266E²⁶; and position 48: p.E101K^51,52, p.E140K^30,113,122; p.E228K^34,123, p.E228Q³⁴. Note the two disease-associated substitutions of Asp with Glu at position 47, which is generally considered a conservative – and often non-pathogenic – substitution. However, in CR-domains there is not enough space in the Calcium cage to accommodate the larger glutamate side chain at position 47⁷³. Uniprot also lists disease-associated variants for CaCa positions in other proteins: a variant in LRP2 at position 37 associates with intellectual disability (p.D3779N^LRP2)¹²⁴ and another LRP2 variant at position 47 causes Stickler syndrome (p.D3828G^LRP2)¹²⁵. Uniprot further lists disease-associated variants in LRP5 (p.E1367K^LRP5 in patients with EVR^28,49), TMRPSS3 (p.D103G^TMPRSS3 causal of deafness^126,127) and TMRPSS6 (variants p.D521G^{TMPRSS6 105}, p.D521N^{TMPRSS6 128,129} and p.E522K^{TMPRSS6 129} considered causative of IRIDA) (Table 9). [0380] There is also evidence that CaCa variants in SORL1 is associated with AD. Studies report carriers of variant p.D1389V (position 37, CR8) only in AD patients, and these have very early onset (<51 years)^130-132. Other studies identified variant p.D1545E of CR11 (position 47; CADD score 15.9)¹³⁰, p.D1182N (position 41, CR3), and p.D1267E (position 47, CR5)¹¹⁰ in AD patients only. Interestingly, the p.D1267E and p.D1545E variants have very low CADD scores (~16) presumably because a substitution of an Asp with a Glu is generally considered benign, only not when present in a CR-domain Calcium cage. It was found that the CaCa p.D1545V (position 47, CR11) variant is acting as a dominant negative and causal variant of AD in an Icelandic family 133. [0381] The ADES-ADSP dataset includes such variants (p.D1108N, p.D1219G, p.D1261G, p.D1267N, p.D1345N, p.D1389V, p.D1502G, p.D1535N, p.D1545N, p.D1545G, p.D1545E) at positions in Calcium cages exclusively in AD cases (n=13) with a relatively early age at onset (median 60 years, ranging from 47-73 years) such that they are associated with a strong increased risk of AD (OR = INF) and in practice should be considered as causative for AD as loss-of-function variants that is now accepted as causal for AD¹³⁴. [0382] Asx-turn: aspartate at position 44: [0383] In SORL1 all eleven CR-domains contain an aspartate at position 44, which forms the Asx-turn⁷³. Functional studies indicated that in LDLR, even the slightest modification of this residue results in FH, exemplified by the conservative aspartate to asparagine mutation in an LDLR CR-domain, because both carboxylate oxygens of the aspartate are necessary for hydrogen bonding⁷³. The large alignment of CR-domain sequences confirms a strong preference for aspartate at position 44, and it may thus be considered a hotspot for pathogenic mutations. Uniprot lists four disease-associated variants at this position: p.D175N^LDLR (causal of FH in Afrikaners¹²¹), p.D175Y^LDLR (in FH patients¹³⁵), p.D224V^LDLR (causal of elevated LDL cholesterol in FH patients¹¹⁷), and p.D137N^LRP4 (variant is considered causal of CLSS³⁸). [0384] In the ADES-ADSP dataset, it was observed variants p.D1105H and p. D1146N at this position in SORL1, in respectively a 64- and a 48-year-old AD patient and none in controls 40. Functional tests in cell culture studies showed strongly reduced shedding of D1105H mutant SORL1, and found low sSORL1 levels in CSF from two carriers of the variant, supporting these SORL1 variants as pathogenic (Holstege and Andersen, unpublished). [0385] Hydrophobic “core”: phenylalanine and Isoleucine at positions 21 and 30 [0386] These two positions in the CR-domain sequence are strongly conserved and stabilize the N-terminal part of CR-domains^71,72. In vitro studies showed that mutation of residues at these two positions destabilized the CR-domain folding and impaired ligand-binding activity of LDLR¹³⁶. Surprisingly, the DMDM analysis of disease-associated variants in Uniprot did not find any pathogenic variants for neither of these two positions in any CR-domain containing proteins, including LDLR (FIG. 4D). This is surprising but suggests that despite being positions with strongly conserved amino acids, it may not be dangerous to substitute with other residues at these positions. [0387] 4.d CR-domain alignment [0388] Mapping of naturally occurring variants found in human CR-domain containing proteins, and being listed as associated with pathology at uniprot.org. The alignment follows the SORL1 alignment shown on top, and pathogenic variants are indicated by underline. 1 10 20 30 40 50 CR1 1075-1113 -----------ENTC-LRNQYRC-SNGNCINSIWWCDFDNDCGDMSDE---- RNCP-- CR2 1114-1154 -----------TTICDLDTQFRCQESGTCIPLSYKCDLEDDCGDNSDE---- SHCE-- CR3 1155-1193 -----------MHQC-RSDEYNC-SSGMCIRSSWVCDGDNDCRDWSDE---- ANCT-- CR4 1194-1236 ---------AIYHTC-EASNFQC-RNGHCIPQRWACDGDTDCQDGSDE-- DPVNCE-- CR5 1237-1271 ------------KKC---NGFRC-PNGTCIPSSKHCDGLRDCSDGSDE----QHC--- CR6 1272-1316 ----------- EPLCTHFMDFVCKNRQQCLFHSMVCDGIIQCRDGSDEDAAFAGCS-- CR7 1317-1359 ------QDPEFHKVC-DEFGFQC-QNGVCISLIWKCDGMDDCGDYSDE--- -ANC--- CR8 1360-1405 ------ENPTEAPNCSRYFQFRC-ENGHCIPNRWKCDRENDCGDWSDE--- -KDCGD- CR9 1406-1456 -SHILPFSTPGPSTC-LPNYYRC-SSGTCVMDTWVCDGYRDCADGSDE- ---EACPLL CR10 1457-1507 ANVTAASTPTQLGRC- DRFEFECHQPKTCIPNWKRCDGHQDCQDGRDE----ANCP-- CR11 1508-1550 --------THSTLTC-MSREFQCEDGEACIVLSERCDGFLDCSDESDE---- KACS— (SEQ ID NO: 115) 4100010030210230100115211237031355--000041 (total=63) --------TH STLTC –MSEFmCEDGgACIVLS RCDGFLDCSDESDE C LDLR: VGDRC-ERNEFQC-QDGKCISYKWVCDGSAECQDGSDE--SQETCLS Δ=GG VTC-KSGDFSCΔRVNRCIPQFWRCDGQVDCDNGSDE----QGCP PKTC-SQDEFRC-HDGKCISRQFVCDSDRDCLDGSDE----ASCPV LTC-GPASFQC-NSSTCIPQLWACDNDPDCEDGSDE--WPQRCRG LYVFQGDSSPC-SAFEFHC-LSGECIHSSWRCDGGPDCKDKSDE----ENCA VATC-RPDEFQC-SDGNCIHGSRQCDREYDCKDMSDE----VGCV NVTLCEGPNKFKC-HSGECITLDKVCNMARDCRDWSDE--PIKECG (SEQ ID NO: 183) TMPRSS6: PC--PGEFLCSVNGLCVPA---CDGVKDCPNGLDE----RNC VC--RATFQCKEDSTCISLPKVCDGQPDCLNGSDE----EQCQ Δ=PQ PC-GTFTFQC-EDRSCVKKPNΔCDGRPDCRDGSDE----EHCD (SEQ ID NO: 184) COP9: DDC--GNDFQC-STGRCIKMRLRCNGDNDCGDFSDE----DDCES (SEQ ID NO: 185) LRP4: Δ =ALGEC AC-GRSHFTCAVSΔTCIPAQWQCDGDNDCGDHSDE----DGCI LPTC-SPLDFHC-DNGKCIRRSWVCDGDNDCEDDSDE----QDCP PREC-EEDEFPC-QNGYCIRSLWHCDGDNDCGDNSDE-----QCD MRKC-SDKEFRC-SDGSCIAEHWYCDGDTDCKDGSDE----ENCP SAVPAPPC-NLEEFQC-AYGRCILDIYHCDGDDDCGDWSDE----SDCS SHQPC-RSGEFMC-DSGLCINAGWRCDGDADCDDQSDE----RNCT TSMC-TAEQFRC-HSGRCVRLSWRCDGEDDCADNSDE----ENCE NTGSPQC-ALDQFLC-WNGRCIGQRKLCNGVNDCGDNSDE- SPQQNCRPR (SEQ ID NO: 186) LRP5: Δ =AT TC-SPDQFACΔGEIDCIPGAWRCDGFPECDDQSDE----EGCP VC-SAAQFPC-ARGQCVDLRLRCDGEADCQDRSDE----ADCD AIC-LPNQFRC-ASGQCVLIKQQCDSFPDCIDGSDE----LMCEI (SEQ ID NO: 187) Corin: LLCGRGENFLC-ASGICIPGKLQCNGYNDCDDWSDE----AHC NC-SENLFHC-HTGKCLNYSLVCDGYDDCGDLSDE----QNC DCNPTTEHRC-GDGRCIAMEWVCDGDHDCVDKSDE----VNC SCHSQGLVEC-RNGQCIPSTFQCDGDEDCKDGSDE----ENCSV EC-SPSHFKC-RSGQCVLASRRCDGQADCDDDSDE----ENC GCKERDLWECPSNKQCLKHTVICDGFPDCPDYMDE----KNC SFC-QDDELEC-ANHACVSRDLWCDGEADCSDSSDE----WDCVT (SEQ ID NO: 188) TMPRSS3: DC--SGKYRCRSSFKCIELIARCDGVSDCKDGEDE----YRCV (SEQ ID NO: 189) CFAI: VCYTQKADSPMDDFFQC-VNGKYISQMKACDGINDCGDQSDE----LCCK AC-QGKGFHC-KSGVCIPSQYQCNGEVDCITGEDE----VGCA (SEQ ID NO: 190) [0389] 4.e Identity of mapped CR variants: disease proteins and disease variants [0390] Table 9. Summary of included proteins containing naturally occurring variants associated with diseases in CR domains shared with SORL1.

Table 9 cont...

[0391] 4.f CR disease variants listed according to domain positions [0392] Disease-mutations domain-mapping analysis with identification of pathogenic variants in other proteins with CR-domains (as listed in Table 10). Here variants are mapped onto domain positions following alignment of internally repeated sequences in the SORL1 domain sequences. The number of hits for each position depicted in the bar diagram of FIG.4D. Table 10. Pathogenic SORL1 CR domain mutations.

; C 5 p.C46S(LDLR), p.C89Y(LDLR), Loss of Cys p.C510R(TMPRSS6), p.C510S(TMPRSS6), p.C119G(C9) ; D 7 p.D90G(LDLR), p.D90N(LDLR), Loss of Cys p.D90Y(LDLR), p.D168A(LDLR), p.D168H(LDLR), p.D168N(LDLR), p.D168Y(LDLR) 1 p.G243D(CFI) ; fp 1 p.Q92E(LDLR) 3 p.A50S(LDLR), p.A50T(LDLR), p.R300G(LDLR) ; D 6 p.D172N(LDLR), p.D221G(LDLR), Loss of Asp p.D221N(LDLR), p.D221Y(LDLR), p.D301A(LDLR), p.D301G(LDLR) ; C 9 p.C95G(LDLR), p.C134F(LDLR), Loss of Cys p.C134W(LDLR), p.C173W(LDLR), p.C222Y(LDLR), p.C261F(LDLR), p.C302W(LDLR), p.C302Y(LDLR), p.C1361G(LRP5) 0 ; D 4 p.D175N(LDLR), p.D175Y(LDLR), Loss of Asp p.D224V(LDLR), p.D137N(LRP4)

[0393] 5 The FnIII-cassette (residues 1551-2121) [0394] 5.a Sequence details [0395] Although the region containing the six FnIII-domains corresponds to almost a third of the entire SORL1 extracellular part (the ectodomain), surprisingly little is known about its function. Many mutations observed in AD patients locate within the FnIII-domains of SORL1, which suggests that this receptor region represents an important structural and/or functional aspect of SORL1^110,143,144. In other proteins, FnIII-domains are commonly involved in ligand binding, but for the SORL1 protein, no interaction partner has yet been identified to bind to this region⁶⁷. It can therefore be speculated that this region is important for the structural integrity of SORL1, and may be involved in bending of the full modular receptor, thereby arranging binding surfaces in space. Interaction “partners” may therefore rather be another SORL1 molecule to form SORL1- dimers²⁴, or other domains within the same SORL1 protein instead of foreign ligands. [0396] FnIII-domains were originally identified in the modular protein Fibronectin, hence the name of the domain¹⁴⁵. Fibronectin, which includes 15 copies of the FnIII-domains, plays myriad fundamental biological roles such as adhesion, cell migration, and hemostasis, and similar multifunctionality is also true for many other proteins containing FnIII-domains. This domain type is present in a high number of animal and bacterial protein families including extracellular matrix proteins, cell surface receptors, kinases and phosphatases, muscle proteins, etc.¹⁴⁶. Accordingly, in contrast to the VPS10p-domain and the YWTD/EGF- and CR-domains that are representative of two distinct receptor families, a similar clear affiliation for FnIII-domain containing proteins is not possible. More than 2,100 domains are listed in PFAM as being FnIII-domains¹⁴⁶. The structure of the second SORL1 FnIII-domain is deposited in the protein databank (2DM4.pdb), but not yet described in any publication. [0397] Binding motif for SORL1 FnIII-domains with interacting partners not yet clear [0398] FnIII-domains may occur as single repeats in proteins, but they are more frequently clustered as 2-6 adjacent domains¹⁴⁶. In membrane anchored receptor proteins, including SORL1, the clustered FnIII-domains are most often located directly proximal to the plasma membrane, where they may engage in contact with other proteins. While ligand interactions are characterized by RGD- or GSWGS-motifs in some FnIII-domain-containing receptors^147-151, a unifying motif for ligand binding has not (yet) been identified for FnIII-domains in general nor for the six SORL1 domains in particular. [0399] Structure and important amino acids [0400] A typical FnIII-domain structure has an ellipsoid shape with approximate dimensions 38 Å x 20 Å x 25 Å

The incoming and outgoing amino acid sequence ends at opposite sides of the folded domain (FIGs. 5A-5F), which is in agreement with one of its main functions: to act as a spacer for proper positioning of protein structures¹⁵². This fold is topologically closely related to that of Immunoglobulin (IgG)-like domains: however, the FnIII- domains lack the conserved disulfide bonds, and strands A and C’ are interchanged between sheets relative to the IgG domains¹⁵². FnIII-domains are typically composed of a sequence with 90-100 residues, arranged in seven β-strands (named A, B, C, C’, E, F, and G) forming two anti-parallel β-sheets (strands: A-B-E and strands: C-C’-F-G, respectively) (FIGs. 5A-5F). It is remarkable that despite high similarity in tertiary structure, sequence identity across FnIII-domains is conspicuously low, typically less than 20% between domains in general¹⁵³, which complicates alignment of FnIII-domain sequences. However, the presence of a few highly conserved amino acids enables unambiguous identification of strands B, C, and F (FIGs.5A-5F). [0401] Strand B is characterized by a tryptophan (position 25) preceded by two hydrophobic residues at positions 21 and 23; strand C contains a tyrosine (position 41) followed by two hydrophobic residues at positions 43 and 45, with the latter position very often occupied by an additional tyrosine residue; strand F begins with a tyrosine (position 83) followed by three additional hydrophobic residues at positions 85, 87, and 89, with the latter position often being an alanine. As the hydrophobic residues alternate within a β-strand secondary structure, their side chains point towards the same side of their respective strand, such that they form a large hydrophobic domain-core – sometimes described as ‘the glue’ between the two β-blades (FIGs. 5A-5F). The four remaining strands do not contain highly conserved residues, complicating their identification based on their primary structure. However, pairs of alternating hydrophobic residues are likely located in these β-strands as well, such that they can contribute to a hydrophobic core. This is often the case for strand A (positions 11 and 13) where the two hydrophobic amino acids are between 5 and 8 amino acids upstream of strand B, and either one or two prolines at the very beginning (positions 6 and 7) of the FnIII-domain sequence (FIG. 5D). The other three strands (C’, E, and G) have very little sequence conservation and can’t be identified based on their amino acid sequence analysis, and their location is better identified needs by secondary structure prediction tools. [0402] Both the first and the sixth FnIII-domain of SORL1 include two cysteine residues, suggesting that these two domains contain an intradomain disulfide bond. This is supported by a model showing how their side chains, which may be in close proximity, can facilitate intradomain disulfide bond formation in the folded conformation (FIG.9). A single, likely unpaired, cysteine is located in strand B of the fourth FnIII-domain, but predicted to point its side chain into a hydrophobic core and not be surface exposed. [0403] Bottom Loops – including The Tyrosine Corner [0404] Following the conserved folding topology, the loop regions between strands can be grouped as part of the “top” or “bottom” of a FnIII-domain (FIGs.5A-5B). The BC-, C’E- and FG-loops combined with the N-terminal incoming sequence form the top of each FnIII-domain, whereas the AB-, CC’- and EF-loops form the bottom of the domain. Some of these loops also contain conserved residues informative for sequence alignment. Most prominently, in the loop connecting strands E and F (EF-loop) that crosses from one sheet to the other, a leucine (position 77) is located six residues upstream of the tyrosine (position 83) in the beginning of strand F. In many FnIII-domains, including two of the SORL1 domains, this loop also contains a conserved proline (position 79) frequently accompanied by a glycine (position 80) (FIGs. 5A-5B). This structural motif is known as “the tyrosine corner”, which contributes strongly to the stability of FnIII-domains: the side chain of Leu-77 packs next to the Tyr-83 ring¹⁵⁴. Moreover, the -OH group of the Tyr-83 engages in H-bonding with the backbone of the residue five residues upstream (ie. position 78), naming the FnIII-domain as the Δ5 subtype of tyrosine corners¹⁵⁵. While all other loops can elongate without significant loss of conformational stability, the length of the EF- loop is important to maintain a stable domain fold¹⁵⁶. [0405] Top Loops – antigen binding homology and N-glycosylations [0406] Among the loops at the top, a few conserved positions can be noticed: the BC-loop often begins with at least one proline at positions 27 and/or 28 as well as a glycine at position 36, and the FG-loop preferentially contains a glycine at position 94 – often together with another glycine at position 96 (FIG. 5F). This is not evident from the six SORL1 sequences due to the low conservation at these positions, but is clearer when looking at the alignment across multiple Fn3-domain sequences (FIG.5F). [0407] Within – or close to – each of the six C’E-loops of the SORL1 FnIII-domain is an NXT-motif, each of which represents a potential glycosylation acceptor site¹⁵⁷ (FIG.5D). From the alignment of almost 300 FnIII-domain sequences, an N-glycan acceptor site was noticed to be frequently present in the C’E-loop. The function of these glycans probably varies for individual FnIII-domains. A FnIII-domain in the interleukin 21 receptor (IL21R) carries a large glycan at the C’E-loop, and this modification was first shown to be essential to keep the relative orientation between two neighboring domains in a fixed position, allowing interactions with residues from the adjacent FnIII-domain¹⁵⁸. Second, it was shown that this glycan is essential for the successful transport of IL21R to the cell surface¹⁵⁹. It was recently found that the composition of N-glycans in SORL1 regulates the proteolytic cleavage by sheddase (TACE) of the membrane-bound SORL1 protein at the cell surface, and thus shedding of the soluble SORL1 ectodomain¹⁶⁰. It is tempting to speculate that the regulatory glycan(s) locate in the proximity of the TACE cleavage site, i.e. somewhere in the FnIII-domain region, and that the glycan(s) induce steric/conformational changes of SORL1, allowing the sheddase to access the cleavage site located just C-terminal to the sixth FnIII-domain¹⁶⁰. [0408] For IgG-domains, the top loops correspond to antigen binding regions (FIGs.5A- 5B). Possibly, the top loops of the SORL1 FnIII-domains may bind extrinsic ligands. However, there are still many unclarities: many FnIII-domains occur in tandem arrays of varying lengths, and the structure-function relationship of the entire region is highly dependent on the relative orientations between domain pairs, often measured as “tilt” and “twist” angles between domains 161 (see FIG.8A-8B). These measures are in part determined by the “linkers” between the domains but certainly also by the amino acid composition located in the loop regions. [0409] Trp-ladders [0410] Many FnIII-domains share a motif that resembles a ladder with steps provided by alternating aromatic and charged amino acid side chains¹⁶². Since the aromatic “steps” are often tryptophan residues, this ladder is termed the “tryptophan-ladder”. Generally, such ladders contain six or more “steps”, but they may also be shorter. Upon inspection of the SORL1 FnIII-domain sequences, the presence of two short Trp-ladders was observed in the first and second domains most distal to the membrane, with steps made by (FnIII1: R1593, W1600, K1626, and H1636 and FnIII2: E1690, W1699, R1723, and W1735). The function of these motifs is not completely understood. However, for some proteins it is suggested that they interact directly with sulphated glycoconjugates¹⁶³. It has been demonstrated that some N-glycans in the VPS10p-domain of SORL1 are terminally sulphated¹⁶⁴, raising the hypothesis that they may be intrinsic targets of the Trp-ladders in FnIII-region, possibly regulating SORL1-dimer formation and/or self-binding of bent-conformations of SORL1 (see FIG.8C-8D). [0411] 5.c SORL1 variants in FnIII-domains [0412] Trp at position 25 (strand B): [0413] The FnIII-domain is vulnerable for mutation of the Trp at position 25, for which Uniprot lists seven disease-associated variants: p.W2744C^USH2A (segregate with USH2A in a family¹⁶⁵), p.W3521R^USH2A (in patients with USH2A¹⁶⁶), p.W1036L^L1CAM (in patients with HSAS, and functional test of the mutant protein show defective cellular transport¹⁶⁷), p.W1925R^FN1 (causal of GFND2¹⁶⁸), p.W571R^ANOS1 (in patients with Kallmann Syndrom/HH1¹⁶⁹), p.W792R^MYBPC3 (in patients with CM44¹⁷⁰), and p.W68R^GHR (in patients with LARS¹⁷¹). In line with the the orthologue data, a report describe identification of an AD patient carrying p.W1862C (position 25 in the fourth FnIII-domain)¹⁷², which suggests that variants at this position in SORL1 domains may associate with an increased risk for AD. [0414] Tyr at position 83 (Tyr-corner): [0415] The tyrosine at position 83 at the beginning of strand F is conserved across all FnIII-domains including those in SORL1 (FIG.5D, 5F). The DMDM analysis found that five of the six other proteins for which Uniprot lists disease-associated substitutions for this position, each time the Tyr was replaced by a Cys: in Tie2, p.Y611C^TEK (reduced response to ligand and decreased ligand-induced phosphorylation GLC3E¹⁷³), in the insulin receptor, p.Y818C^IR (abolishes post-translational processing, LEPRC^174,175), in Fibronectin causal for GFND2 p.Y973C^FN1 (GFND2¹⁶⁸), in L1CAM, p.Y784C^L1CAM (HSAS¹⁷⁶) and in the growth hormone receptor, p.Y226C^GHR (causal of LARS¹⁷⁷) (Table 11). [0416] It has previously been reported that variant p.Y1816C that locate to the third FnIII- domain of SORL1 was found in AD patients and but not controls¹¹⁰. Interestingly, also in the case of SORL1, the tyrosine is substituted by a cysteine, such that a possible pathogenic effect may either be due to loss of the tyrosine or due to introduction of the cysteine, or both. It was noted that all the other proteins that harbor this type of variant form active dimers by their FnIII-region, which suggests that such mutations, including p.Y1816C in SORL1, may act via impaired dimerization. [0417] Position 88 (strand F): [0418] For position 88, located between the alternating hydrophobic residues in strand F, there is no sequence conservation (Fig.2g, FIG.5D, 5F). However, the side chain of the residue at this position will expose towards the domain surface. Intriguingly, Uniprot lists as many as 9 disease-associated variants at this position (FIG. 5E), of which 8 correspond to arginine replacements: p.R926W^IR (mutated IR with markedly impaired insulin binding and impaired post- translational processing in patients with LEPRCH^175,178), p.R312P^CRLF1 (CISS1¹⁷⁹), p.R224W^IL2RG (XSCID¹⁸⁰), p.R201L^IL21R (mutant receptor with defective trafficking, misfolding, and impaired processing IMD56^158,159), p.R213W^IL12RB1 (IMD30¹⁸¹), p.R114C^IFNGR2 (misfolding and abnormal glycosylation, mistrafficking, reduced response to INFG, IMD28^182,183), p.R257L^MPL (CAMT¹⁸⁴), and p.R308C^CSF3R (decreased localization to plasma membrane and decreased receptor signaling, SCN7¹⁸⁵). Detailed analysis of the variant in IL21R revealed how this arginine side chain is required for interaction with a glycan from a neighboring FnIII-domain and the relative domain-domain orientation¹⁵⁸. The SORL1 sequence includes only an arginine at position 88 in the fourth FnIII-domain, and no variants is yet identified for this residue. [0419] Positions 94 and 96 (glycines in FG-loop): [0420] From Uniprot seven disease-associated variants were identified at position 96 of the FnIII-domain according to the DMDM analysis (FIG.5E). There is a slight preference for Gly at this position according to the FnIII-domain consensus sequence, but it is not nearly as conserved as Gly at position 94. (FIG. 5F, FIG. 12). However, it was noticed that in five of the seven identified disease variants for position 96, a Gly was substituted. Furthermore, four of these variants were observed when the Gly two residues upstream (at position 94) in the sequence was also present: p.G698R^L1CAM (causal for hydrocephalus HSAS/MASA and mutation is inherited in a mendelian fashion segregating with disease^186,187), p.G805E^DCC (causal of isolated agenesis of the corpus callosum (MRMV1) in a family, and mutation disturb nestrin-1 binding binding to the FG-loop of the DCC FnIII-domain¹⁸⁸), p.G2757V^SPEG (causal of Centronuclear Myopathy with Dilated Cardiomyopathy (CNM5) in a small family¹⁸⁹), and p.G516R^EPHB4 (mutation segregate with the Capillary Malformation-Arteriovenous Malformation (CMAVM2)-phenotype in three small families¹⁹⁰). It may be speculated that co-occurrence of both Gly residues could have functional relevance relating to their localization in the FG-loop region preferring to accommodate residues with small side chains. In SORL1, only the second FnIII-domain contains this double Gly at positions 94 and 96 (amino acids 1730 and 1732) (FIG. 11). Very interestingly variant p.G1732A corresponding to position 96 is reported to segregate with AD in a Swedish family⁶³, in support of this variant being pathogenic. [0421] Table 11. Summary of included proteins containing naturally occurring variants associated with diseases in FnIII domains shared with SORL1.

Table 11 cont...

[0422] 5.f FnIII disease variants listed according to domain positions [0423] Disease-mutations domain-mapping analysis with identification of pathogenic variants in other proteins with FnIII-domains (as listed in Table 12). Here variants are mapped onto domain positions following alignment of internally repeated sequences in the SORL1 domain sequences. The number of hits for each position depicted in the bar diagram of FIG.5E. [0424] Table 12. Pathogenic SORL1 FnIII domain mutations.

[0425] 6 Transmembrane and cytoplasmic domains (residues 2122-2214) [0426] 6.a Sequence details [0427] Membrane-anchoring domain [0428] Immediately following the FnIII-domains is a 16 amino acid long stalk region (residues 2122-2137) suggested to lift the ectodomain a short distance from the plasma membrane, enabling TACE-dependent cleavage, leading to ectodomain shedding when mature SORL1 is at the cell surface^160,192. After the stalk region, SORL1 contains a 23-amino acid single-pass transmembrane (TM) domain (residues 2138-2160), presumably alpha-helical, and a cytoplasmic domain (CD; often referred to as the ‘tail’) including 54 amino acids (residues 2161-2214) (FIG. 6C). [0429] The TM-domains of mammalian SORL1 proteins are highly conserved during evolution, with human and insects sharing >95% sequence identity¹⁹³ (FIGs. 6A-6C). The number of amino acids in the TM-domain may influence the localization of a protein within the cell¹⁹⁴. With this reasoning, the number of residues in the SORL1 TM-domain might underlie its manifestation in the membranes of the trans-Golgi and trafficking network. Similar to most membrane-anchored proteins, the amino acid composition of the SORL1 TM-domain is mainly characterized by hydrophobic residues that form non-polar interactions that stabilize the helix structure within the phospholipid bilayer. Therefore, the preservation of the hydrophobicity of TM-domains is key for proper insertion of the protein into the membrane: substitutions of hydrophobic residues with polar or charged residues in the LDLR TM-domain prevented membrane insertion, which was causative for familial hypercholesterolemia^195,196. Thus far, it is unknown whether mutations in the SORL1-TM domain will have similar effects. [0430] The intracellular cytoplasmic domain [0431] Similar to most members of the LDLR and VPS10p receptor families, a short (~50 amino acid) cytoplasmic tail constitutes the intracellular part of SORL1. This tail determines the complex intracellular sorting itinerary that SORL1 follows (FIGs.6A-6C). Binding to different intracellular adaptor proteins via short motifs in the tail determines key sorting steps of SORL1 and its cargo, such as endocytosis and intracellular trafficking between Golgi/TGN and endo- lysosomal compartments (see below) (FIGs.6A-6C). Deletion of the entire tail leads to the direct vesicular transportation of the receptor from the TGN to the plasma membrane and, upon cleavage by sheddase (Ie. TACE), its release into extracellular space^65,197. [0432] GGA [0433] The very C-terminal part of SORL1 contains a DXXLL-like motif (²²⁰⁸DVPMV²²¹²), which is a target for the Golgi-localized proteins GGA1, GGA2 and GGA3. These adaptors regulate trafficking of a set of membrane-spanning proteins from Golgi to endosomal compartments and – at least in the case of GGA3 – from endosome towards lysosome 198,199 200. suggests that SORL1 can sort directly from Golgi to the endosome after its synthesis. The minimal motif required for binding of GGA adaptors to the SORL1 cytoplasmic domain is characterized by two acidic residues²²⁰⁷DD²²⁰⁸ preceding methionine M²²¹¹ of the hydrophobic cluster at the very C-terminal end²⁰¹. In 2009, the structure of part of the SORL1 tail was determined in complex with the VHS domain of GGA1²⁰² confirming that the GGA adaptor directly binds these residues. This highly conserved motif is crucial for SORL1 function: a mutation in this motif yields a receptor with compromised trafficking to the cell surface^197,203,204. The overlapping²²¹²VIA²²¹⁴ motif was recently shown to bind PICK1, suggesting that also this protein is capable of regulating SORL1’s intracellular itinerary²⁰⁵. [0434] FANSHY [0435] The SORL1 tail also includes the²¹⁷²FANSHY²¹⁷⁷ motif, which is strictly conserved from human to insects suggesting an indispensable physiological function (FIGs.6A- 6C). This motif is similar to the (F/Y)XNPXY motif as identified in the cytoplasmic domain of many proteins including APP, LDLR, and LRP, in which it serves as an endocytosis signal²⁰⁶. However, in SORL1, the proline residue is absent, and here, the motif is instead required for binding the retromer core complex (VPS26, VPS29 and VPS35), which is involved in the recycling of various transmembrane receptors between the endosomal network to the cell surface or in the retrograde trafficking to the Golgi/TGN²⁰⁷. The phenylalanine-2172 of the²¹⁷²FANSHY motif is essential for association of the SORL1 tail with the VPS26 subunit of the retromer complex²⁰⁸. [0436] The tail-motif of several receptors is the simple NXXY motif, i.e also without a proline residue as well as the preceding aromatic F/Y residue, and these receptors can be bound to endosomal recycling proteins such as SNX17, SNX27, and SNX31²⁰⁹, raising the possibility that the FANSHY site in the SORL1 tail may interact not only with the retromer complex for endosomal sorting, but also with the newly described SNX17-dependent retriever complex²¹⁰ or with the SNX27-retromer complex, which may assist SORL1 cycling from endosomes to the cell surface²¹¹. Interestingly, a fragment of the intracellular domain spanning the FANSHY motif folds into an amphiphatic α-helical structure with the potential for sensing membrane curvature as yet another determinant of SORL1 intracellular transport²¹². [0437] Acidic [0438] An acidic cluster in the tail of SORL1 (corresponding to residues²¹⁹⁰DDLGEDDED²¹⁹⁸ (SEQ ID NO: 136)) is reported to bind cytoplasmic adaptor proteins including PACS1, depending on cellular localization and cell type^197,213-215. In clathrin-vesicles, SORL1-binding goes via the AP1 and AP2 adaptor-binding proteins, which bind the EXXXLL- like motif (²¹⁹⁷EDAPMI²²⁰² (SEQ ID NO: 191)). Interactions with the AP1, AP2 and PACS1 adaptor proteins regulate mainly retrograde sorting pathways from cell surface to endosome (AP2) or endosomes to TGN (PACS1). However, AP1 is also involved in directing cargo in the anterograde direction from TGN towards endosomes, and described to do so partly in concert with GGAs^216,217. Receptors carrying substitutions within this acidic motif have a strong defect in endocytosis, due to lack of AP2 binding^197,213. It has also been reported that the relatively unknown HSPA12A cytosolic protein binds to the acidic motif within the tail of SORL1²¹⁸. [0439] Phosphorylation [0440] Twelve of the 54 amino acids of the SORL1 tail are potential targets of phosphorylation (Ser/Thr/Tyr) and several of these residues occur in consensus target sequences for specific kinases²¹⁹, suggesting phosphorylation might play important functions in the sorting of SORL1 (FIG. 6C). For example, the ROCK2 kinase can phosphorylate serine (S²²⁰⁶), which modifies the cytoplasmic domain of SORL1SORL1 such that ectodomain shedding of SORL1 is increased²²⁰. Particularly, the presence of both a tyrosine and a serine in the FANSHY motif may provide possible phosphorylation-dependent regulatory mechanisms of SORL1 endosomal sorting. The significance of such modifications is currently under investigation. [0441] 6.c SORL1 variants in transmembrane and tail-domains [0442] The 16 residues that make up the stalk and transmembrane, represent a small fraction of the entire SORL1 protein. The ADES-ADSP dataset includes a variant that maps to the stalk region: the relatively prevalent p.T2134M variant which was observed in 22 cases and 13 controls⁴⁰, associating with a 1.7-fold increased AD risk (OR = 1.7295% CI: 0.87 - 3.42 p=0.08), however, the much larger GWAS study does not support a pathogenic role of this variant (OR=1.14; p=0.4904)²²¹. Functional testing indicated that mutated receptor was unable to protect APP from cleavage into Aβby γ-secretase when compared to non-mutated SORL1, likely because the formation of a complex with APP was perturbed²²². Also, lower levels of SORL1 located to the cell surface of transfected cells, suggesting impaired trafficking properties of mutant SORL1. [0443] Little is known about how the 23-residue TM region affects SORL1 function, making it difficult to assess whether a variant will provide AD risk. But as pathogenic variants in the TM of LDLR have been reported to associate with FH¹⁹⁵, some variants in the SORL1 TM region could also be speculated to be pathogenic. [0444] Position 3 in the cytoplasmic tail, very close to the TM region, is part of a highly conserved sequence rich in positively charged amino acids (²¹⁶¹KHRR²¹⁶⁴ (SEQ ID NO: 192)). These four residues are suggested to constitute a nuclear localization motif that is responsible for the translocation of the cytoplasmic tail of SORL1 when liberated from the membrane after γ- secretase cleavage and with a role in signaling processes²²³. The ADES-ADSP dataset includes two variants at this position: p.R2163W observed in one case and p.R2163Q observed in one control. The dataset further includes several variants within the conserved²¹⁷²FANSHY motif, which may lead to a perturbed interaction with retromer and perturbed engagement in endosomal recycling. The ADES-ADSP dataset includes variants p.A2173T (conservation: 40/40; “likely pathogenic”) observed in an AD case, p.S2175R (resulting from two independent genetic changes with different allele frequencies; conservation 40/40) that was observed in 11 cases and 10 controls, such that pathogenicity of this substitution is questionable. The dataset further includes the p.H2176R substitution, observed in one AD case. Together, the assessment of pathogenicity- levels for substitutions in the FANSHY motif require additional testing of variant effects. Finally, the ADES-ADSP dataset includes 3 variants that substitute key residues of the acidic/DXXXLL and gga/DXXVI: p.D2190N observed in an AD case and in a control, p.E2194K in two AD cases and a control and p.D2207G in an AD case. While such very conserved variants are likely linked with SORL1 dysfunction, it was observed them both in cases and controls such that more evidence is necessary to estimate their effects. [0445] 7 Summary of domain position prioritization for AD risk [0446] Prioritization of positions likely to harbor pathogenic mutations based on either domain sequence conservation or because the disease-mutation domain-mapping analysis show enrichment for disease mutations for domains in other proteins. [0447] Table 13. Composite list of pathogenic SORL1 mutations by domain.

*Parentheses on L1767 indicates that there is a strong preference for W at this domain position which is not strictly conserved. [0448] 8 SORL1 sequences for alignment: species conservation [0449] A total of 40 different SORL1 protein sequences are included in the species alignment (see below accession numbers). [0450] This alignment allows look-up if genetic variants that make substitutions in the human protein leads to inclusion of amino acids present in SORL1 from other species – in which case such a variant is more likely to be tolerated than if the position is strictly conserved across all species. Homo sapiens (human): NP_003096.2/Q92673-1 Macaca mulatta (rhesus macaque): XP_014971461.2/H9ZCQ1-1 Pan troglodytes (chimpanzee): XP_016777658.1/H2Q4Z6-1 Sus scrofa (pig): XP_020918668.1/I3L8K1-1 Capra hircus (goat): XP_017915127.1/A0A452FGN5-1 Ovis aries (sheep): XP_027835138.1/W5QA68-1 Equus caballus (horse): XP_023500779.1/F7CG82-1 Bos taurus (cow): NP_001179686.1/E1BPZ1-1 Loxodonta africana (elephant): XP_003418317.2/G3T328-1 Canis lupus familiaris (dog): XP_536545.2/ E2R5F5-1 Canis lupus dingo (wolf): XP_025320979.1 Vulpes vulpes (fox): XP_025854818.1/A0A3Q7SF13-1 Ursus arctos horribilis (bear): XP_026361326.1 Felis catus (cat): XP_023094970.1/M3WIG3-1 Panthera pardus (leopard): XP_019324393.1 Oryctolagus cuniculus (rabbit): NP_001076133.1/Q95209-1 Rattus norvegicus (rat): NP_445971.1/P0DSP1-1 Mus musculus (mouse): NP_035566.2/O88307-1 Ornithorhynchus anatinus (platypus): XP_028930988.1/F7D9P5-1 Gallus gallus (chicken): NP_001292089.1/E1BUD4-1 Anas platyrhynchos (duck): XP_027299930.1 Columba livia (pigeon): XP_021152551.1/A0A2I0LS76-1 Haliaeetus leucocephalus (eagle): XP_010579730.1 Falco cherrug (falcon): XP_027662563.1 Aptenodytes forsteri (penguin): XP_009279556.1 Danio rerio (zebra fish): XP_005157607.1/X1WHE3-1 Salmo salar (salmon): XP_014017958.1/A0A1S3NRA8-1 Amphiprion ocellaris (clown fish): XP_023117170.1 Pygocentrus nattereri (piranha): XP_017568534.1 Esox lucius (pike): XP_010891973.1 Hippocampus comes (seahorse): XP_019716899.1 Rhincodon typus (whale shark): XP_020382540.1 Xenopus tropicalis (frog): XP_031762503.1/A0A1L8FLB9-1 Pelodiscus sinensis (turtle): XP_025045904.1/ K7F2T1-1 Alligator mississippiensis (alligator): XP_014449241.1/ A0A151NQK7-1 Crocodylus porosus (crocodile): XP_019402601.1 Gekko japonicus (gecko): XP_015277064.1 Python bivittatus (python): XP_007431813.2 Anolis carolinensis (anole): XP_016850209.1/ H9G6H6-1 Podarcis muralis (lizard): XP_028563124 [0451] Phylogenetic tree generation: [0452] To create a comprehensive phylogenetic tree, the SORL1 amino acid sequences from x of the >300 different species with known SORL1 protein sequences were obtained from the NCBI website (REF). Sequences were selected based on (1) having a sequence length >1,000 aa, and (2) obtaining a maximally diverse selection of animals within each species subclass. The phylogenetic tree was constructed using the MEGA7 software and edited with GravitDesigner. [0453] Conservation analysis: alignment of 40 representative SORL1 sequences [0454] To determine semi-quantitative conservation of any residue within the human SORL1 sequence across species, representative sequences were aligned (FIGs.1A-1C, FIG.13). This alignment reveals whether an introduced amino acid by novel SORL1 genetic variants is present in SORL1 from other species. [0455] The conformational space in SORL1 [0456] Elongated or compact - Flexible or rigid structures? [0457] Thus far, all attempts to solve the structure of the full SORL1 extracellular region have failed. Therefore, it is currently unknown how all the presented domains of the full-length SORL1 protein fold relative to each other. In accordance with the different SORL1 functions, the protein structure may also adopt different conformations. SORL1 engages in the binding and sorting of cargo through cellular compartments, each with distinct pH levels and capacity to modify post-translationally attached N-glycosylations and perhaps phosphorylations¹⁶⁰. [0458] Schematic illustrations of the SORL1 molecule often show each domain lined up one after the other, extending to a predicted ~700 Å (=70 nm) (FIG.8A). Such a linear conformation may be relevant at the plasma membrane if SORL1 uses its VPS10p-domain to scavenge extracellular ligands. Or, since the receptor can locate to the postsynapse, the elongated SORL1-conformation could reach out across the synaptic cleft to binding partners at the presynapse. However, when SORL1 is located in tubular extensions of the endosome (described to have a diameter of only 20-50 nm²²⁴), it is highly unlikely that SORL1 will adopt this conformation²⁰⁸. Here, SORL1 may adopt one or more compact conformations, similar to what has been found for LDLR and integrins^225-227. [0459] The FnIII-domain region may behave as a single compact structure, connected with the two β-propellers by the flexible CR-cluster. The region of the FnIII-domains may be described as a single and rather solid unit²²⁸. In many receptor proteins the consecutive FnIII- domains have a “rod-like” structure, with an angle between two neighboring FnIII-domains close to 180 degrees: if all six FnIII-domains of SORL1 adopt this rod-like structure, the total structure would span ~210 Å. Two neighboring FnIII-domains can also

with an angle typically around 120 degrees¹⁵²: if all six SORL1 FnIII-domains adopt this “wiggling” structure they span only ~140 Å (FIG.8B). [0460] It is still unclear whether the two β-propeller domains in SORL1 have a fixed or flexible orientation relative to one another. The two adjacent β-propeller domains may behave as a combined rigid structural block, which would be in accordance with the rigid connection between tandem β-propellers observed in LRP5 and LRP6. In this scenario the 5 amino acids (⁷⁵³PLAEE⁷⁵⁷ (SEQ ID NO: 193)) around the 10CC-YWTD linker that separates the two propellers, would not function as a hinge. Nevertheless, the 10CC-domain position relative to the VPS10p-domain may change with pH as described⁵, arguing that this model may be over- simplified. [0461] In contrast, the sequence directly following the EGF-domain of SORL1 may act as a first hinge region (H1, FIG. 8B), paralleling the EGF-domain of integrin (also of the 8 Cys- type) that act as a hinge region between larger rigid units⁶². The site between the end of the CR- cluster and beginning of the FnIII-domains of SORL1 may serve as a second hinge region (H2), similar to the hinge region in LDLR that is found after its CR-cluster^100,225,229. Interestingly, this second hinge would then locate next to the extremely long linkers in the SORL1 CR-cluster and allow for substantial structural flexibility for this region. These two hinge regions might bring the receptor from a very “elongated” fold toward a more “compact” form (FIG. 9B). With such a flexible CR-cluster it is unclear whether the YWTD- or the VPS10p-domain propeller is closest to the cell membrane (FIG. 9C). However, most VPS10p-domain receptors have the VPS10p- domain closest to the membrane (FIG.10), suggesting that this a preferred position that may relate to shared functionalities. [0462] Monomer, dimer – or equilibrium [0463] The ability of SORL1 to bind, traffic, and release cargo may depend on its flexibility but also on possible dimer formation. SORCS1 and SORCS2 exist mainly as a dimer; when the PKD-domains C-terminal to their VPS10p-domains interact, the top-face of their β- propellers are available for ligand binding, important for cell surface signaling^230,231. [0464] When sortilin is internalized in endosomes it dimerizes upon the pH-drop, leading to ligand-release^232-234. With the drop in pH, the side chains of a stretch of His residues on the top face of the VPS10p-domain β-propeller become protonated, leading to a conformational change of the VPS10p-domain loops, allowing dimerization at the top faces between two propeller- domains, enabling ligand displacement. It is unlikely that identical dimerization mechanisms occur for the SORL1 VPS10p-domain because the SORL1 sequence does not include any PKD- domains that drive dimer formation of SORCS1 and SORCS2. Neither does the SORL1 VPS10p- domain sequence hold the His residues responsible for pH-dependent rearrangements in sortilin, nor the residues in the loops important for the direct contacts between the two VPS10p-domains 233,235 [0465] However, nearly all known receptor-like molecules containing FnIII-domains have the capacity to form dimers¹⁴⁶, SORL1 dimerization may be mediated by its FnIII-domains¹⁴⁶ (FIG.8D). Similar to SORL1, the extracellular region of growth-hormone-, prolactin-, and insulin receptors have FnIII-domains that are located close to the plasma membrane and their activity is crucially associated with dimer conformation in the presence of bound ligands. The dimerization by FnIII-domains of Tie1 and Tie2 receptors, from the tyrosine kinase family, is crucial for its activation²³⁶. While more studies are necessary to explore a potential role for FnIII-domains in SORL1-dimerization, it is interesting to notice that several key ligands of SORL1 (e.g. BDNF, APP, TrkB, HER2/3, GLUA1) exist in equilibrium between mono- and dimeric structures^237-239. [0466] While members of the LDLR family are mainly monomers, they also release ligands upon endosome internalization^100,226. Here, the pH drop in endosomes leads to protonation of several histidine residues of the LDLR YWTD β-propeller. At the cell surface, LDLR has an elongated conformation and ligands bind to the CR-domains. Upon entering the endosome, the receptor adopts a more compact form: the β-propeller becomes protonated, and serves an alternative binding partner for the CR-domains which leads to displacement of the internalized ligand^225,240. The released ligand is free for transport to lysosomal degradation while the receptor —in its closed conformation— is recycled through the acidic environments back to the cell surface, where it may once again adopt its open conformation, allowing CR-domains to interact with new ligands²⁴¹. In contrast with LDLR, several cargo ligands for SORL1 (incl. APP and HER2) have the highest affinity for SORL1-binding at low pH^68,242, allowing SORL1 to escort ligands out of the endosome to either the TGN or to the cell surface^239,242 This requires efficient ligand binding within the endosome. Notably, the SORL1 YWTD β-propeller sequence does not contain the His residues necessary for the pH-triggered release of ligands from the CR-domains 23 [0467] Support of “hidden” disulfides [0468] Based on the presented domain boundaries as defined by sequence alignments and expected domain folds, a ‘compact’ schematic diagram of SORL1 was presented, including all its 2,214 amino acids while taking into account the suggested presence of disulfides and β-strand secondary structures (FIG.9). This diagram provides support for the presence of three disulfides that were not yet identified: (1) a disulfide between C⁸⁰¹ and C⁸¹⁶ at the β2-blade of the YWTD- domain, (2) a disulfide between C¹⁵⁸⁶ and C¹⁶³¹ in the first FnIII-domain, and (3) a disulfide between C²¹⁰¹ and C²¹⁰⁸ in the sixth FnIII-domain. (FIG.9). In particular, the second suggested disulfide is separated by 45 amino acids in the primary structure, which can be appreciated only when taking the conserved topology of the 7-stranded FnIII-domain scaffold into consideration. Both cysteine residues are predicted to point their side chain towards the hydrophobic interior of the FnIII-domain β-blade sandwich as they occur “in-frame” with the alternating hydrophobic residues (see FIG.5D). [0469] While many of these considerations about SORL1 conformation await experimental validation, they may contribute to a better understanding of the nature of variant pathogenicity: SORL1 folding, and thus activity, may not be compromised due to misfolding of single domains only, but also by damaging intramolecular interactions affecting bent and/or dimeric conformations. it is proposed that next to variant effect prediction algorithms, the potential damagingness of genetic variants should be assessed based on features unique for SORL1: their position in the 3D alignments, and whether that position associates with disease in homologous proteins. References for Example 1 1 Thomas, G. Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol 3, 753-766 (2002). 2 Jacobsen, L. et al. Activation and functional characterization of the mosaic receptor SORL1/LR11. J. Biol. Chem.276, 22788-22796 (2001). 3 Hermey, G. The Vps10p-domain receptor family. 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Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SORL1. Cell. Mol. Life Sci.75, 301-322, doi:10.1007/s00018-017-2625-7 (2018). 239 Pietila, M. et al. SORL1 regulates endosomal trafficking and oncogenic fitness of HER2. Nat. Commun.10, 2340, doi:10.1038/s41467-019-10275-0 (2019). 240 Blacklow, S. C. Versatility in ligand recognition by LDL receptor family proteins: advances and frontiers. Curr. Opin. Struct. Biol.17, 419-426, doi:S0959- 440X(07)00124-8 [pii] 10.1016/j.sbi.2007.08.017 (2007). 241 Huang, S., Henry, L., Ho, Y. K., Pownall, H. J. & Rudenko, G. Mechanism of LDL binding and release probed by structure-based mutagenesis of the LDL receptor. J. Lipid Res.51, 297-308, doi:10.1194/jlr.M000422 (2010). 242 Al-Akhrass, H. et al. A feed-forward loop between SORL1 and HER3 determines heregulin response and neratinib resistance. Oncogene 40, 1300-1317, doi:10.1038/s41388-020-01604-5 (2021). Example 2 [0470] This example describes the relationship with known disease-causing variants in homologous proteins. Additionally, this example describes predictions of pathogenicity associated with SORL1 variants as it relates to Alzheimer’s disease. [0471] Introduction SORL1, the sortilin-related receptor with type-A repeats, is also known as LR11 or by its gene name SORL1. Since 2007, a multitude of studies associated both common and rare variants in the SORL1 gene with Alzheimer’s disease (AD) 1-4, and GWAS studies have recurrently shown that a non-coding single nucleotide polymorphism (SNP) near the SORL1 gene (rs11218343) is associated with significant modified risk for the common, late onset form of AD (LOAD) 5-7 while a second SNP (rs74685827) was recently identified to independently associate with increased risk of AD 8. Furthermore, several exome sequencing studies identified a large number of potentially deleterious SORL1 missense variants 9-11. In fact, a recent exome sequencing study that compared rare variants between AD cases and controls indicated that of all genes in the human genome, the SORL1 gene encompassed the most pathogenic variants 12. GnomAD currently lists almost 3,500 previously identified SORL1 variants 13, and only a subset of these are risk-increasing or possibly causative of AD. An estimated 2.75% of non- related early onset AD (EOAD) patients and 1.5% of non-related late onset AD cases carry such a pathogenic variant, while an even larger fraction of AD patients carries a rare SORL1 variant with lower predicted pathogenicity 12. This is a much larger fraction than the <1% of early onset AD cases affected by PSEN1, PSEN2 or APP carriers combined 14. Rare loss-of-function variants in SORL1 (i.e. truncating nonsense, frameshift or splice variants) are observed almost exclusively in AD cases suggesting that SORL1 is haploinsufficient {Verheijen, 2016 #4019}{Holstege, 2017 #4065}{Campion, 2019 #4213}. Carrying a loss-of-function variant was shown to lead to a >40-fold increased risk of EOAD and to an >10-fold increased risk for LOAD 12. [0472] Next to the evidence presented by genetic studies, additional evidence implicating the role of SORL1 in AD-associated mechanisms comes from studies showing that loss of SORL1 function triggers hallmark pathologies of AD. SORL1 is a type-1 transmembrane receptor that has long been known to function with the retromer endosomal trafficking complex 15,16. Recent studies have clarified how SORL1 binds with retromer, forming a scaffold that stabilizes the highly dynamic tubules through which cargo is transported out of endosomes 17,18. SORL1 deficiency in human and non-human cell lines and in different animal models, which serves as a model for SORL1 haploinsufficiency, as observed in individuals who carry a truncating SORL1 variant 9 is shown to impair endosomal recycling and to trigger hallmark features of AD’s amyloid, tau, and synaptic pathologies 19-21. While the aggregate effect on AD risk of rare loss-of-function variants is well described 12,22, >90% of the observed SORL1 variants are missense variants and it is currently unknown which among these hundreds of variants are pathogenic. However, the effect on AD of each missense variant is unique 10: while the common missense variant E270K does not associate with AD in GWAS 8, a recent study suggests that the rare D1545V missense variant leads to an autosomal dominant inheritance pattern of AD in an Icelandic family 23. However, for most carriers of SORL1 variants, pedigrees are not available. In cases for which pedigrees were available, they included at most four generations of affected family members, with a variable age at onset per affected family member. This complicates the evaluation of variant penetrance such that alternative approaches to assess pathogenicity are warranted. The outstanding question was addressed by relying on the distinct molecular architecture of SORL1 (FIG.1). SORL1 is a mosaic protein, which comprises functional domains of both the low-density lipoprotein receptor (LDLR) and the vacuolar protein sorting-10 protein (VPS10p) families, but almost one third of the SORL1 protein cannot be assigned to a specific protein family (FIG.10). The full SORL1 sequence spans 2,214 residues, and after post-translational removal of a 28 amino acid signal peptide (SP), the processed human receptor contains 2,186 amino acids encoded by 48 exons: a pro-peptide (ProP), a VPS10p-domain with an adjacent 10CC region, a YWTD-repeated domain, an epidermal growth factor (EGF)-domain, clusters of complement-type repeat (CR)-domains and fibronectin-type III (FnIII) domains, a transmembrane (TM) domain, and a cytoplasmic tail (FIG.1) 24. Whereas the CR-cluster and VPS10p-domain have been shown to interact directly with multiple ligands including APP and Amyloid-β, respectively, the binding partners and functions of the YWTD- and FnIII-domains are largely unknown 25. [0473] Guided by its modular structure, a sequence alignment of SORL1’s many clustered domains or repeated sequences within the larger domains was performed. Mutations in other monogenic diseases whose protein domains are homologous to those of SORL1 were relied upon to identify domain positions predicted to be pathogenic sites. A set of SORL1 variants previously identified in the ADES/ADSP exome sequencing study of unrelated AD cases and cognitively healthy controls 12 were interrogated and tested to what extent variants in SORL1 that reside at the disease-associated domain positions occurred in these individuals. [0474] Methods: SORL1 Domain Sequence-Mapping Manual alignment of the SORL1 sequence was performed under the listed considerations: VPS10p: Alignment of the 10 internally repeated sequences is based on b-blade boundaries and identified b-strand sequences as defined by the solved crystal structure in its uncomplexed form 26. There is only a limited conservation across the 10 sequences, so alignment is primarily done focusing on positions containing amino acid residues with hydrophobic side chains. [0475] YWTD: Alignment of the 6 internally repeated sequences is based on b-blade boundaries of domains from the homologous LDLR domain 27 and guided by its b-strand sequences and conservation of a number of hydrophobic residues. Gaps in the alignment are preferentially assigned to positions in loop regions between b-strands. The sequences of YWTD- domains from SORL1 and 14 other domains from proteins from the LDLR family are presented in Section 2d. [0476] EGF: The single eight-cysteines SORL1 domain of the EGF-type is aligned either with 15 EGF-domain sequences from the LDLR family (selected from domains located C- terminal to YWTD-domains) or with 8 EGF-domain sequences from the integrins (Section 3d). [0477] CR: Alignment of the 11 individual CR-domain sequences from SORL1 is done according to domain boundaries as defined by the genomic exon sequences. These domains sequences were also aligned with an additional 32 sequences from proteins containing pathogenic variants (Section 4d) [0478] FnIII: Alignment of the 6 individual FnIII-domain sequences is done based on a secondary structure prediction to identify the suggested position of 42 b-strands together with the presence of 4 highly conserved residues at domain positions 25 (W, strand B), 41 (Y, strand C), 77 (L, EF-loop), and 83 (Y, strand F) and allowing loops to accommodate most gaps. The SORL1 domains were aligned with FnIII-sequences from proteins containing disease-mutations in their FnIII-domains, allowing the alignment to take into account also the partial conservation at positions 6, 7, 11, 13, 72, 74 and 94 (Section 5d). [0479] TM/CD: This part of the human SORL1 sequence was aligned with 14 SORL1 sequences form mammalian and less related species. [0480] SORL1-Specific Disease-Mutation Domain-Mapping SORL1-SPECIFIC DISEASE-MUTATION DOMAIN-MAPPING The domain-mapping of disease-mutations (DMDM) approach displays an aggregate view of human pathogenic mutations by its position in a protein domain 28. This tool requires the ability to accurately assign the correct position of an observed variant within a domain sequence, and thus requires highly accurate alignments as here performed for the SORL1 domains. The VPS10- and EGF-domain sequences as well as the transmembrane and tail sequences were not included in the analysis: the VPS10p family is under-investigated, and there are no disease- associated variants firmly established for the other four family members (sortilin, SorCS1, SorCS2, SorCS3) (FIG.10). However, the VPS10p-domain is the only domain in SORL1 for which the structure has been determined 26, such that SORL1 variants with unknown significance in the VPS10p-domain may be assessed based on the crystal structure to determine their impact on conformation folding/stability/energy. The EGF-domain in SORL1 is longer than the typical 40 amino acid EGF-domain, and thus alignments to other domains is not accurate and a disease mapping approach could therefore not be applied for this SORL1 domain. The transmembrane and tail sequences are considered SORL1 specific and has no direct comparable sequences in other proteins. [0481] In contrast, the disease-mutation domain-mapping tool was applicable to SORL1 domains having strong sequence consensus with homologous domains in other proteins such as the YWTD- CR-, and FnIII-domains (comprising almost 2/3 of the entire receptor). To limit variants to a manageable number, sequences from human proteins in Uniprot.org were included and manually curated a comprehensive overview of disease-associated variants using information provided by “Natural variants” involved in diseases (i.e., listed under “Pathology & Biotech” in sequences. YWTD: The sequence corresponding to the YWTD-domain is termed “LDL-receptor class B” by Uniprot and annotated as PS51120 (LDLRB) in PROSITE. In this database 14 of the 67 proteins with this domain type are human, of which 6 proteins included a total of 102 unique disease-associated variants that could be mapped (histogram bars in FIG.2E) onto the YWTD-domain sequence (FIG.2). CR: The CR-domains are annotated as “LDL- receptor class A” in Uniprot and by PS50068 (LDLRA) in PROSITE. In the Uniprot database, 44 of the 168 proteins with CR-domains are human, of which 8 proteins contained at least one disease-associated variant within their CR-domain(s). This enabled the mapping of (residues 1040 and 1042 indicated by light grey) 63 different variants to the CR-domain sequences (FIG. 4). FnIII: These domains are reported by Uniprot as “Fibronectin type-III” and correspond to PS50853 (FN3) in PROSITE that list as many as 804 known Eukaryotic proteins of which 194 are human. Naturally occurring disease-associated variants were identified in 35 of the 194 proteins, which enabled the mapping of 222 unique disease-associated variants (histogram bars in FIG.5E) across the FnIII-domain sequence (Section 5e). Due to limited sequence conservation and variable number of amino acids between positions 50-71 of many FnIII- domain sequences, variants that mapped to this part of FnIII-domains were not included in the DMDM analysis. [0482] A few additional variants that are not yet included in the Uniprot database at the time of the analysis were added for pathogenic variants identified by literature (shown in italics in the alignments). [0483] Finally, the number of disease-variants identified were plotted for each position within these three domain sequences, allowing the unambiguous identification of domain positions most likely to contain pathogenic variants when mutated in SORL1 (FIGs.2D, 4D, and 5E). [0484] From the domain sequence alignments that established residues important for domain folding/stability (based on requirement of sequence conservation) in combination with the DMDM analysis informing on the prevalence of disease-associated mutations at given domain positions, a list/filter was generated for the entire SORL1 protein highlighting positions that are believed to be of ‘high priority’ or ‘moderate priority’ risk for developing AD. This filter can be applied for interrogations of larger case/control dataset (Holstege accompanying paper) or in a simpler manner by predicting whether single variants correspond to a dangerous position (Table 13). [0485] Results Figure 1 represents a model that summarizes the domain affiliation of all the 2,214 amino acids of full-length human SORL1, which are explained in detail below and in Section 1-6 in Example 1. This diagram will form the basis for presentation of information for all identified SORL1 variants online (www.alzforum.org/mutations). [0486] The VPS10p-and 10CC-domains (residues 1-753) Propetide and signal peptide (residues 1-81): After mRNA translation, the SORL1 protein includes a Signalpeptide (SP: 1-28) and a Propeptide (ProP: 29-81) that precedes the VPS10p- domain of SORL1. These peptides are removed from the mature protein by a signal peptidase upon entry to the ER and by Furin in late Golgi/TGN compartments, respectively 29. [0487] VPS10p (residues 82-617): The VPS10p-domain itself is folded into a ten-bladed b-propeller structure with each of the ten blades composed of four antiparallel b-strands arranged around a central conical tunnel. Two loop regions are known to be important for binding activities of the VPS10p-domain extending the sequences of the sixths and sevenths blade 26. [0488] The four repeated b-strands in each blade served as guide-sequence for the alignment of the ten blade sequences (FIG.10). The domain structure depends on hydrophobic residues at several positions in the different b-strands (positions 5, 6, 19, 20, 21, 39, 40, and 41) and based on their contribution to domain stabilization (Section 1 in Example 1), it may be predicted that substitution of these residues to non-hydrophobic residues likely leads to a moderately increased risk for AD, whereas it may be predicted that conservative substitutions at these positions are less harmful. [0489] VPS10p Asp-box and loops: Several residues in each blade are (partly) conserved. An Asp-box motif is completely or partially present in all b-blade sequences (FIG. 1): the exact function of the motif is not clarified, but based on speculations how these residues contribute to folding stability 30, it may be suggested that mutations that affect this motif might confer a high risk for AD. The sequence folding into the b-propeller domain includes only few Cys residues, such that an introduction of an additional Cys may not be pathogenic. However, a disulfide in the loop 2 that connects the seventh and eight blade, suggest that a mutation to a cysteine in either of the loop regions may be harmful. Variant p.Y391C was previously identified in the sequence of Loop 1, which was observed in 12 unrelated AD cases (mean age at onset 67.4 years) and in zero controls in the ADES/ADSP dataset 12, which supports the expectations that such variants are pathogenic. [0490] The overall low sequence conservation between the ten blades complicates pathogenicity prediction. Therefore, it may be suggested to inspect the VPS10p-domain crystal structure for further insight for a given amino acid (RCSB PDB 3WSZ) 26. Second, the conservation of the residue in SORL1 from other species can often inform whether a residue was conserved during evolution, but also whether the introduced ‘new’ residue is tolerated in other SORL1 proteins, which would suggest that pathogenicity is less likely. An alignment of 40 selected SORL1 sequences is provided to identify positions that has not been conserved during evolution (FIG.13). [0491] Cys residues in the 10CC domain (residues 618-753): The 10CC region, which directly follows the b-propeller domain, is split into two shorter 10CCa and 10CCb subdomains, which stabilize the b-propeller fold of the VPS10p-domain. The domain has ten highly conserved Cys residues, and it may be predicted that loss of any of these Cys residues, or a gain of an additional Cys in the 10CC sequence, leads to SORL1 protein misfolding and an increased risk of AD. Therefore, such variants are among the high prioritized variants (Table 13), and the ADES/ADSP dataset finds two such variants (p.C716W and p.Y722C) in 3 cases (mean age at onset 63.7 years) and absent from controls. [0492] YWTD-repeated β-propeller (residues 754-1013) Immediately following the VPS10p- and 10CC-domains, SORL1 contains a region spanning 260 amino acids containing five incomplete copies of a characteristic YWTD-tetrapeptide (FIG. 2C). YWTD-repeat regions generally fold into a compact 6-bladed β-propeller, each blade containing four antiparallel β-strands organized around a central pseudo symmetrical axis, forming an internal tunnel {Springer, 1998 #147}{Jeon, 2001 #1386}. The six repeated sequences that each form one blade, served as guide for the alignment of the six blade sequences (FIG.10; FIG.2). [0493] YWTD positions 16, 17, 18, 19: Conserved positions in the YWTD motif itself were identified (positions 16-19), and at positions 27 (Ile), 29 (Arg), and 35 (Gly), and where the side chains from these residues assist to stabilize domain folding, and it may be speculated that genetic variants that leads to changes of these residue, will likely associate with a highly increased AD-risk. Indeed, it was found that position 19 (identifying 7 different disease variants of which six variants were substitution of an Asp) were the position most frequently affected by disease-mutations in the homologous YWTD-domains from LDLR family members (Section 3f in Example 1). In aggregate, it was observed variants at positions 16-19 in the SORL1 protein for a total of 8 AD cases (mean age at onset 59.0 years) and none for controls 12. The variants at YWTD-positions 16-19 in SORL1 may thus be risk-increasing or even causative for AD, and should be regarded as high priority positions when variants are observed in a patient-carrier. [0494] YWTD positions 8, 41, 42, and 47: Further, the fold of the six-bladed propeller depends on hydrophobic core interactions, similar to the VPS10p-domain, such that it may be predicted that substitutions of hydrophobic residues at positions 6, 8, 41, 42, and 47 into non- hydrophobic residues will provide a moderately increased risk of AD. [0495] YWTD position 38: YWTD-repeated β-propellers are found in all core members of the LDLR family (Fig.1) 31, and mutations in these proteins that lead to monogenic disease indicated that substitution of certain positions in the SORL1 domain might increase the risk of AD. For example, when Arg residues at position 38 in the YWTD-domain of LDLR, LRP4 or LRP5 are substituted by other residues, this leads to autosomal dominant inherited forms of diseases (Section 2e in Example 1). Since the Arg at position 38 is not conserved across blades (proteins), prediction of pathogenicity based on sequence alignments alone is impossible. SORL1 includes two blades with an Arg residue at position 38 (R866 in β3 and R953 in β5). The ADES-ADSP dataset includes three unrelated AD cases, with age at onset ranging between 46 and 58 years, that carry p.R953H; this variant was not observed in controls 12. This supports (but given the low numbers, does not prove) that rare SORL1 variants at position 38 are likely pathogenic. [0496] EGF-domain (residues 1014-1074) The SORL1 protein contains only one copy of a 61 amino acid EGF-domain such that internal sequence-alignments are not available to guide residue pathogenicity prediction. Since eight Cys residues in this domain are all expected to participate in disulfide bonding, it may be predicted that substitution of/with Cys residues (both Cys removal or introduction) will likely lead to a strongly increased AD-risk (FIG.3). The EGF-domains from the LDLR family members are only ~40 amino acid long, making it impossible to identify disease-associated residue substitutions in SORL1 based on disease-associated substitutions in homologous EGF-domains from these proteins (Section3d in Example 1). Deletion of the entire SORL1- EGF-domain, as identified in a family with AD 32, is likely to impair receptor activity. However, it is likely that, apart for substitutions involving cysteines, pathogenicity prediction of mutations in the EGF- domain will rely on in-silico pathogenicity prediction models in combination with functional studies as described elsewhere 33. [0497] CR-cluster (residues 1075-1550) [0498] SORL1 contains eleven CR-domains, each containing ~40 amino acids with several strictly conserved residues, which, when substituted by other residues are likely to profoundly increase the risk of AD. This applies to (1) 6 Cys residues at positions 15, 23, 29, 36, 42, 55, which form three invariable disulfide bridges 34,35. (2) 4 conserved acidic residues (at positions 37, 41, 47, 48) involved in the coordination of a Calcium ion (Ca2+) for each domain. (3) A pair of conserved Asp and Ser residues at positions 44 and 46, that forms what is known as an Asx-turn structure. Furthermore, the CR-domains in SORL1 also contain a pair of Gly residues (positions 27 and 38) that is conserved in eight of the eleven CR-domains, together with a pair of conserved hydrophobic residues at positions 21 (Phe) and 30 (Ile) in the more N- terminal part of the sequence (FIG.4). But as the domain mapping approach did not find these positions enriched for disease-mutations, it may be suggested that variants that target these CR- domain positions in SORL1 lead to a moderately increased risk for AD. [0499] Odd Numbered Cysteines (ONC), domain positions 15, 23, 29, 36, 42, 55 and random Cys introductions: Numerous disease-associated variants involved replacement or introduction of Cys in LDLR family members, incl. LDLR, LRP4, and LRP5, leading to an ‘odd number of cysteines’ (ONC). This was also observed for CR-domain-containing proteins outside the LDLR family, e.g. the transmembrane proteinase TMPRSS6 and the COP9 protein involved in the complement cascade. Together, these observations suggest that introduction of a Cys, or removal of one of the six Cys is a disease-causing event across CR-domain bearing proteins, and it is likely also true for SORL1 (Section 4e in Example 1). Indeed, in a Swedish family a variant leading to p.R1303C in the sixth CR-domain was identified to segregate with AD in a small pedigree 32, and in a Saudi Arabian family, a variant leading to p.R1084C in the first CR- domain segregated with AD 36. Both variants resulted in CR-domains with 7 Cys residues. Also, a 59-year-old AD patient who carried a variant leading to p.C1192Y was reported, this variant results in the third CR-domain having 5 Cys residues 37. Furthermore, variants leading to p.C1344R was reported to associate with a possible family history in a Finnish family 32, as well as the p.C1453S and p.C1249S variants were identified in AD patients only 9. Also, ONC variants in SORL1 identified in aggregate for the ADES-ADSP dataset were observed predominantly in AD cases (n=36; mean age at onset 67.8 years) compared to controls (n=8) 12. Hence, ONC substitutions in that dataset associate with a >6-fold increased risk of AD (OR = 6.3195% CI: 2.45 - 16.24, p=5.1E-6; Fisher Exact test). As a note, there is a similarity between ONC variants in SORL1 associated with AD and variants in NOTCH3 causal of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), where stereotypic causal variants also result in an odd-number of cysteines in EGF-domains of NOTCH3 carrying 32-34 copies of this domain type 38. [0500] Calcium Cage (CaCa), domain positions 37, 41, 47, and 48: In proteins with CR- domains, residues at positions 37 and 41 and 47 are all Asp (in SORL1, there is a single exception; Gln1301 at pos 41 in CR6) and positions 48 are all Glu (Section 4d in Example 1). The side chains of residues at these positions coordinate Ca2+ establishing an octahedral ‘Calcium cage’ (CaCa) (FIG.4) which is needed for domain folding 39-41. As a consequence, substitutions of these variants may be strongly associated with disease. In LDLR, substitutions of CaCa residues lead to Familial hypercholesterolemia (FH) 42,43. Disease-causing variants for CaCa positions were identified in other proteins, e.g. LRP2, LRP5 and TMPRSS3 and TMPRSS6. Two disease-associated substitutions of Asp with Glu at position 47 were also noted to be of interest (Section 4e in Example 1), which is generally considered a conservative – and often non-pathogenic – substitution. However, in CR-domains there is not enough space in the Calcium cage to accommodate the larger Glu side chain at position 4740. Each SORL1 protein includes 44 CaCa positions that can be mutated (4 possible positions in 11 domains), such that compared to other protein-features, disruption of the CaCa feature is relatively common. Carriers of CaCa disrupting genetic variants in SORL1 were previously reported only for AD patients: p.D1545E of CR11 (position 47; CADD score 15.9) 44, p.D1182N (position 41, CR3), and p.D1267E (position 47, CR5) 9 and p.D1389V (position 37, CR8) 44-46. Notably, a p.D1545V (position 47, CR11) variant is likely a dominant negative variant and was shown segregate with AD in an Icelandic family, providing the first evidence for SORL1 as an autosomal dominant Alzheimer gene 23. Furthermore, the ADES-ADSP dataset includes 11 calcium cages-affecting genetic variants, exclusively in AD cases (OR = INF): p.D1108N, p.D1219G, p.D1261G, p.D1267N, p.D1345N, p.D1389V, p.D1502G, p.D1535N, p.D1545N, p.D1545G, p.D1545E. These occurred in 13 unrelated AD cases with a relatively early age at onset (median 60 years, ranging from 47-73 years). Together, CaCa-related variants are associated with a highly increased risk of AD, and possibly causal for AD. [0501] Asx-turn, domain positions 44, 46: The side chain of the conserved Asp at position 44 forms a structure known as an “Asx-turn” making a hydrogen bond with the backbone amides of two residues: one residue upstream at position 43, and two residues downstream, a conserved Ser amino acid at position 4647. Based on the sequence conservation and a number of disease-associated variants for other proteins, variants in SORL1 that locate to these two positions should also be considered as likely to increase risk of AD (Section 4f in Example 1). Indeed, the variants p.D1105H and p.D1146N are identified in 2 AD cases (mean age at onset 56.2 years) in the ADES/ADSP data and absent from the control cohort; while more evidence is beneficial, these findings suggest that these variants are pathogenic. [0502] We predict that only functionally important Asp residues in the CR-domains are pathogenic: for example, variant p.D1309N affects an Asp at domain position 50 which does not appear to have a functional consequence; this variant was not identified in AD patients in the ADES/ADSP dataset, although it was observed in 2 controls. [0503] FnIII-cassette (residues 1551-2121) [0504] FnIII-domains are typically composed of a sequence with 90-100 residues, arranged in seven β-strands (named A, B, C, C’, E, F, and G) forming two anti-parallel β-sheets (strands: A-B-E and strands: C-C’-F-G, respectively) (Fig.2g; FIG.5). It is remarkable that despite high similarity in tertiary structure, sequence identity across FnIII-domains is conspicuously low, typically less than 20% between domains 48, which complicates alignment of FnIII-domain sequences. However, the presence of a few highly conserved amino acids enables unambiguous identification of strands B, C, and F as described below (and explained in more detail in Section 5 in Example 1 ). Strand B is characterized by a Trp (position 25) preceded by two hydrophobic residues at positions 21 and 23; strand C contains a Tyr (position 41) followed by two hydrophobic residues at positions 43 and 45, with the latter position very often occupied by an additional Tyr; strand F begins with a Tyr (position 83) followed by three additional hydrophobic residues at positions 85, 87, and 89, with the latter position often being Ala. As the hydrophobic residues alternate within a ^-strand secondary structure, their side chains point towards the same side of their respective strand, such that they form a large hydrophobic domain-core – sometimes described as ‘the glue’ between the two ^-blades of the sandwich fold (FIG.5). In contrast to the VPS10p-domain and the YWTD/EGF- and CR- domains that are representative of two distinct receptor families, a similar clear affiliation for FnIII-domain containing proteins is not possible. However, more than 2,100 domains are listed in PFAM as being FnIII-domains 49, thus allowing for the performance of a comprehensive disease-mutation domain-mapping approach also for this domain, relying on a large number of different proteins associated with a variety of different diseases ( Section 5e in Example 1). [0505] FnIII-domain positions 25, 41, and 83: Based on the sequence conservation alone, it may be predicted that any substitution of amino acids at the three key positions (25, 41, and 83) are highly likely to associate with increased risk for disease. The disease-mutation domain-mapping analysis indicated that variants affecting positions 25 and 83 are among the most frequently mutated residues, with respectively 7 and 6 different disease mutations identified (Section 5f in Example 1). The proteins with disease-mutations at these positions are Usherin (USH2A), L1CAM, Fibronectin (FN1), Anosmin (ANOS1), MYBPC3 and the Growth- hormone receptor (for the Trp at position 25) and L1CAM, Insulin receptor (INSR), Fibronectin, Growth-hormone receptor and Tie2 (TEK) (for Tyr replacement mutations at position 83) suggests that variants at these two positions are often pathogenic. It has previously been reported that the SORL1 variant p.Y1816C (corresponding to position 83 in the third FnIII- domain of SORL1) was found in AD patients but not controls 9, and also the ADES/ADSP dataset confirmed that this mutation was exclusively identified in 6 unrelated cases of AD (median age at onset 60.2 years) and not in controls 12. This is a high number taking into account that these are all non-related individuals, in strong support that this variant is risk increasing and possibly causal for AD. Indeed, for three of these cases a clear family history for AD and the SORL1 p.Y1816C can be established. [0506] FnIII-domain positions 21, 23, 43, 45, 85, 87, and 89: The hydrophobic side chains of amino acids at positions 21, 23, 43, 45, 85, 87, and 89 all contribute to the ‘hydrophobic glue’ of the folded FnIII-domain sandwich, and it may be suggested that substitutions of these residues in SORL1 to residues that are not hydrophobic will moderately increase risk of AD. [0507] Notably, conservative substitutions at these positions are unlikely to increase AD risk, as exemplified by the common variant p.V2097I (position 87, the sixth FnIII-domain of SORL1) which occurs in 33 controls and 48 AD cases of the ADES/ADSP dataset (OR=1.48; P= 8.2E-02), suggesting that such variants do not significantly associate with increased risk of AD 12. [0508] FnIII-domain positions 11, 13, 6, 7: The four remaining β-strands do not contain highly conserved residues and thus much more difficult to unambiguously identify without a solved structure (FIG.5). However, pairs of alternating hydrophobic residues may contribute to a hydrophobic core: positions 11 and 13 in strand A are often two hydrophobic amino acids approximately 5-8 amino acids upstream of strand B. Similar as for the hydrophobic residues at the other strands, it may be predicted that subsitutions at positions 11 and 13 will have a moderate effect on disease-risk. On the other hand, depending on the subdomain, one or two Pro residues at positions 6 and 7 of the FnIII-domain sequence are partly conserved. Their location indicate a functional role to form the turn of the protein backbone prior to the following b-strand and start of the FnIII-domain ( Section 5d in Example 1), such that it may be predicted that substitution at these positions are likely to associate with high risk of disease.3 cases of AD were found with substitutions at these Pro-positions, mean age at onset 76 years. [0509] The other three strands (C’, E, and G) have very little sequence conservation complicating the identification of their locations based on amino acid sequence analysis. A trustful alignment of amino acids at FnIII-domain positions 50-71 and 99-111 with homologous proteins for the identification of disease-associated substitutions could not be completed (FIG.5, Section 5f in Example 1). [0510] FnIII-domain positions 77, 79, 80, 83: the tyrosine corner: The loop connecting strands E and F (EF-loop) that crosses from one sheet to the other, contains a Leu (position 77) located six positions upstream of the conserved Tyr at position 83 in the beginning of strand F. In many FnIII-domains, including two of the SORL1 domains, this loop also contains a conserved Pro (position 79) frequently accompanied by a Gly (position 80) (FIG.5). This structural motif is known as “the tyrosine corner”, which contributes strongly to the stability of FnIII-domains: the side chain of Leu-77 packs next to the Tyr-83 ring 50. Moreover, the -OH group of the Tyr-83 engages in hydrongen bonding with the backbone of the residue five residues upstream (ie. position 78), naming the FnIII-domain in SORL1 as the β5 subtype of tyrosine corners 51. While all other loops can elongate without significant loss of conformational stability, the length of the EF-loop is helpful to maintain a stable domain fold 52. As a result of the high sequence conservation and functional importance it may be suggested that variants corresponding to positions 77 and 79 should be considered as highly risk increasing when affecting Leu or Pro, respectively. [0511] FnIII-domain loop positions 27, 28, 36, 94 and 96: The loops at the top of the FnIII-domain contain several conserved positions: the BC-loop often begins with one or two Pro at positions 27 and/or 28 and a Gly at position 36, and the FG-loop preferentially contains a Gly at position 94 – often in combination with a Gly at position 96 (Section 5d in Example 1). Accordingly, a high priority was assigned for these risk positions. [0512] Seven disease-associated variants at position 96 of the FnIII-domain were identified according to the domain-mapping analysis (Section 5f in Example 1). According to the FnIII-domain consensus sequence, the Gly at position 96 was not conserved, whereas the Gly at position 94 was partly conserved (FIG.5D). Nevertheless, in five of the seven identified disease variants for position 96, a Gly was substituted. Furthermore, four of these variants were observed when the Gly two residues upstream (at position 94) in the sequence was also present, and it may be speculated that co-occurrence of the two Gly residues could have functional relevance relating to their localization in the FG-loop region, preferring to accommodate residues with small side chains. In SORL1, only the second FnIII-domain contains this double Gly at positions 94 and 96 (amino acids 1730 and 1732). Interestingly, variant p.G1732A corresponding to position 96 is reported to segregate with AD in a Swedish family 32, in support of this variant being pathogenic. [0513] FnIII-domain hot spot position 88: For position 88 of the FnIII-domain, eight variants were identified in different proteins and associated with different diseases, suggesting that position 88 may be a a mutational hotspot (Section 5f in Example 1). Notably, each of these disease-causing variants correspond to the substitution of an Arg, suggesting that an Arg at this position serves an indispensable function. For SORL1, only R1910 at position 88 in the fourth FnIII-domain contains an Arg, and thus far no variants have been reported for this position in SORL1. However, it may be predicted that any mutation affecting position 1910 will highly increase risk of AD. [0514] Transmembrane and cytoplasmic domains (residues 2122-2214) [0515] Immediately following the FnIII-domains is a 16 amino acid long stalk region (residues 2122-2137) suggested to lift the ectodomain a short distance from the plasma membrane, enabling TACE-dependent cleavage, leading to ectodomain shedding when mature SORL1 is at the cell surface 53,54. After the stalk region, SORL1 contains a 23-amino acid single-pass transmembrane (TM) domain (residues 2138-2160), presumably alpha-helical, and a cytoplasmic domain (CD; often referred to as the ‘tail’) including 54 amino acids (residues 2161-2214). These regions of SORL1 are not amenable for sequence alignment with other proteins, but for completion and to guide understanding the impact of potential disease-causing variants in SORL1 that target this region, a detailed description of these regions and their contribution to SORL1 activity is included in Section 6 in Example 1. [0516] Tail motif residues 2172-2177, 2190-2198, and 2207-2214: Binding of cytosolic proteins that assist in the intracellular trafficking of SORL1 has been shown to mainly rely on the three motives: FANSHY (residues 2172-2177), ‘acidic’ (residue 2190-2198), and ‘gga’ (2207-2214). Variants that lead to changes of these amino acids may provide a moderate risk- increase for AD. [0517] Discussion Here, it is shown that variants in the SORL1 gene that affect specific SORL1 protein functions may severely increase AD risk, or some may even be causative for AD, often with a very early age at onset. One of these variants has been observed in an Icelandic family with an autosomal dominant inheritance pattern of AD {Bjarnadottir, 2023 #4460}, indicating that SORL1 may be considered the fourth autosomal dominant Alzheimer gene 10, next to APP, PSEN1, and PSEN2. These genes biologically converge on inducing endosomal traffic jams 56,57 and all induce amyloid secretion from neurons. However, apart from very few variants, pedigrees of SORL1 variant carriers are either not available, or uninformative for analysis of penetrance, complicating determining the variant pathogenicity. [0518] Here it is addressed this issue by relying on structural information and known pathogenic variants in proteins containing homologous domains as those present in SORL1. Using this disease-mapping approach, we identified a number of positions in the receptor sequence that are likely to contain variants that increase the risk of developing AD, or that might even be causal for AD were identified. The presentation of potentially protein impairing variants within the full protein sequence can be considered a compendium that can be exploited by a range of investigators. Most notably, CaCa substitutions and ONC changes in the CR-domains were identified, that was either entirely restricted to AD patients [OR = INF] or associated with a highly increased risk [OR =6.3] of developing AD, respectively. But also other findings were in strong support of the described approach: for example that variants that lead to substitutions of the YWTD-motif occurred also exclusively in patients with AD. [0519] This comprehensive compendium, describing the many aspects of the SORL1 protein function and the genetic variation in the SORL1 gene will inform a wide array of researchers. For structural biologists and biochemists, interested on the effect of variation on protein fold and SORL1 function, the compendium provides deeper insight to SORL1 structure- function relationships. 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Cell Example 3: Enhanced shedding of SORLAWT, SORLA^R953C, SORLA^D1545V, and SORLA^Y1816C in HEK293 cells that express exogenous mini-receptor [0521] This Example relates to western blot analyses of SORL1 mini-receptor expression and modulation of the endosomal recycling pathway. HEK293 cells were co- transfected with plasmids encoding SORLA-WT, SORLA-Y1816C, SORLA-D1545V or SORLA-R953C either in the presence of a control plasmid (-mini) or the expression plasmid for the mini-receptor (+mini). Both cell lysates and conditioned medium were collected and analyzed for both shed (medium) and cellular (lysates) full-length SORLA as well as SORL1 mini-receptor. Each of the four full-length versions of SORLA leads to similar cellular expression, but the introduction of each of these three pathogenic variants (SORLA^R953C, SORLA^D1545V, and SORLA^Y1816C) reduces the production of shed SORLA (sSORLA), where the level of shed sSORLA for SORLA^R953C is almost completely absent. Cellular expression of the mini-receptor was evident by the similar signal across the four SORLA constructs at ~100kDa. The co-expression of the mini-receptor lead to a higher production of the shed full- length sSORLA fragment (FIG.14). The co-expression of mini-receptor increases the shedding of the eGluc-SORLA reporter construct containing the pathogenic variants R953C, D1545V, and Y1816C. For the variants D1545V and Y1816C expression of exogenous mini- receptor rescue the shedding to a level similar to what is found for WT in the absence of the mini-receptor. Example 4: Enhanced shedding of eGluc-SORLAR^953C, eGluc-SORLA^D1545V, and eGluc- SORLA^Y1816C reporters in HEK293 cells transfected with mini-receptor [0522] This Example relates to eGluc-SORLA reporter assay analyses of SORL1 mini-receptor expression and modulation of the endosomal recycling pathway of cargo to the cell surface. Using double-transfection of HEK293 cells with plasmids for either eGLuc- SORL-WT reporter, or version of the reporter construct with the R953C, D1545V, or Y1816C mutations introduced, either with an empty control plasmid or with a plasmid that leads to expression of the SORL1 mini-receptor, the presence of SORL1 the mini-receptor to affect the endosome recycling of different mutant receptors was tested. For all three pathogenic variants (R953C, D1545V, and Y1816C), the co-transfection of the mini-receptor lead to a significantly increased shedding of the reporter domain into the medium, suggesting that the mini-receptor can be used to increase endosome recycling pathways in cells from carriers of these genetic variants. For each of the tested SORLA variants including the eGLuc-WT, the presence of the mini-receptor increased the shedding of the reporter into the medium from the cells by 4-5-fold compared to the control plasmid (FIG.15). The co-expression of mini- receptor increases the shedding of the eGluc-SORLA reporter construct containing either of the pathogenic variants R953C, D1545V, and Y1816C. Example 5: Enhanced cell-surface expression of SORLA^R953C and SORLA^D1545V in HEK293 cells transfected with mini-receptor [0523] This Example relates to flow cytometry analyses of SORL1 mini-receptor expression and modulation of the endosomal recycling pathway of cargo to the cell surface. HEK293 cells were co-transfected with plasmids encoding GFP-tagged SORLA-D1545V or SORLA-R953C either in the presence of a control plasmid (+pcDNA) or the expression plasmid for the SORL1 mini-receptor (+3Fn-mini). The cells were stained for the expression of SORLA at the cell surface with an antibody that does not recognize the mini-receptor, and the cell surface expression of the full-length mutated receptor was determined by FACS focusing only the pool of GFP-positive cells (those that have been transfected). The mean of the cell surface expression in presence of mini-receptor was plotted as relative to the mean of the surface expression in the control cells, and we identified that for both the mutated construct that the mini-receptor significantly increased the level at the cell surface (FIG.16). The co-expression of mini-receptor increases cell surface expression of SORLA-GFP reporter constructs containing either of the pathogenic variants R953C and D1545V which have been identified as high-priority variants. INCORPORATION BY REFERENCE [0524] The present application refers to various issued patent, published patent applications, scientific journal articles, and other publications, all of which are incorporated herein by reference. The details of one or more embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the Detailed Description, the Figures, the Examples, and the Claims. EQUIVALENTS [0525] While several inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the function and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the inventive teachings is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure. [0526] All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and/or ordinary meanings of the defined terms. [0527] All references, patents and patent applications disclosed herein are incorporated by reference with respect to the subject matter for which each is cited, which in some cases may encompass the entirety of the document. [0528] The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.” [0529] The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc. [0530] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. [0531] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc. [0532] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited. NUMERATED EMBODIMENTS [0533] The following numerated Embodiments represent non-limiting aspects of the invention: 1. A method for treating a neurological disease in a cell, biological sample, or subject comprising obtaining a query SORL1 gene sequence from the cell, biological sample, or subject, identifying the presence of a disease-associated mutation in the query SORL1 gene sequence, and administering to the cell, biological sample, or subject an agent that modulates endosomal trafficking. 2. A method for modulating endosomal trafficking in a cell, biological sample, or subject comprising obtaining a query SORL1 gene sequence from the cell, biological sample, or subject, identifying the presence of a disease-associated mutation in the query SORL1 gene sequence, and administering to the cell, biological sample, or subject an agent that modulates endosomal trafficking. 3. A method of identifying a patient for treatment comprising obtaining a query SORL1 gene sequence from the cell, biological sample, or subject, identifying the presence of a disease- associated mutation in the query SORL1 gene sequence, and administering to the cell, biological sample, or subject an agent that modulates endosomal trafficking. 4. The method of any one of embodiments 1-3, wherein identifying the presence of the disease- associated mutation in the query SORL1 gene sequence comprises aligning the query SORL1 gene sequence against a reference SORL1 gene sequence comprising the disease-associated mutation. 5. The method of any one of embodiments 1-5, wherein the disease-associated mutation occurs in VPS10p domain, 10CC domain, YWTD domain, EGF domain, a CR domain, the FnIII domain, the transmembrane domain, or the cytoplasmic tail domain. 6. The method of any one of embodiments 1-5, wherein the disease-associated mutation comprises a pathogenic mutation as set forth in Table 8. 7. The method of any one of embodiments 1-6, wherein the disease-associated mutation does not occur at a position in SORL1 selected from the group consisting of 101, 115, 140, 146, 191, 205, 269, 270, 303, 332, 371, 391, 416, 446, 459, 474, 480, 508, 528, 552, 560, 577, 581, 583, 636, 639, 642, 656, 674, 679, 695, 729, 734, 743744, 762, 786, 807, 818, 833, 852, 870, 884, 885, 942, 961, 980, 1000, 1002, 1074, 1080, 1081, 1084, 1094, 1099, 1113, 1116, 1156, 1167, 1181, 1187, 1207, 1222, 1222, 1246, 1258, 1276, 1276, 1279, 1291, 1304, 1310, 1311, 1322, 1379, 1383, 1392, 1409, 1435, 1442, 1447, 1454, 1470, 1481, 1483, 1490, 1501, 1504, 1522, 1526, 1535, 1543, 1548, 1563, 1584, 1594, 1620, 1657, 1668, 1675, 1680, 1697, 1697, 1729, 1732, 1747, 1809, 1813, 1816, 1866, 1873, 1885, 1895, 1910, 1958, 1967, 2000, 2007, 2014, 2038, 2065, 2079, 2083, 2090, 2097, 2106, 2134, 2147, 2158, and 2160. 8. The method of any one of embodiments 1-11, wherein the disease-associated mutation occurs at any one of positions: (a) R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹, Y³⁵⁰,

S²³⁴, D²³⁶, G²³⁸, T²⁴⁰, W²⁴¹, S²⁸⁰, D²⁸², S²⁸⁶, S³²⁹, S³⁷⁵, G³⁷⁹, F³⁸², T⁴⁴³, D⁴⁴⁵, G⁴⁴⁷, T⁴⁴⁹, W⁴⁵⁰, S⁵²³, G⁵²⁷, W⁵³⁰, S⁵⁶⁴, N⁵⁶⁶, G⁵⁶⁸, T⁵⁷⁰, W⁵⁷¹, C⁴⁶⁷, or C⁴⁷³ in the VPS10p domain; (b) C⁶²⁵, C⁶⁴³, C⁶⁶⁰, C⁶⁷⁵, C⁶⁷⁷, C⁶⁸⁴, C⁶⁹⁹, C⁷¹⁶, C⁷³⁶, and C⁷⁵² in the 10CC domain; (c) L⁷⁹³, F⁷⁹⁵, L⁸⁰², L⁸³⁷, F⁸³⁹, L⁸⁴⁶, L⁸⁸¹, L⁸⁸³, M⁸⁹⁰, I⁹²⁶, V⁹²⁸, I⁹³³, I⁹⁶⁶, V⁹⁶⁸, I⁹⁷³, M¹⁰⁰⁷, I¹⁰⁰⁹,

I⁹⁴³, I⁹⁸³, R⁷⁷¹, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, G⁷⁷⁷, G⁸¹⁹, G⁸⁶³, G⁹⁰⁹, G⁹⁵⁰, G⁹⁹¹, R⁸⁶⁶, R⁹⁵³, C⁸⁰¹, or C⁸¹⁶ in the YWTD doman; (d) C¹⁰²¹, C¹⁰²⁶, C¹⁰³⁰, C¹⁰⁴⁰, C¹⁰⁴², C¹⁰⁵⁸, C¹⁰⁶⁰, and C¹⁰⁷¹ in the EGF domain; (e) S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹²⁹⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁴⁰, G¹⁴⁹³, G¹⁵³⁶, D¹⁰⁹⁸, D¹¹⁰², D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸², D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, D¹²⁶⁷, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁴⁹, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁴⁴, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁵³, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁰, C¹⁵⁴⁹, D¹¹⁰⁵, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴, D¹³⁵², D¹³⁹⁶, D¹⁴⁴⁶, D¹⁴⁹⁹, or D¹⁵⁴² in a CR domain; (f) L¹⁵⁶¹, W¹⁵⁶³, L¹⁶⁵⁹, L¹⁶⁶¹, I¹⁷⁵³, I¹⁷⁵⁵, L¹⁸⁴⁸, A¹⁸⁵⁰, L¹⁹³⁸, V¹⁹⁴⁰, L²⁰³⁰, I²⁰³², V¹⁵⁷¹, L¹⁵⁷³, I¹⁶⁶⁹, L¹⁷⁶³, F¹⁷⁶⁵, V¹⁸⁵⁸, C¹⁸⁶⁰, V¹⁹⁴⁸, I¹⁹⁵⁰, V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², W¹⁷³⁵, P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, (L¹⁷⁶⁷), W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, P¹⁹⁵⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹,

(g) F²¹⁷², A²¹⁷³, N²¹⁷⁴, S²¹⁷⁵, H²¹⁷⁶, Y²¹⁷⁷, D²¹⁹⁰, D²¹⁹¹, L²¹⁹², G²¹⁹³, E²¹⁹⁴, D²¹⁹⁵, D²¹⁹⁶, E²¹⁹⁷,

domain; or any combination thereof. 9. The method of any one of embodiments 1-11, wherein the disease-associated mutation occurs at any one of positions: (a) R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹, F⁴¹⁴,

(b) C⁶²⁵, C⁶⁴³, C⁶⁶⁰, C⁶⁷⁵, C⁶⁷⁷, C⁶⁸⁴, C⁶⁹⁹, C⁷¹⁶, C⁷³⁶, and C⁷⁵² in the 10CC domain; (c) L⁷⁹³, F⁷⁹⁵, L⁸⁰², L⁸³⁷, F⁸³⁹, L⁸⁴⁶, L⁸⁸¹, L⁸⁸³, M⁸⁹⁰, I⁹²⁶, V⁹²⁸, I⁹³³, I⁹⁶⁶, V⁹⁶⁸, I⁹⁷³, M¹⁰⁰⁷, I¹⁰⁰⁹, L⁷⁸², V⁸²⁵, I⁸²⁶, I⁸⁶⁹, V⁸⁷⁰, L⁹¹⁵, V⁹¹⁶, I⁹⁵⁶, L⁹⁵⁷, I⁹⁹⁶, L⁹⁹⁷, L⁷⁸⁷, L⁸³¹, L⁸⁷⁵, V⁹²⁰, L⁹⁶⁰, L¹⁰⁰¹, R⁸⁷⁹, W⁸⁹⁵, N⁹²⁴, Y⁹⁶⁴, W⁹⁷⁸, Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶, Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³, I⁹⁸³, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, G⁷⁷⁷, G⁸¹⁹, G⁸⁶³, G⁹⁰⁹, G⁹⁵⁰, G⁹⁹¹, R⁸⁶⁶, R⁹⁵³, C⁸⁰¹, or C⁸¹⁶ in the YWTD domain; (d) C¹⁰²¹, C¹⁰²⁶, C¹⁰³⁰, C¹⁰⁴⁰, C¹⁰⁴², C¹⁰⁵⁸, C¹⁰⁶⁰, or C¹⁰⁷¹ in the EGF domain; (e) S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁹³, G¹⁵³⁶, D¹⁰⁹⁸, D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹,

C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁹, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴, D¹³⁵², D¹³⁹⁶, D¹⁴⁴⁶, D¹⁴⁹⁹, or D¹⁵⁴² in a CR domain; (f) L¹⁵⁶¹, W¹⁵⁶³, L¹⁶⁵⁹, L¹⁶⁶¹, I¹⁷⁵³, I¹⁷⁵⁵, L¹⁸⁴⁸, A¹⁸⁵⁰, L¹⁹³⁸, V¹⁹⁴⁰, L²⁰³⁰, I²⁰³², V¹⁵⁷¹, L¹⁵⁷³, I¹⁶⁶⁹, L¹⁷⁶³, F¹⁷⁶⁵, V¹⁸⁵⁸, C¹⁸⁶⁰, V¹⁹⁴⁸, I¹⁹⁵⁰, V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², W¹⁷³⁵, P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, (L¹⁷⁶⁷), W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹, P¹⁹⁹⁸,

(g) F²¹⁷², A²¹⁷³, S²¹⁷⁵, H²¹⁷⁶, Y²¹⁷⁷, D²¹⁹⁰, D²¹⁹¹, L²¹⁹², G²¹⁹³, E²¹⁹⁴, D²¹⁹⁵, D²¹⁹⁶, E²¹⁹⁷, D²¹⁹⁸,

any combination thereof. 10. The method of any one of embodiments 1-9, wherein the disease-associated mutation is a mutation implicated in neurological disease. 11. The method of embodiment 10, wherein the neurological disease is a neurodegenerative disease, optionally wherein the neurodegenerative disease is selected from the group consisting of Parkinson’s Disease, Dementia, Pick’s Disease, Lewy Body Dementia, Huntington’s Disease, Alzheimer’s Disease, Early-Onset Alzheimer’s Disease, Late-Onset Alzheimer’s Disease and Familial Alzheimer’s Disease. 12. The method of any one of embodiments 1-11, wherein the disease-associated mutation occurs in the VPS10p domain of SORL1. 13. The method of embodiment 12, wherein the disease-associated mutation confers a moderate risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s Disease)and occurs at any position selected from the group consisting of R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹, Y³⁵⁰, F⁴¹⁴, L⁴⁹⁵, Y⁵³⁹, Y⁵⁴⁰, V⁵⁸³, Y⁵⁸⁴, I¹¹⁷, V¹¹⁸, A¹¹⁹, Y¹⁷⁷, I¹⁷⁸, F¹⁷⁹, L²¹⁸, L²¹⁹, L²²⁰, I²⁶⁴, Y²⁶⁵, I²⁶⁶, Y³⁰⁶, M³⁰⁷, F³⁰⁸, V³⁵⁹, F³⁶⁰, V³⁶¹, Y⁴²⁴, I⁴²⁵, A⁴²⁶,I⁵⁰⁴, I⁵⁰⁵, A⁵⁰⁶, I⁵⁴⁸, I⁵⁴⁹, V⁵⁹⁶, F⁵⁹⁷, V¹³⁵, Y¹³⁶, V¹³⁷, L¹⁸⁷, W¹⁸⁸, I¹⁸⁹, L²³¹, W²³², V²⁷⁷, F²⁷⁸, L³²⁶, W³²⁷, V³²⁸, L³⁷², Y³⁷³, I³⁷⁴, V⁴⁴¹, I⁴⁴², V⁵²⁰, Y⁵²¹, I⁵²², L⁵⁶¹, Y⁵⁶³, L⁶¹³, and V⁶¹⁵. 14. The method of embodiment 12, wherein the disease-associated mutation confers a moderate risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s Disease)and occurs at any position selected from the group consisting of R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹, F⁴¹⁴, L⁴⁹⁵, Y⁵³⁹, Y⁵⁴⁰, V⁵⁸³, Y⁵⁸⁴, I¹¹⁷, V¹¹⁸, A¹¹⁹, Y¹⁷⁷, I¹⁷⁸, F¹⁷⁹, L²¹⁸, L²¹⁹, L²²⁰, I²⁶⁴, Y²⁶⁵, I²⁶⁶, Y³⁰⁶, F³⁰⁸, V³⁵⁹, F³⁶⁰, V³⁶¹, Y⁴²⁴, I⁴²⁵, A⁴²⁶,I⁵⁰⁴, I⁵⁰⁵, A⁵⁰⁶, I⁵⁴⁸, I⁵⁴⁹, V⁵⁹⁶, F⁵⁹⁷, V¹³⁵, Y¹³⁶, V¹³⁷, L¹⁸⁷, W¹⁸⁸, I¹⁸⁹, L²³¹, W²³², V²⁷⁷, F²⁷⁸,

15. The method of embodiment 12, wherein the disease-associated mutation confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s Disease)and occurs at any position selected from the group consisting of S¹³⁸, D¹⁴⁰, G¹⁴², S¹⁴⁴, F¹⁴⁵, T¹⁹⁰, D¹⁹², T¹⁹⁶, S²³⁴, D²³⁶, G²³⁸, T²⁴⁰, W²⁴¹, S²⁸⁰, D²⁸², S²⁸⁶, S³²⁹, S³⁷⁵, G³⁷⁹, F³⁸², T⁴⁴³, D⁴⁴⁵, G⁴⁴⁷, T⁴⁴⁹, W⁴⁵⁰, S⁵²³, G⁵²⁷, W⁵³⁰, S⁵⁶⁴, N⁵⁶⁶, G⁵⁶⁸, T⁵⁷⁰, W⁵⁷¹, C⁴⁶⁷, and C⁴⁷³. 16. The method of embodiment 12, wherein the disease associated mutation confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s Disease)and occurs at any position selected from the group consisting of S¹³⁸, G¹⁴², S¹⁴⁴, F¹⁴⁵, T¹⁹⁰, D¹⁹², T¹⁹⁶, S²³⁴, D²³⁶, G²³⁸, T²⁴⁰, W²⁴¹, S²⁸⁰, D²⁸², S²⁸⁶, S³²⁹, S³⁷⁵, G³⁷⁹, F³⁸², T⁴⁴³, D⁴⁴⁵, G⁴⁴⁷,

17. The method of any one of embodiments 1-11, wherein the disease-associated mutation occurs in the 10CC domain of SORL1. 18. The method of embodiment 17, wherein the disease-associated mutation confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s Disease) and occurs at any position selected from the group consisting of C⁶²⁵, C⁶⁴³, C⁶⁶⁰, C⁶⁷⁵, C⁶⁷⁷, C⁶⁸⁴, C⁶⁹⁹, C⁷¹⁶, C⁷³⁶, and C⁷⁵². 19. The method of any one of embodiments 1-11, wherein the disease-associated mutation occurs in the YWTD motif of SORL1. 20. The method of embodiment 19, wherein the disease associated mutation confers a moderate risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s Disease) and occurs at any position selected from the group consisting of L⁷⁹³, F⁷⁹⁵, L⁸⁰², L⁸³⁷, F⁸³⁹, L⁸⁴⁶, L⁸⁸¹, L⁸⁸³, M⁸⁹⁰, I⁹²⁶, V⁹²⁸, I⁹³³, I⁹⁶⁶, V⁹⁶⁸, I⁹⁷³, M¹⁰⁰⁷, I¹⁰⁰⁹, L⁷⁸², V⁸²⁵, I⁸²⁶, I⁸⁶⁹, V⁸⁷⁰,

21. The method of embodiment 19, wherein the disease associated mutation confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s Disease) and occurs at any position selected from the group consisting of Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶,

D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³, I⁹⁸³, R⁷⁷¹, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, G⁷⁷⁷, G⁸¹⁹, G⁸⁶³, G⁹⁰⁹, G⁹⁵⁰, G⁹⁹¹, R⁸⁶⁶, R⁹⁵³, C⁸⁰¹, and C⁸¹⁶. 22. The method of embodiment 19, wherein the disease associated mutation confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s Disease) and occurs at any position selected from the group consisting of Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶, Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³, I⁹⁸³, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, G⁷⁷⁷, G⁸¹⁹, G⁸⁶³, G⁹⁰⁹, G⁹⁵⁰, G⁹⁹¹, R⁸⁶⁶, R⁹⁵³, C⁸⁰¹, and C⁸¹⁶. 23. The method of any one of embodiments 1-11, wherein the disease-associated mutation occurs in the EGF domain or SORL1. 24. The method of embodiment 21, wherein the EGF domain is deleted. 25. The method of embodiment 23, wherein the disease-associated mutation comprises an insertion of a cysteine residue in the EGF domain. 26. The method of embodiment 23, wherein the disease associated mutation confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s Disease) and occurs at any position selected from the group consisting of C¹⁰²¹, C¹⁰²⁶, C¹⁰³⁰, C¹⁰⁴⁰, C¹⁰⁴², C¹⁰⁵⁸, C¹⁰⁶⁰, and C¹⁰⁷¹. 27. The method of any one of embodiments 1-11, wherein the disease-associated mutation occurs in a CR domain of SORL1. 28. The method of embodiment 27, wherein the disease associated mutation confers a moderate risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s Disease) and occurs at any position selected from the group consisting of S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸,

L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹²⁹⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁴⁰, G¹⁴⁹³, and G¹⁵³⁶. 29. The method of embodiment 27, wherein the disease associated mutation confers a moderate risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s Disease) and occurs at any position selected from the group consisting of S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁹³, and G¹⁵³⁶. 30. The method of embodiment 27, wherein the disease associated mutation confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s Disease) and occurs at any position selected from the group consisting of D¹⁰⁹⁸, D¹¹⁰², D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸², D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹,

31. The method of embodiment 27, wherein the disease associated mutation confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s Disease) and occurs at any position selected from the group consisting of D¹⁰⁹⁸, D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁹, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴,

32. The method of any one of embodiments 1-11, wherein the disease-associated mutation occurs in the FnIII-domain of SORL1. 33. The method of embodiment 32, wherein the disease associated mutation confers a moderate risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s Disease) and occurs at any position selected from the group consisting of L¹⁵⁶¹, W¹⁵⁶³, L¹⁶⁵⁹, L¹⁶⁶¹, I¹⁷⁵³, I¹⁷⁵⁵, L¹⁸⁴⁸, A¹⁸⁵⁰, L¹⁹³⁸, V¹⁹⁴⁰, L²⁰³⁰, I²⁰³², V¹⁵⁷¹, L¹⁵⁷³, I¹⁶⁶⁹, L¹⁷⁶³, F¹⁷⁶⁵, V¹⁸⁵⁸, C¹⁸⁶⁰, V¹⁹⁴⁸, I¹⁹⁵⁰, V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴,

34. The method of embodiment 32, wherein the disease associated mutation confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s Disease) and occurs at any position selected from the group consisting of P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, (L¹⁷⁶⁷), W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, P¹⁹⁵⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹, P¹⁹⁹⁸, R¹⁹¹⁰, C¹⁵⁸⁶, C¹⁶³¹, C²¹⁰¹, and C²¹⁰⁸. 35. The method of embodiment 32, wherein the disease associated mutation confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s Disease) and occurs at any position selected from the group consisting of P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, (L¹⁷⁶⁷), W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹, P¹⁹⁹⁸, R¹⁹¹⁰, C¹⁵⁸⁶, C¹⁶³¹, C²¹⁰¹, and C²¹⁰⁸. 36. The method of any one of embodiments 1-11, wherein the disease-associated mutation occurs in the cytoplasmic tail domain of SORL1. 37. The method of embodiment 36, wherein the disease associated mutation confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s Disease) and occurs at any position selected from the group consisting of F²¹⁷², A²¹⁷³, N²¹⁷⁴, S²¹⁷⁵, H²¹⁷⁶, Y²¹⁷⁷, D²¹⁹⁰, D²¹⁹¹, L²¹⁹², G²¹⁹³, E²¹⁹⁴, D²¹⁹⁵, D²¹⁹⁶, E²¹⁹⁷, D²¹⁹⁸, D²²⁰⁷, D²²⁰⁸, V²²⁰⁹, P²²¹⁰, M²²¹¹, V²²¹², I²²¹³, and A²²¹⁴. 38. The method of embodiment 36, wherein the disease associated mutation confers a high risk of developing a neurological disease (e.g., a neurodegenerative disease such as Alzheimer’s Disease) and occurs at any position selected from the group consisting of F²¹⁷², A²¹⁷³, S²¹⁷⁵, H²¹⁷⁶, Y²¹⁷⁷, D²¹⁹⁰, D²¹⁹¹, L²¹⁹², G²¹⁹³, E²¹⁹⁴, D²¹⁹⁵, D²¹⁹⁶, E²¹⁹⁷, D²¹⁹⁸, D²²⁰⁷, D²²⁰⁸, V²²⁰⁹, P²²¹⁰, M²²¹¹, V²²¹², I²²¹³, and A²²¹⁴. 39. The method of any one of embodiments 1-38, wherein administrating the agent comprises administering a small molecule therapy, a gene therapy, a gene-editing therapy, or any combination thereof. 40. The method of embodiment 39, wherein the small molecule therapy comprises administration of an aminoguanidine hydrazone or a retromer chaperone. 41. The method of embodiment 39 or 40, wherein the gene therapy comprises administration of an engineered nucleic acid or a transgene encoding retromer protein VPS35, VPS26a, or VPS26b. 42. The method of any one of embodiments 39-41, wherein the gene therapy comprises administration of an antisense oligonucleotide (ASO) comprising sequence complementarity to a SORL1 mRNA transcript comprising the disease-associated mutation. 43. The method of embodiment 42, wherein the ASO is an exon-skipper. 44. The method of any one of embodiments 39-43, wherein the gene therapy comprises administration of an engineered nucleic acid encoding a SORL1 variant. 45. The method of embodiment 44, wherein the SORL1 variant comprises: (a) at least two SORL1 FnIII domains, (b) a SORL1 transmembrane domain, and (c) a SORL1 cytoplasmic tail domain. 46. The method of embodiment 45, wherein the SORL1 variant comprises, three, four, five, or six FnIII domains. 47. The method of embodiment 45 or 46, wherein at least one of the SORL1 variant FnIII domains is selected from the group consisting of FnIII-1, FnIII-2, FnIII-3, FnIII-4, FnIII-5, and FnIII-6. 48. The method of any one of embodiments 45-47, wherein at least one of the SORL1 variant FnIII domains comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 15-20. 49. The method of any one of embodiments 45-47, wherein at least one of the SORL1 variant FnIII domains comprises the amino acid sequence set forth in SEQ ID NO: 15-20. 50. The method of any one of embodiments 45-49, wherein the SORL1 variant transmembrane domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 22. 51. The method of any one of embodiments 45-49, wherein the SORL1 variant transmembrane domain comprises the amino acid sequence set forth in SEQ ID NO: 22. 52. The method of any one of embodiments 45-51, wherein the SORL1 variant cytoplasmic tail domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 23. 53. The method of any one of embodiments 45-51, wherein the SORL1 variant cytoplasmic tail domain comprises the amino acid sequence set forth in SEQ ID NO: 23. 54. The method of any one of embodiments 45-53, wherein at least one of the SORL1 variant FnIII domains comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 15-20, the SORL1 transmembrane domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 22, and the SORL1 cytoplasmic tail domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 23. 55. The method of any one of embodiments 45-53, wherein at least one of the SORL1 variant FnIII domains comprises the amino acid sequence set forth in SEQ ID NO: 15-20, the SORL1 transmembrane domain comprises the amino acid sequence set forth in SEQ ID NO: 22, and the SORL1 cytoplasmic tail domain comprises the amino acid sequence set forth in SEQ ID NO: 23. 56. The method of any one of embodiments 37-48, wherein the SORL1 variant further comprises an N-terminal or C-terminal tag. 57. The method of embodiment 56, wherein the N-terminal or C-terminal tag is hemagglutinin (HA) or is three instances of FLAG (3X-FLAG). 58. The method of embodiment 57, wherein the N-terminal tag is HA. 59. The method of embodiment 57, wherein the N-terminal tag is 3X-FLAG. 60. The method of any one of embodiment 45-59, wherein the SORL1 variant comprises a mutant FANSHY motif. 61. The method of any one of embodiments 45-60, wherein the SORL1 variant is provided in a transgene flanked by adeno-associated virus (AAV) inverted terminal repeats (ITRs) or long terminal repeats (LTRs). 62. The method of embodiment 61, wherein the transgene comprising the SORL1 variant is provided in a vector. 63. The method of embodiment 62, wherein the vector is a lentiviral vector and the transgene is flanked by LTRs. 64. The method of embodiment 63, wherein the vector comprises from 5′ to 3′ a first LTR, an HIV-1 psi (^) packaging sequence, a rev response element (RRE), a central polypurine tract with a downstream central termination sequence (cPPT/CTS), a CAG promoter comprising the CMV enhancer, the chicken beta-actin promoter and the chimeric intron, an Ig-kappa leader sequence, the SORL1 variant, the WPRE, a second LTR, an M13 rev sequence, a lac operator, a lac promoter, a CAP binding site, an origin of replication (ori), an ampicillin resistance gene, an AmpR promoter, and the SV40 poly(A) signal. 65. The method of embodiment 63, wherein the vector comprises from 5′ to 3′ a first LTR, an HIV-1 psi (^) packaging sequence, a rev response element (RRE), a central polypurine tract with a downstream central termination sequence (cPPT/CTS), a CAG promoter comprising the CMV enhancer, the chicken beta-actin promoter and the chimeric intron, an Ig-kappa leader sequence, the SORL1 variant further comprising the three N-terminal FLAG tags, the WPRE, a second LTR, an M13 rev sequence, a lac operator, a lac promoter, a CAP binding site, an origin of replication (ori), an ampicillin resistance gene, an AmpR promoter, and the SV40 poly(A) signal. 66. The method of embodiment 62, wherein the vector is a recombinant adeno-associated viral (AAV) vector and the transgene is flanked by ITRs 67. The method of embodiment 66, wherein the vector comprises from 5′ to 3′ a first ITR, a CAG promoter comprising the CMV enhancer, the chicken beta-actin promoter and the chimeric intron, an Ig-kappa leader sequence, the SORL1 variant comprising the N-terminal hemagglutinin HA tag, WPRE3, the bovine growth hormone (bGH) polyA signal, a second ITR, an origin of replication (ori), a neomycin/kanamycin resistance gene, an AmpR promoter, and a f1 ori. 68. The method of embodiment 66, wherein the vector comprises from 5′ to 3′ a first ITR, a CAG promoter comprising the CMV enhancer, the chicken beta-actin promoter and the chimeric intron, an Ig-kappa leader sequence, the SORL1 variant, the WPRE3, the bovine growth hormone (bGH) polyA signal, a second ITR, an origin of replication (ori), a neomycin/kanamycin resistance gene, an AmpR promoter, and a f1 ori. 69. The method of any one of embodiments 62-68, wherein the vector comprises a polynucleotide that is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% sequence identical to any one of SEQ ID NOs: 3-8, 10-12, or 29-32. 70. The method of any one of embodiments 62-68, wherein the vector comprises the polynucleotide sequence set forth in any one of SEQ ID NOs: 3-8, 10-12, or 29-32. 71. The method of any one of embodiments 63-65 or 69-70, wherein the vector is provided in a lentivirus. 72. The method of any one of embodiments 66-70, wherein the vector is provided in a recombinant adeno-associated virus. 73. The method of any one of embodiments 39-72, wherein the gene-editing therapy comprises a nuclease and a guide RNA (gRNA) comprising a sequence that is complementary to SORL1. 74. The method of any one of embodiments 39-73, wherein the gene-editing therapy corrects a disease-associated mutation in SORL1. 75. The method of any one of embodiments 39-74, wherein the method increases SORL1 activity in the cell, biological sample, or subject. 76. The method of any one of embodiments 39-75, wherein the method increases sAPPα in the cell, biological sample, or subject. 77. The method of any one of embodiments 39-76, wherein the method decreases Aβ30, Aβ40, and/or Aβ42 in the cell, biological sample, or subject. 78. The method of any one of embodiments 39-77, wherein the method increases VPS35 activity in the cell, biological sample, or subject. 79. A method for identifying mutations in SORL1 that are associated with abnormal endosomal trafficking comprising aligning a clustered domain or repeat sequence within a query SORL1 gene sequence against a reference sequence corresponding to a disease-associated gene variant and identifying mutations in the query SORL1 gene sequence that align with a disease-associated domain position in the reference sequence, wherein the disease-associated domain position comprises homology to one or more cluster domains or repeat sequences of the query SORL1 gene sequence. 80. The method of embodiment 79, wherein the cluster domain or repeat sequence corresponds to VPS10p domain, 10CC domain, YWTD motif, EGF domain, a CR domain, the FnIII-domain, the transmembrane, or cytoplasmic tail domain. 81. The method of embodiment 79 or 80, wherein the query SORL1 gene sequence is obtained from a cell, biological sample, or subject. 82. The method of any one of embodiments 79-81, wherein the subject or the cell or biological sample are derived from a subject suspected of having, diagnosed with, or at risk of developing a neurological disease. 83. The method of embodiment 82, wherein the neurological disease is a neurodegenerative disease. 84. The method of embodiment 83, wherein the neurodegenerative disease is selected from the group consisting of Parkinson’s Disease, Dementia, Pick’s Disease, Lewy Body Dementia, Huntington’s Disease, Alzheimer’s Disease, Early-Onset Alzheimer’s Disease, Late-Onset Alzheimer’s Disease, and Familial Alzheimer’s Disease. 85. The method of any one of embodiments 79-84, wherein the method further comprises assaying the endosomal trafficking activity of SORL1 in the biological sample. 86. The method of any one of embodiments 79-85, wherein the method further comprises assaying the activity or protein level of sAPPα, Aβ30, Aβ40, Aβ42, and/or VPS35 in the biological sample.

Claims

CLAIMS What is claimed is: 1. A method comprising administering an agent to a cell, biological sample, or subject characterized as having or suspected of having a disease-associated mutation in SORL1 which is encoded by a mutant SORL1 gene sequence. 2. A method for treating a neurological disease in a cell, biological sample, or subject comprising obtaining a query SORL1 gene sequence from the cell, biological sample, or subject, identifying the presence of a sequence encoding a disease-associated mutation in SORL1 in the query SORL1 gene sequence, and administering to the cell, biological sample, or subject an agent that modulates endosomal trafficking. 3. A method for modulating endosomal trafficking in a cell, biological sample, or subject comprising obtaining a query SORL1 gene sequence from the cell, biological sample, or subject, identifying the presence of a sequence encoding a disease-associated mutation in SORL1 in the query SORL1 gene sequence, and administering to the cell, biological sample, or subject an agent that modulates endosomal trafficking. 4. A method of identifying a patient for treatment comprising obtaining a query SORL1 gene sequence from the cell, biological sample, or subject, identifying the presence of a sequence encoding a disease-associated mutation in SORL1 in the query SORL1 gene sequence, and administering to the cell, biological sample, or subject an agent that modulates endosomal trafficking. 5. The method of any one of claims 2-4, wherein identifying the presence of the sequence encoding a disease-associated mutation in SORL1 in the query SORL1 gene sequence comprises aligning the query SORL1 gene sequence against a reference SORL1 gene sequence comprising the sequence encoding the disease-associated mutation in SORL1. 6. The method of any one of claims 1-5, wherein the disease-associated mutation occurs in VPS10p domain, 10CC domain, YWTD domain, EGF domain, the CR domain, the FnIII domain, the transmembrane domain, or the cytoplasmic tail domain of SORL1.

7. The method of any one of claims 1-6, wherein the disease-associated mutation comprises a pathogenic mutation as set forth in Table 13. 8. The method of any one of claims 1-7, wherein the disease-associated mutation does not occur at a position in SORL1 selected from the group consisting of 101, 115, 140, 146, 191, 205, 269, 270, 303, 332, 371, 391, 416, 446, 459, 474, 480, 508, 528, 552, 560, 577, 581, 583, 636, 639, 642, 656, 674, 679, 695, 729, 734, 743744, 762, 786, 807, 818, 833, 852, 870, 884, 885, 942, 961, 980, 1000, 1002, 1074, 1080, 1081, 1084, 1094, 1099, 1113, 1116, 1156, 1167, 1181, 1187, 1207, 1222, 1222, 1246, 1258, 1276, 1276, 1279, 1291, 1304, 1310, 1311, 1322, 1379, 1383, 1392, 1409, 1435, 1442, 1447, 1454, 1470, 1481, 1483, 1490, 1501, 1504, 1522, 1526, 1535, 1543, 1548, 1563, 1584, 1594, 1620, 1657, 1668, 1675, 1680, 1697, 1697, 1729, 1732, 1747, 1809, 1813, 1816, 1866, 1873, 1885, 1895, 1910, 1958, 1967, 2000, 2007, 2014, 2038, 2065, 2079, 2083, 2090, 2097, 2106, 2134, 2147, 2158, and 2160. 9. The method of any one of claims 1-8, wherein the disease-associated mutation occurs at any one of positions:

I²⁶⁶, Y³⁰⁶, M³⁰⁷, F³⁰⁸, V³⁵⁹, F³⁶⁰, V³⁶¹, Y⁴²⁴, I⁴²⁵, A⁴²⁶,I⁵⁰⁴, I⁵⁰⁵, A⁵⁰⁶, I⁵⁴⁸, I⁵⁴⁹, V⁵⁹⁶, F⁵⁹⁷, V¹³⁵, Y¹³⁶, V¹³⁷, L¹⁸⁷, W¹⁸⁸, I¹⁸⁹, L²³¹, W²³², V²⁷⁷, F²⁷⁸, L³²⁶, W³²⁷, V³²⁸, L³⁷², Y³⁷³, I³⁷⁴, V⁴⁴¹, I⁴⁴², V⁵²⁰, Y⁵²¹, I⁵²², L⁵⁶¹, Y⁵⁶³, L⁶¹³, V⁶¹⁵, S¹³⁸, D¹⁴⁰, G¹⁴², S¹⁴⁴, F¹⁴⁵, T¹⁹⁰, D¹⁹², T¹⁹⁶, S²³⁴, D²³⁶, G²³⁸, T²⁴⁰, W²⁴¹, S²⁸⁰, D²⁸², S²⁸⁶, S³²⁹, S³⁷⁵, G³⁷⁹, F³⁸², T⁴⁴³, D⁴⁴⁵, G⁴⁴⁷, T⁴⁴⁹, W⁴⁵⁰, S⁵²³, G⁵²⁷, W⁵³⁰, S⁵⁶⁴, N⁵⁶⁶, G⁵⁶⁸, T⁵⁷⁰, W⁵⁷¹, C⁴⁶⁷, or C⁴⁷³ in the VPS10p domain; (b) C⁶²⁵, C⁶⁴³, C⁶⁶⁰, C⁶⁷⁵, C⁶⁷⁷, C⁶⁸⁴, C⁶⁹⁹, C⁷¹⁶, C⁷³⁶, and C⁷⁵² in the 10CC domain; (c) L⁷⁹³, F⁷⁹⁵, L⁸⁰², L⁸³⁷, F⁸³⁹, L⁸⁴⁶, L⁸⁸¹, L⁸⁸³, M⁸⁹⁰, I⁹²⁶, V⁹²⁸, I⁹³³, I⁹⁶⁶, V⁹⁶⁸, I⁹⁷³, M¹⁰⁰⁷, I¹⁰⁰⁹, L⁷⁸², V⁸²⁵, I⁸²⁶, I⁸⁶⁹, V⁸⁷⁰, L⁹¹⁵, V⁹¹⁶, I⁹⁵⁶, L⁹⁵⁷, I⁹⁹⁶, L⁹⁹⁷, L⁷⁸⁷, L⁸³¹, L⁸⁷⁵, V⁹²⁰, L⁹⁶⁰, L¹⁰⁰¹, R⁸⁷⁹, W⁸⁹⁵, N⁹²⁴, Y⁹⁶⁴, W⁹⁷⁸, Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶, Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, T⁹³⁶, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³, I⁹⁸³, R⁷⁷¹, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, G⁷⁷⁷, G⁸¹⁹, G⁸⁶³, G⁹⁰⁹, G⁹⁵⁰, G⁹⁹¹, R⁸⁶⁶, R⁹⁵³, C⁸⁰¹, or C⁸¹⁶ in the YWTD doman; (d) C¹⁰²¹, C¹⁰²⁶, C¹⁰³⁰, C¹⁰⁴⁰, C¹⁰⁴², C¹⁰⁵⁸, C¹⁰⁶⁰, and C¹⁰⁷¹ in the EGF domain; (e) S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹²⁹⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁴⁰, G¹⁴⁹³, G¹⁵³⁶, D¹⁰⁹⁸, D¹¹⁰², D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸², D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, D¹²⁶⁷, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁴⁹, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁴⁴, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁵³, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁰, C¹⁵⁴⁹, D¹¹⁰⁵, D¹¹⁴⁶, D¹¹⁸⁵,

(f) L¹⁵⁶¹, W¹⁵⁶³, L¹⁶⁵⁹, L¹⁶⁶¹, I¹⁷⁵³, I¹⁷⁵⁵, L¹⁸⁴⁸, A¹⁸⁵⁰, L¹⁹³⁸, V¹⁹⁴⁰, L²⁰³⁰, I²⁰³², V¹⁵⁷¹, L¹⁵⁷³, I¹⁶⁶⁹, L¹⁷⁶³, F¹⁷⁶⁵, V¹⁸⁵⁸, C¹⁸⁶⁰, V¹⁹⁴⁸, I¹⁹⁵⁰, V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², W¹⁷³⁵, P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, P¹⁹⁵⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹,

domain; (h) or any combination thereof. 10. The method of any one of claims 1-8, wherein the disease-associated mutation occurs at any one of positions:

(b) C⁶²⁵, C⁶⁴³, C⁶⁶⁰, C⁶⁷⁵, C⁶⁷⁷, C⁶⁸⁴, C⁶⁹⁹, C⁷¹⁶, C⁷³⁶, and C⁷⁵² in the 10CC domain; (c) L⁷⁹³, F⁷⁹⁵, L⁸⁰², L⁸³⁷, F⁸³⁹, L⁸⁴⁶, L⁸⁸¹, L⁸⁸³, M⁸⁹⁰, I⁹²⁶, V⁹²⁸, I⁹³³, I⁹⁶⁶, V⁹⁶⁸, I⁹⁷³, M¹⁰⁰⁷, I¹⁰⁰⁹, L⁷⁸², V⁸²⁵, I⁸²⁶, I⁸⁶⁹, V⁸⁷⁰, L⁹¹⁵, V⁹¹⁶, I⁹⁵⁶, L⁹⁵⁷, I⁹⁹⁶, L⁹⁹⁷, L⁷⁸⁷, L⁸³¹, L⁸⁷⁵, V⁹²⁰, L⁹⁶⁰, L¹⁰⁰¹, R⁸⁷⁹, W⁸⁹⁵, N⁹²⁴, Y⁹⁶⁴, W⁹⁷⁸, Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶, Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³,

the YWTD domain; (d) C¹⁰²¹, C¹⁰²⁶, C¹⁰³⁰, C¹⁰⁴⁰, C¹⁰⁴², C¹⁰⁵⁸, C¹⁰⁶⁰, or C¹⁰⁷¹ in the EGF domain; (e) S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁹³, G¹⁵³⁶, D¹⁰⁹⁸, D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁹, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴, D¹³⁵², D¹³⁹⁶, D¹⁴⁴⁶, D¹⁴⁹⁹, or D¹⁵⁴² in the CR domain; (f) L¹⁵⁶¹, W¹⁵⁶³, L¹⁶⁵⁹, L¹⁶⁶¹, I¹⁷⁵³, I¹⁷⁵⁵, L¹⁸⁴⁸, A¹⁸⁵⁰, L¹⁹³⁸, V¹⁹⁴⁰, L²⁰³⁰, I²⁰³², V¹⁵⁷¹, L¹⁵⁷³, I¹⁶⁶⁹, L¹⁷⁶³, F¹⁷⁶⁵, V¹⁸⁵⁸, C¹⁸⁶⁰, V¹⁹⁴⁸, I¹⁹⁵⁰, V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², W¹⁷³⁵, P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹, P¹⁹⁹⁸,

(h) any combination thereof.

11. The method of any one of claims 1-10, wherein the disease-associated mutation is a mutation implicated in a neurological disease. 12. The method of claim 11, wherein the neurological disease is a neurodegenerative disease, optionally wherein the neurodegenerative disease is selected from the group consisting of Parkinson’s Disease, Dementia, Pick’s Disease, Lewy Body Dementia, Huntington’s Disease, Alzheimer’s disease, Early-Onset Alzheimer’s disease, Late-Onset Alzheimer’s disease, and Familial Alzheimer’s disease. 13. The method of any one of claims 1-12, wherein the disease-associated mutation occurs in the VPS10p domain of SORL1. 14. The method of claim 13, wherein the disease-associated mutation confers a moderate risk of developing a neurological disease and occurs at any position selected from the group consisting of R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹, I²⁶⁶, Y³⁰⁶, M³⁰⁷, F³⁰⁸, V³⁵⁹, F³⁶⁰, V³⁶¹, Y⁴²⁴, I⁴²⁵, A⁴²⁶,I⁵⁰⁴, I⁵⁰⁵, A⁵⁰⁶, I⁵⁴⁸, I⁵⁴⁹, V⁵⁹⁶, F⁵⁹⁷, V¹³⁵, Y¹³⁶, V¹³⁷, L¹⁸⁷, W¹⁸⁸, I¹⁸⁹, L²³¹, W²³², V²⁷⁷, F²⁷⁸, L³²⁶, W³²⁷, V³²⁸, L³⁷², Y³⁷³, I³⁷⁴, V⁴⁴¹, I⁴⁴², V⁵²⁰, Y⁵²¹, I⁵²², L⁵⁶¹, Y⁵⁶³, L⁶¹³, and V⁶¹⁵. 15. The method of claim 13, wherein the disease-associated mutation confers a moderate risk of developing a neurological disease and occurs at any position selected from the group consisting of R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹,

and C⁴⁷³.

17. The method of claim 13, wherein the disease associated mutation confers a high risk of developing a neurological disease and occurs at any position selected from the group consisting G³⁷⁹, F³⁸², T⁴⁴³, D⁴⁴⁵, G⁴⁴⁷, T⁴⁴⁹, W⁴⁵⁰, S⁵²³, G⁵²⁷, W⁵³⁰, S⁵⁶⁴, N⁵⁶⁶, G⁵⁶⁸, T⁵⁷⁰, W⁵⁷¹, C⁴⁶⁷, and C⁴⁷³. 18. The method of any one of claims 1-12, wherein the disease-associated mutation occurs in the 10CC domain of SORL1. 19. The method of claim 18, wherein the disease-associated mutation confers a high risk of developing a neurological disease and occurs at any position selected from the group consisting of C⁶²⁵, C⁶⁴³, C⁶⁶⁰, C⁶⁷⁵, C⁶⁷⁷, C⁶⁸⁴, C⁶⁹⁹, C⁷¹⁶, C⁷³⁶, and C⁷⁵². 20. The method of any one of claims 1-12, wherein the disease-associated mutation occurs in the YWTD motif of SORL1. 21. The method of claim 20, wherein the disease associated mutation confers a moderate risk of developing a neurological disease and occurs at any position selected from the group consisting of L⁷⁹³, F⁷⁹⁵, L⁸⁰², L⁸³⁷, F⁸³⁹, L⁸⁴⁶, L⁸⁸¹, L⁸⁸³, M⁸⁹⁰, I⁹²⁶, V⁹²⁸, I⁹³³, I⁹⁶⁶, V⁹⁶⁸, I⁹⁷³, M¹⁰⁰⁷, I¹⁰⁰⁹, L⁷⁸², V⁸²⁵, I⁸²⁶, I⁸⁶⁹, V⁸⁷⁰, L⁹¹⁵, V⁹¹⁶, I⁹⁵⁶, L⁹⁵⁷, I⁹⁹⁶, L⁹⁹⁷, L⁷⁸⁷, L⁸³¹, L⁸⁷⁵, V⁹²⁰, L⁹⁶⁰, L¹⁰⁰¹, R⁸⁷⁹, W⁸⁹⁵, N⁹²⁴, Y⁹⁶⁴, and W⁹⁷⁸. 22. The method of claim 20, wherein the disease associated mutation confers a high risk of developing a neurological disease and occurs at any position selected from the group consisting of Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶, Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, T⁹³⁶, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³, I⁹⁸³, R⁷⁷¹, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, 23. The method of claim 20, wherein the disease associated mutation confers a high risk of developing a neurological disease and occurs at any position selected from the group consisting of Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶, Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³, I⁹⁸³, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, G⁷⁷⁷, G⁸¹⁹,

24. The method of any one of claims 1-12, wherein the disease-associated mutation occurs in the EGF domain or SORL1. 25. The method of claim 22, wherein the EGF domain is deleted. 26. The method of claim 24, wherein the disease-associated mutation comprises an insertion of a cysteine residue in the EGF domain. 27. The method of claim 24, wherein the disease associated mutation confers a high risk of developing a neurological disease and occurs at any position selected from the group consisting 28. The method of any one of claims 1-12, wherein the disease-associated mutation occurs in the CR domain of SORL1. 29. The method of claim 28, wherein the disease associated mutation confers a moderate risk of developing a neurological disease and occurs at any position selected from the group consisting of S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹²⁹⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁴⁰, G¹⁴⁹³, and G¹⁵³⁶. 30. The method of claim 28, wherein the disease associated mutation confers a moderate risk of developing a neurological disease and occurs at any position selected from the group consisting of S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁹³, and G¹⁵³⁶. 31. The method of claim 28, wherein the disease associated mutation confers a high risk of developing a neurological disease and occurs at any position selected from the group consisting of D¹⁰⁹⁸, D¹¹⁰², D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸², D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁴⁹, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁴⁴, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁵³, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁰, C¹⁵⁴⁹, D¹¹⁰⁵, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴, D¹³⁵², D¹³⁹⁶, D¹⁴⁴⁶, D¹⁴⁹⁹, and D¹⁵⁴². 32. The method of claim 28, wherein the disease associated mutation confers a high risk of developing a neurological disease and occurs at any position selected from the group consisting of D¹⁰⁹⁸, D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁹, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴, D¹³⁵², D¹³⁹⁶, D¹⁴⁴⁶, D¹⁴⁹⁹, and D¹⁵⁴². 33. The method of any one of claims 1-12, wherein the disease-associated mutation occurs in the FnIII-domain of SORL1. 34. The method of claim 33, wherein the disease associated mutation confers a moderate risk of developing a neurological disease and occurs at any position selected from the group consisting of L¹⁵⁶¹, W¹⁵⁶³, L¹⁶⁵⁹, L¹⁶⁶¹, I¹⁷⁵³, I¹⁷⁵⁵, L¹⁸⁴⁸, A¹⁸⁵⁰, L¹⁹³⁸, V¹⁹⁴⁰, L²⁰³⁰, I²⁰³², V¹⁵⁷¹,

35. The method of claim 33, wherein the disease associated mutation confers a high risk of developing a neurological disease and occurs at any position selected from the group consisting of P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, P¹⁹⁵⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, C²¹⁰⁸. 36. The method of claim 33, wherein the disease associated mutation confers a high risk of developing a neurological disease and occurs at any position selected from the group consisting of P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹, P¹⁹⁹⁸, R¹⁹¹⁰, C¹⁵⁸⁶, C¹⁶³¹, C²¹⁰¹, and C²¹⁰⁸. 37. The method of any one of claims 1-12, wherein the disease-associated mutation occurs in the cytoplasmic tail domain of SORL1. 38. The method of claim 37, wherein the disease associated mutation confers a high risk of developing a neurological disease and occurs at any position selected from the group consisting of F²¹⁷², A²¹⁷³, N²¹⁷⁴, S²¹⁷⁵, H²¹⁷⁶, Y²¹⁷⁷, D²¹⁹⁰, D²¹⁹¹, L²¹⁹², G²¹⁹³, E²¹⁹⁴, D²¹⁹⁵, D²¹⁹⁶, E²¹⁹⁷, D²¹⁹⁸, D²²⁰⁷, D²²⁰⁸, V²²⁰⁹, P²²¹⁰, M²²¹¹, V²²¹², I²²¹³, and A²²¹⁴. 39. The method of claim 37, wherein the disease associated mutation confers a high risk of developing a neurological disease and occurs at any position selected from the group consisting of F²¹⁷², A²¹⁷³, S²¹⁷⁵, H²¹⁷⁶, Y²¹⁷⁷, D²¹⁹⁰, D²¹⁹¹, L²¹⁹², G²¹⁹³, E²¹⁹⁴, D²¹⁹⁵, D²¹⁹⁶, E²¹⁹⁷, D²¹⁹⁸, D²²⁰⁷, D²²⁰⁸, V²²⁰⁹, P²²¹⁰, M²²¹¹, V²²¹², I²²¹³, and A²²¹⁴. 40. The method of any one of claims 1-39, wherein administering the agent comprises administering a small molecule therapy, a biologic, a gene therapy, a gene-editing therapy, or any combination thereof. 41. The method of claim 40, wherein the small molecule therapy comprises administration of an aminoguanidine hydrazone or a retromer chaperone. 42. The method of claim 39 or 40, wherein the gene therapy comprises administration of an engineered nucleic acid or a transgene encoding retromer protein VPS35, VPS26a, or VPS26b.

43. The method of any one of claims 39-42, wherein the gene therapy comprises administration of an inhibitory nucleic acid comprising sequence complementarity to a SORL1 mRNA transcript encoding the disease-associated mutation, wherein the inhibitory nucleic acid is an antisense oligonucleotide (ASO) or an interfering RNA. 44. The method of claim 43, wherein the inhibitory nucleic acid comprises a sequence that hybridizes to a sequence comprising 10 or more nucleotides that are contiguous in any one of SEQ ID NOs: 60-108. 45. The method of claim 43 or 44, wherein the ASO is an exon-skipper or promotes exon inclusion. 46. The method of claim 45, wherein the ASO hybridizes to an exon splice repressor in exon 2 or exon 19 of a SORL1 gene. 47. The method of claim 46, wherein the ASO comprises 15 or more contiguous nucleotides set forth in any one of SEQ ID NOs: 121-126. 48. The method of claim 43 or 44, wherein the interfering RNA is a small-interfering RNA, a short-hairpin RNA, or a microRNA. 49. The method of any one of claims 40-44, wherein the gene therapy comprises administration of an engineered nucleic acid comprising a polynucleotide encoding a SORL1 variant. 50. The method of claim 45, wherein the SORL1 variant comprises: (a) at least two SORL1 FnIII domains, (b) a SORL1 transmembrane domain, and (c) a SORL1 cytoplasmic tail domain. 51. The method of claim 50, wherein the SORL1 variant comprises, three, four, five, or six FnIII domains.

52. The method of claim 50 or 51, wherein at least one of the SORL1 variant FnIII domains is selected from the group consisting of FnIII-1, FnIII-2, FnIII-3, FnIII-4, FnIII-5, and FnIII-6. 53. The method of any one of claims 50-52, wherein at least one of the SORL1 variant FnIII domains comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 15-20. 54. The method of any one of claims 50-53, wherein at least one of the SORL1 variant FnIII domains comprises the amino acid sequence set forth in any one of SEQ ID NOs: 15-20. 55. The method of any one of claims 50-54, wherein the SORL1 variant transmembrane domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 22. 56. The method of any one of claims 50-55, wherein the SORL1 variant transmembrane domain comprises the amino acid sequence set forth in SEQ ID NO: 22. 57. The method of any one of claims 50-56, wherein the SORL1 variant cytoplasmic tail domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 23 or 127. 58. The method of any one of claims 50-57, wherein the SORL1 variant cytoplasmic tail domain comprises the amino acid sequence set forth in SEQ ID NO: 23 or 127. 59. The method of any one of claims 50-58, wherein at least one of the SORL1 variant FnIII domains comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 15-20, the SORL1 transmembrane domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 22, and the SORL1 cytoplasmic tail domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 23 or 127.

60. The method of any one of claims 50-59, wherein at least one of the SORL1 variant FnIII domains comprises the amino acid sequence set forth in any one of SEQ ID NOs: 15-20, the SORL1 transmembrane domain comprises the amino acid sequence set forth in SEQ ID NO: 22, and the SORL1 cytoplasmic tail domain comprises the amino acid sequence set forth in SEQ ID NO: 23 or 127. 61. The method of any one of claims 49-60, wherein the SORL1 variant further comprises an N-terminal or C-terminal tag. 62. The method of claim 61, wherein the N-terminal or C-terminal tag is hemagglutinin (HA) or is three instances of FLAG (3X-FLAG). 63. The method of claim 62, wherein the N-terminal tag is HA. 64. The method of claim 62, wherein the N-terminal tag is 3X-FLAG. 65. The method of any one of claim 49-64, wherein the SORL1 variant comprises a mutant FANSHY motif. 66. The method of any one of claim 49-64, wherein the SORL1 variant comprises a wild- type FANSHY motif. 67. The method of any one of claims 49-66, wherein the engineered nucleic acid comprises a nucleotide sequence which is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43-59. 68. The method of any one of claims 49-67, wherein the engineered nucleic acid comprises the nucleic acid sequence of any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43-59. 69. The method of any one of claims 49-68, wherein the polynucleotide encoding the SORL1 variant is operably linked to at least one regulatory sequence.

70. The method of claim 69, wherein the at least one regulatory sequence comprises a promoter. 71. The method of claim 70, wherein the promoter is a native promoter, a constitutive promoter, an inducible promoter, or a tissue-specific promoter. 72. The method of claim 70 or 71, wherein the promoter is a CAG promoter. 73. The method of any one of claims 69-72, wherein the at least one regulatory sequence comprises an enhancer which is operably linked to the polynucleotide encoding the SORL1 variant. 74. The method of any one of claims 69-71, wherein the at least one regulatory sequence comprises a poly-adenylation poly(A) signal. 75. The method of claim 74, wherein the poly(A) signal is a bovine growth hormone (bGH) poly(A) signal or a SV40 poly(A) signal. 76. The method of any one of claims 69-75, wherein the at least one regulatory sequence comprises a Woodchuck post-transcriptional regulatory element (WPRE). 77. The method of claim 76, wherein the WPRE is a WPRE3. 78. The method of any one of claims 49-77, wherein the engineered nucleic acid is provided in a transgene flanked by adeno-associated virus (AAV) inverted terminal repeats (ITRs) or long terminal repeats (LTRs). 79. The method of claim 78, wherein the transgene comprising the polynucleotide encoding SORL1 variant is provided in a vector. 80. The method of claim 79, wherein the vector is a lentiviral vector and the transgene is flanked by LTRs.

81. The method of claim 80, wherein the vector comprises from 5′ to 3′ a first LTR, an HIV- 1 psi (^) packaging sequence, a rev response element (RRE), a central polypurine tract with a downstream central termination sequence (cPPT/CTS), a CAG promoter, an Ig-kappa leader sequence, the transgene comprising the polynucleotide encoding the SORL1 variant, a Woodchuck post-transcriptional regulatory element (WPRE), and a second lentivirus LTR. 82. The method of claim 80, wherein the vector comprises from 5′ to 3′ a first LTR, an HIV- 1 psi (^) packaging sequence, a rev response element (RRE), a central polypurine tract with a downstream central termination sequence (cPPT/CTS), a CAG promoter, an Ig-kappa leader sequence, the transgene comprising the polynucleotide encoding the SORL1 variant, a Woodchuck post-transcriptional regulatory element (WPRE), a second lentivirus LTR, an M13 rev sequence, a lac operator, a lac promoter, a CAP binding site, an origin of replication (ori), an ampicillin resistance (AmpR) gene, an AmpR promoter, and a SV40 poly(A) signal. 83. The method of any one of claims 80-82, wherein the vector is provided in a lentivirus. 84. The method of claim 80, wherein the vector is an AAV vector and the transgene is flanked by ITRs. 85. The method of claim 84, wherein the vector comprises from 5′ to 3′ a first ITR, a CAG promoter, an Ig-kappa leader sequence, the transgene comprising the polynucleotide encoding the SORL1 variant, a Woodchuck post-transcriptional regulatory element 3 (WPRE3), a bovine growth hormone (bGH) polyA signal, a second AAV ITR. 86. The method of claim 84, wherein the vector comprises from 5′ to 3′ a first ITR, a CAG promoter, an Ig-kappa leader sequence, the transgene comprising the polynucleotide encoding the SORL1 variant, a Woodchuck post-transcriptional regulatory element 3 (WPRE3), a bovine growth hormone (bGH) polyA signal, a second AAV ITR, an origin of replication (ori), a neomycin/kanamycin resistance gene, an ampicillin resistance (AmpR) gene promoter, and a f1 ori. 87. The method of any one of claims 84-86, wherein the vector is provided in a recombinant adeno-associated virus.

88. The method of claim 87, wherein the recombinant adeno-associated virus is comprises at least one AAV capsid protein of serotype AAV9. 89. The method of any one of claims 40-88, wherein the gene-editing therapy comprises a Cas molecule and a guide RNA (gRNA) comprising a sequence that is complementary to a sequence in a SORL1 gene. 90. The method of claim 89, wherein the gRNA hybridizes to a sequence comprising 10 or more nucleotides that are contiguous in any one of SEQ ID NOs: 60-108 or a reverse complement thereof. 91. The method of claim 89 or 90, wherein the gRNA is a single-gRNA (sgRNA). 92. The method of any one of claims 89-91, wherein the gRNA comprises one or more chemical modifications. 93. The method of claim 92, wherein the one or more chemical modifications comprises one or more chemically modified nucleobases and/or one or more chemically modified antinucleotide linkages. 94. The method of any one of claims 89-93, wherein the Cas molecule is a Cas endonuclease, a Cas nickase, or a catalytically inactive Cas molecule. 95. The method of claim 94, wherein the Cas nickase or the catalytically inactive Cas molecule is fused to a cytosine deaminase, an adenosine deaminase, or a guanine deaminase. 96. The method of claim 95, wherein a fusion protein comprising the Cas molecule fused to the cytosine deaminase comprises a uracil glycosylase inhibitor. 97. The method of any one of claims 89-94, wherein the gene-editing therapy comprises a repair template, wherein the repair template comprises a heterologous nucleic acid flanked by a first homology that is complementary to a first sequence in a SORL1 gene and a second homology arm that is complementary to a second sequence in a SORL1 gene.

98. The method of claim 97, wherein the heterologous nucleic acid comprises a wild-type SORL1 gene sequence corresponding to the sequence encoding the disease-associated mutation in SORL1, the first sequence comprises 20 or more contiguous nucleotides in any one of SEQ ID NOs: 60-108, the second sequence comprises 20 or more contiguous nucleotides in any one of SEQ ID NOs: 60-108. 99. The method of claim 98, wherein the wild-type SORL1 sequence in the heterologous nucleic acid comprises any one of SEQ ID NOs: 61-108 or a portion thereof. 100. The method of any one of claims 89-99, wherein administering gene-editing therapy comprises administering a first polynucleotide encoding the Cas molecule and a second polynucleotide encoding the gRNA. 101. The method of claim 100, wherein administering the gene-editing therapy comprises administering a nucleic acid comprising the first polynucleotide and the second polynucleotide. 102. The method of claim 100 or 101, wherein the first polynucleotide and/or the second polynucleotide are provided in a recombinant lentivirus or a recombinant adeno-associated virus (rAAV). 103. The method of any one of claims 100-102, wherein the first polynucleotide is operably linked to at least one regulatory sequence and/or the second polynucleotide is operably linked to at least one regulatory sequence. 104. The method of any one of claims 97-99, wherein the repair template is operably linked to at least one regulatory sequence. 105. The method of any one of claims 40-104, wherein the gene-editing therapy corrects the sequence encoding the disease-associated mutation. 106. The method of any one of claims 40-105, wherein the method increases SORL1 levels and/or activity in the cell, biological sample, or subject.

107. The method of any one of claims 40-106, wherein the method increases sAPPα levels and/or activity in the cell, biological sample, or subject. 108. The method of any one of claims 40-107, wherein the method increases APP levels and/or activity at the cell surface in the cell, biological sample, or subject. 109. The method of any one of claims 40-108, wherein the method increases AMPA receptor levels and/or activity at the cell surface in the cell, biological sample, or subject. 110. The method of any one of claims 40-109, wherein the method increases VPS26a levels and/or activity, VPS26b levels and/or activity, and/or VPS35 levels and/or activity in the cell, biological sample, or subject. 111. The method of any one of claims 40-110, wherein the method decreases Aβ30, Aβ40, and/or Aβ42 levels and/or activity in the cell, biological sample, or subject. 112. A method for identifying mutations in a SORL1 gene sequence or a SORL1 amino acid sequence that are associated with abnormal endosomal trafficking comprising aligning a clustered domain or repeat sequence within a query SORL1 gene sequence or a query a SORL1 amino acid sequence against a reference sequence corresponding to a disease-associated gene variant and identifying mutations in the query SORL1 gene sequence or the query SORL1 amino acid sequence that align with a disease-associated domain position in the reference sequence, wherein the disease-associated domain position comprises homology to one or more cluster domains or repeat sequences of the query SORL1 gene sequence or the query SORL1 amino acid sequence. 113. The method of claim 112, wherein the cluster domain or repeat sequence corresponds to VPS10p domain, 10CC domain, YWTD motif, EGF domain, the CR domain, the FnIII-domain, the transmembrane, or cytoplasmic tail domain of SORL1. 114. The method of claim 112 or 113, wherein the query SORL1 gene sequence or the query SORL1 amino acid sequence is obtained from a cell, biological sample, or subject.

115. The method of any one of claims 112-114, wherein the cell or biological sample are derived from a subject suspected of having, diagnosed with, or at risk of developing a neurological disease. 116. The method of claim 115, wherein the neurological disease is a neurodegenerative disease. 117. The method of claim 116, wherein the neurodegenerative disease is selected from the group consisting of Parkinson’s Disease, Dementia, Pick’s Disease, Lewy Body Dementia, Huntington’s Disease, Alzheimer’s disease, Early-Onset Alzheimer’s disease, Late-Onset Alzheimer’s disease, and Familial Alzheimer’s disease. 118, The method of any one of claims 112-117, wherein the method comprises administering an agent to the cell, biological sample, or subject. 119. The method of any one of claims 1-118, wherein the method further comprises assaying the endosomal trafficking activity of SORL1 in the cell or biological sample. 120. The method of claim 119, wherein the method comprises assaying the endosomal trafficking activity of SORL1 in the cell or biological sample before and/or after administering the agent. 121. The method of any one of claims 1-120, wherein the method further comprises assaying the activity or protein level of sAPPα, sAPPβ, aggregated tau, phosphorylated tau, APP, AMPA receptor, Aβ30, Aβ40, Aβ42, VPS26a, VPs26b, and/or VPS35 in the cell or biological sample. 122. The method of claim 121, wherein the method comprises assaying the activity or protein level of sAPPα, sAPPβ, aggregated tau, phosphorylated tau, APP, AMPA receptor, Aβ30, Aβ40, Aβ42, VPS26a, VPs26b, and/or VPS35 in the cell or biological sample before and/or after administering the agent. 123. An agent or a plurality thereof for use in a method of comprising administering the agent or the plurality thereof to the subject, wherein the agent comprises a small molecule therapy, a biologic, a gene therapy, or a gene-editing therapy and the plurality thereof comprises any combination of the small molecule therapy, the gene therapy or the gene-editing therapy, wherein the subject is characterized as having or is suspected of having a disease-associated mutation in SORL1 which is encoded by a SORL1 gene sequence. 124. The agent or the plurality thereof for use of claim 123, wherein the disease-associated mutation occurs in VPS10p domain, 10CC domain, YWTD domain, EGF domain, the CR domain, the FnIII domain, the transmembrane domain, or the cytoplasmic tail domain of SORL1. 125. The agent or the plurality thereof for use of claim 123 or 124, wherein the disease- associated mutation comprises a pathogenic mutation as set forth in Table 13. 126. The agent or the plurality thereof for use of any one of claims 123-125, wherein the disease-associated mutation does not occur at a position in SORL1 selected from the group consisting of 101, 115, 140, 146, 191, 205, 269, 270, 303, 332, 371, 391, 416, 446, 459, 474, 480, 508, 528, 552, 560, 577, 581, 583, 636, 639, 642, 656, 674, 679, 695, 729, 734, 743744, 762, 786, 807, 818, 833, 852, 870, 884, 885, 942, 961, 980, 1000, 1002, 1074, 1080, 1081, 1084, 1094, 1099, 1113, 1116, 1156, 1167, 1181, 1187, 1207, 1222, 1222, 1246, 1258, 1276, 1276, 1279, 1291, 1304, 1310, 1311, 1322, 1379, 1383, 1392, 1409, 1435, 1442, 1447, 1454, 1470, 1481, 1483, 1490, 1501, 1504, 1522, 1526, 1535, 1543, 1548, 1563, 1584, 1594, 1620, 1657, 1668, 1675, 1680, 1697, 1697, 1729, 1732, 1747, 1809, 1813, 1816, 1866, 1873, 1885, 1895, 1910, 1958, 1967, 2000, 2007, 2014, 2038, 2065, 2079, 2083, 2090, 2097, 2106, 2134, 2147, 2158, and 2160. 127. The agent or the plurality thereof for use of any one of claims 123-126, wherein the disease-associated mutation occurs at any one of positions: (a) R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹, Y³⁵⁰,

S²³⁴, D²³⁶, G²³⁸, T²⁴⁰, W²⁴¹, S²⁸⁰, D²⁸², S²⁸⁶, S³²⁹, S³⁷⁵, G³⁷⁹, F³⁸², T⁴⁴³, D⁴⁴⁵, G⁴⁴⁷, T⁴⁴⁹, W⁴⁵⁰, S⁵²³, G⁵²⁷, W⁵³⁰, S⁵⁶⁴, N⁵⁶⁶, G⁵⁶⁸, T⁵⁷⁰, W⁵⁷¹, C⁴⁶⁷, or C⁴⁷³ in the VPS10p domain; (b) C⁶²⁵, C⁶⁴³, C⁶⁶⁰, C⁶⁷⁵, C⁶⁷⁷, C⁶⁸⁴, C⁶⁹⁹, C⁷¹⁶, C⁷³⁶, and C⁷⁵² in the 10CC domain; (c) L⁷⁹³, F⁷⁹⁵, L⁸⁰², L⁸³⁷, F⁸³⁹, L⁸⁴⁶, L⁸⁸¹, L⁸⁸³, M⁸⁹⁰, I⁹²⁶, V⁹²⁸, I⁹³³, I⁹⁶⁶, V⁹⁶⁸, I⁹⁷³, M¹⁰⁰⁷, I¹⁰⁰⁹,

I⁹⁴³, I⁹⁸³, R⁷⁷¹, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, G⁷⁷⁷, G⁸¹⁹, G⁸⁶³, G⁹⁰⁹, G⁹⁵⁰, G⁹⁹¹, R⁸⁶⁶, R⁹⁵³, C⁸⁰¹, or C⁸¹⁶ in the YWTD doman; (d) C¹⁰²¹, C¹⁰²⁶, C¹⁰³⁰, C¹⁰⁴⁰, C¹⁰⁴², C¹⁰⁵⁸, C¹⁰⁶⁰, and C¹⁰⁷¹ in the EGF domain; (e) S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹²⁹⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁴⁰, G¹⁴⁹³, G¹⁵³⁶, D¹⁰⁹⁸, D¹¹⁰², D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸², D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, D¹²⁶⁷, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁴⁹, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁴⁴, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁵³, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁰, C¹⁵⁴⁹, D¹¹⁰⁵, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴, D¹³⁵², D¹³⁹⁶, D¹⁴⁴⁶, D¹⁴⁹⁹, or D¹⁵⁴² in the CR domain; (f) L¹⁵⁶¹, W¹⁵⁶³, L¹⁶⁵⁹, L¹⁶⁶¹, I¹⁷⁵³, I¹⁷⁵⁵, L¹⁸⁴⁸, A¹⁸⁵⁰, L¹⁹³⁸, V¹⁹⁴⁰, L²⁰³⁰, I²⁰³², V¹⁵⁷¹, L¹⁵⁷³, I¹⁶⁶⁹, L¹⁷⁶³, F¹⁷⁶⁵, V¹⁸⁵⁸, C¹⁸⁶⁰, V¹⁹⁴⁸, I¹⁹⁵⁰, V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², W¹⁷³⁵, P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, P¹⁹⁵⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹,

(g) F²¹⁷², A²¹⁷³, N²¹⁷⁴, S²¹⁷⁵, H²¹⁷⁶, Y²¹⁷⁷, D²¹⁹⁰, D²¹⁹¹, L²¹⁹², G²¹⁹³, E²¹⁹⁴, D²¹⁹⁵, D²¹⁹⁶, E²¹⁹⁷,

domain; (h) or any combination thereof.

128. The agent or the plurality thereof for use of any one of claims 123-127, wherein the disease-associated mutation occurs at any one of positions: (a) R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹, F⁴¹⁴, L⁴⁹⁵, Y⁵³⁹, Y⁵⁴⁰, V⁵⁸³, Y⁵⁸⁴, I¹¹⁷, V¹¹⁸, A¹¹⁹, Y¹⁷⁷, I¹⁷⁸, F¹⁷⁹, L²¹⁸, L²¹⁹, L²²⁰, I²⁶⁴, Y²⁶⁵, I²⁶⁶, Y³⁰⁶, F³⁰⁸, V³⁵⁹, F³⁶⁰, V³⁶¹, Y⁴²⁴, I⁴²⁵, A⁴²⁶,I⁵⁰⁴, I⁵⁰⁵, A⁵⁰⁶, I⁵⁴⁸, I⁵⁴⁹, V⁵⁹⁶, F⁵⁹⁷, V¹³⁵, Y¹³⁶, V¹³⁷, L¹⁸⁷, W¹⁸⁸, I¹⁸⁹, L²³¹, W²³², V²⁷⁷, F²⁷⁸, L³²⁶, W³²⁷, V³²⁸, L³⁷², Y³⁷³, I³⁷⁴, V⁴⁴¹, I⁴⁴², V⁵²⁰, Y⁵²¹, I⁵²², L⁵⁶¹, Y⁵⁶³, L⁶¹³, V⁶¹⁵, S¹³⁸, G¹⁴², S¹⁴⁴, F¹⁴⁵, T¹⁹⁰, D¹⁹², T¹⁹⁶, S²³⁴, D²³⁶, G²³⁸, T²⁴⁰, W²⁴¹, S²⁸⁰, D²⁸², S²⁸⁶, S³²⁹, S³⁷⁵, G³⁷⁹, F³⁸², T⁴⁴³, D⁴⁴⁵, G⁴⁴⁷, T⁴⁴⁹, W⁴⁵⁰, S⁵²³,

C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁹, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴, D¹³⁵², D¹³⁹⁶, D¹⁴⁴⁶, D¹⁴⁹⁹, or D¹⁵⁴² in the CR domain; (f) L¹⁵⁶¹, W¹⁵⁶³, L¹⁶⁵⁹, L¹⁶⁶¹, I¹⁷⁵³, I¹⁷⁵⁵, L¹⁸⁴⁸, A¹⁸⁵⁰, L¹⁹³⁸, V¹⁹⁴⁰, L²⁰³⁰, I²⁰³², V¹⁵⁷¹, L¹⁵⁷³, I¹⁶⁶⁹, L¹⁷⁶³, F¹⁷⁶⁵, V¹⁸⁵⁸, C¹⁸⁶⁰, V¹⁹⁴⁸, I¹⁹⁵⁰, V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², W¹⁷³⁵, P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹, P¹⁹⁹⁸,

(h) any combination thereof. 129. The agent or the plurality thereof for use of any one of claims 123-128, wherein the neurological disease is a neurodegenerative disease, optionally wherein the neurodegenerative disease is selected from the group consisting of Parkinson’s Disease, Dementia, Pick’s Disease, Lewy Body Dementia, Huntington’s Disease, Alzheimer’s disease, Early-Onset Alzheimer’s disease, Late-Onset Alzheimer’s disease, and Familial Alzheimer’s disease. 130. The agent or the plurality thereof for use of any one of claims 123-129, wherein the EGF domain is deleted. 131. The agent or the plurality thereof for use of any one of claims 123-129, wherein the disease-associated mutation comprises an insertion of a cysteine residue in the EGF domain. 132. The agent or the plurality thereof for use of any one of claims 123-131, wherein the disease associated mutation confers a moderate risk or a high risk of developing a neurological disease. 133. The agent or the plurality thereof for use of any one of claims 123-132, wherein the small molecule therapy comprises administration of an aminoguanidine hydrazone or a retromer chaperone. 134. The agent or the plurality thereof for use of any one of claims 123-133, wherein the gene therapy comprises administration of an engineered nucleic acid or a transgene encoding retromer protein VPS35, VPS26a, or VPS26b.

135. The agent or the plurality thereof for use of any one of claims 123-134, wherein the gene therapy comprises administration of an inhibitory nucleic acid comprising sequence complementarity to a SORL1 mRNA transcript encoding the disease-associated mutation, wherein the inhibitory nucleic acid is an antisense oligonucleotide (ASO) or an interfering RNA. 136. The agent or the plurality thereof for use of any one of claims 123-135, wherein the inhibitory nucleic acid comprises a sequence that hybridizes to a sequence comprising 10 or more nucleotides that are contiguous in any one of SEQ ID NOs: 60-108. 137. The agent or the plurality thereof for use of any one of claims 123-136, wherein the ASO is an exon-skipper or promotes exon inclusion. 138. The agent or the plurality thereof for use of claim 137, wherein the ASO hybridizes to an exon splice repressor in exon 2 or exon 19 of a SORL1 gene. 139. The agent or the plurality thereof for use of claim 138, wherein the ASO comprises 15 or more contiguous nucleotides set forth in any one of SEQ ID NOs: 121-126. 140. The agent or the plurality thereof for use of claim 135 or 136, wherein the interfering RNA is a small-interfering RNA, a short-hairpin RNA, or a microRNA. 141. The agent or the plurality thereof for use of any one of claims 123-140, wherein the gene therapy comprises administration of an engineered nucleic acid comprising a polynucleotide encoding a SORL1 variant. 142. The agent or the plurality thereof for use of claim 141, wherein the SORL1 variant comprises: (a) at least two SORL1 FnIII domains, (b) a SORL1 transmembrane domain, and (c) a SORL1 cytoplasmic tail domain. 143. The agent or the plurality thereof for use of claim 141 or 142, wherein the SORL1 variant comprises, three, four, five, or six FnIII domains.

144. The agent or the plurality thereof for use of any one of claims 141-143, wherein at least one of the SORL1 variant FnIII domains comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 15-20, the SORL1 transmembrane domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 22, and/or the SORL1 cytoplasmic tail domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 23 or 127. 145. The agent or the plurality thereof for use of any one of claims 141-144, wherein at least one of the SORL1 variant FnIII domains comprises the amino acid sequence set forth in any one of SEQ ID NOs: 15-20, the SORL1 transmembrane domain comprises the amino acid sequence set forth in SEQ ID NO: 22, and the SORL1 cytoplasmic tail domain comprises the amino acid sequence set forth in SEQ ID NO: 23 or 127. 146. The agent or the plurality thereof for use of any one of claims 141-145, wherein the engineered nucleic acid comprises a nucleotide sequence which is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43-59. 147. The agent or the plurality thereof for use of any one of claims 141-146, wherein the engineered nucleic acid comprises the nucleic acid sequence of any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43-59. 148. The agent or the plurality thereof for use of any one of claims 141-147, wherein the polynucleotide encoding the SORL1 variant is operably linked to at least one regulatory sequence. 149. The agent or the plurality thereof for use of claim 148, wherein the at least one regulatory sequence comprises a promoter.

150. The agent or the plurality thereof for use of any one of claims 141-149, wherein the engineered nucleic acid is provided in a transgene flanked by adeno-associated virus (AAV) inverted terminal repeats (ITRs) or long terminal repeats (LTRs). 151. The agent or the plurality thereof for use of any one of claims 141-150, wherein the vector is provided in a lentivirus or a recombinant adeno-associated virus. 152. The agent or the plurality thereof for use of any one of claims 123-151, wherein the gene-editing therapy comprises a Cas molecule and a guide RNA (gRNA) comprising a sequence that is complementary to a sequence in a SORL1 gene. 153. The agent or the plurality thereof for use of claim 152, wherein the gRNA hybridizes to a sequence comprising 10 or more nucleotides that are contiguous in any one of SEQ ID NOs: 60- 108 or a reverse complement thereof. 154. The agent or the plurality thereof for use of claim 152 or 153, wherein the gRNA is a single-gRNA (sgRNA) and/or wherein the gRNA comprises one or more chemical modifications. 155. The agent or the plurality thereof for use of any one of claims 152-154, wherein the Cas molecule is a Cas endonuclease, a Cas nickase, or a catalytically inactive Cas molecule. 156. The agent or the plurality thereof for use of claim 155, wherein the Cas nickase or the catalytically inactive Cas molecule is fused to a cytosine deaminase, an adenosine deaminase, or a guanine deaminase. 157. The agent or the plurality thereof for use of claim 156, wherein a fusion protein comprising the Cas molecule fused to the cytosine deaminase comprises a uracil glycosylase inhibitor. 158. The agent or the plurality thereof for use of any one of claims 152-155, wherein the gene-editing therapy comprises a repair template, wherein the repair template comprises a heterologous nucleic acid flanked by a first homology that is complementary to a first sequence in a SORL1 gene and a second homology arm that is complementary to a second sequence in a SORL1 gene. 159. The agent or the plurality thereof for use of claim 158, wherein the heterologous nucleic acid comprises a wild-type SORL1 gene sequence corresponding to the sequence encoding the disease-associated mutation in SORL1, the first sequence comprises 20 or more contiguous nucleotides in any one of SEQ ID NOs: 60-108, the second sequence comprises 20 or more contiguous nucleotides in any one of SEQ ID NOs: 60-108. 160. The agent or the plurality thereof for use of claim 159, wherein the wild-type SORL1 sequence in the heterologous nucleic acid comprises any one of SEQ ID NOs: 61-108 or a portion thereof. 161. The agent or the plurality thereof for use of any one of claims 152-160, wherein administering gene-editing therapy comprises administering a first polynucleotide encoding the Cas molecule and a second polynucleotide encoding the gRNA. 162. The agent or the plurality thereof for use of claim 161, wherein administering the gene- editing therapy comprises administering a nucleic acid comprising the first polynucleotide and the second polynucleotide. 163. The agent or the plurality thereof for use of claim 161 or 162, wherein the first polynucleotide and/or the second polynucleotide are provided in a recombinant lentivirus or a recombinant adeno-associated virus (rAAV). 164. The agent or the plurality thereof for use of any one of claims 161-163, wherein the first polynucleotide is operably linked to at least one regulatory sequence and/or the second polynucleotide is operably linked to at least one regulatory sequence. 165. The agent or the plurality thereof for use of any one of claims 158-160, wherein the repair template is operably linked to at least one regulatory sequence. 166. The agent or the plurality thereof for use of any one of claims 123-165, wherein the gene-editing therapy corrects the sequence encoding the disease-associated mutation.

167. Use of an agent or a plurality thereof in the manufacture of a medicament for the treatment of a subject characterized as having or suspected of having a disease-associated mutation in SORL1 which is encoded by a SORL1 gene sequence, wherein the agent comprises a small molecule therapy, a biologic, a gene therapy, or a gene-editing therapy and the plurality thereof comprises any combination of the small molecule therapy, the biologic, the gene therapy or the gene-editing therapy. 168. The use of claim 167, wherein the disease-associated mutation occurs in VPS10p domain, 10CC domain, YWTD domain, EGF domain, the CR domain, the FnIII domain, the transmembrane domain, or the cytoplasmic tail domain of SORL1. 169. The use of claim 167 or 168, wherein the disease-associated mutation comprises a pathogenic mutation as set forth in Table 13. 170. The use of any one of claims 167-169, wherein the disease-associated mutation does not occur at a position in SORL1 selected from the group consisting of 101, 115, 140, 146, 191, 205, 269, 270, 303, 332, 371, 391, 416, 446, 459, 474, 480, 508, 528, 552, 560, 577, 581, 583, 636, 639, 642, 656, 674, 679, 695, 729, 734, 743744, 762, 786, 807, 818, 833, 852, 870, 884, 885, 942, 961, 980, 1000, 1002, 1074, 1080, 1081, 1084, 1094, 1099, 1113, 1116, 1156, 1167, 1181, 1187, 1207, 1222, 1222, 1246, 1258, 1276, 1276, 1279, 1291, 1304, 1310, 1311, 1322, 1379, 1383, 1392, 1409, 1435, 1442, 1447, 1454, 1470, 1481, 1483, 1490, 1501, 1504, 1522, 1526, 1535, 1543, 1548, 1563, 1584, 1594, 1620, 1657, 1668, 1675, 1680, 1697, 1697, 1729, 1732, 1747, 1809, 1813, 1816, 1866, 1873, 1885, 1895, 1910, 1958, 1967, 2000, 2007, 2014, 2038, 2065, 2079, 2083, 2090, 2097, 2106, 2134, 2147, 2158, and 2160. 171. The use of any one of claims 167-170, wherein the disease-associated mutation occurs at any one of positions: (a) R⁶³, G⁶⁴, D⁶⁵, R⁷⁸, R⁷⁹, K⁸⁰, R⁸¹, V¹⁰⁶, V¹⁰⁷, F¹⁶7, Y¹⁶⁸, L²⁰⁹, L²¹⁰, F²⁵¹, F³⁰⁰, Y³⁴⁹, Y³⁵⁰,

S²³⁴, D²³⁶, G²³⁸, T²⁴⁰, W²⁴¹, S²⁸⁰, D²⁸², S²⁸⁶, S³²⁹, S³⁷⁵, G³⁷⁹, F³⁸², T⁴⁴³, D⁴⁴⁵, G⁴⁴⁷, T⁴⁴⁹, W⁴⁵⁰, S⁵²³, G⁵²⁷, W⁵³⁰, S⁵⁶⁴, N⁵⁶⁶, G⁵⁶⁸, T⁵⁷⁰, W⁵⁷¹, C⁴⁶⁷, or C⁴⁷³ in the VPS10p domain; (b) C⁶²⁵, C⁶⁴³, C⁶⁶⁰, C⁶⁷⁵, C⁶⁷⁷, C⁶⁸⁴, C⁶⁹⁹, C⁷¹⁶, C⁷³⁶, and C⁷⁵² in the 10CC domain; (c) L⁷⁹³, F⁷⁹⁵, L⁸⁰², L⁸³⁷, F⁸³⁹, L⁸⁴⁶, L⁸⁸¹, L⁸⁸³, M⁸⁹⁰, I⁹²⁶, V⁹²⁸, I⁹³³, I⁹⁶⁶, V⁹⁶⁸, I⁹⁷³, M¹⁰⁰⁷, I¹⁰⁰⁹, L⁷⁸², V⁸²⁵, I⁸²⁶, I⁸⁶⁹, V⁸⁷⁰, L⁹¹⁵, V⁹¹⁶, I⁹⁵⁶, L⁹⁵⁷, I⁹⁹⁶, L⁹⁹⁷, L⁷⁸⁷, L⁸³¹, L⁸⁷⁵, V⁹²⁰, L⁹⁶⁰, L¹⁰⁰¹, R⁸⁷⁹, W⁸⁹⁵, N⁹²⁴, Y⁹⁶⁴, W⁹⁷⁸, Y⁸⁰³, W⁸⁰⁴, S⁸⁰⁵, D⁸⁰⁶, Y⁸⁴⁷, W⁸⁴⁸, D⁸⁵⁰, F⁸⁹¹, W⁸⁹², T⁸⁹³, D⁸⁹⁴, Y⁹³⁴, W⁹³⁵, T⁹³⁶, D⁹³⁷, Y⁹⁷⁴, W⁹⁷⁵, D⁹⁷⁷, P⁸⁷⁸, P⁹²³, P⁹⁶³, D⁷⁹⁴, D⁹²⁹, I⁷⁶⁹, I⁸¹², I⁸⁵⁶, I⁹⁰², I⁹⁴³, I⁹⁸³, R⁷⁷¹, R⁸¹⁴, R⁹⁰⁴, R⁹⁴⁵, R⁹⁸⁵, G⁷⁷⁷, G⁸¹⁹, G⁸⁶³, G⁹⁰⁹, G⁹⁵⁰, G⁹⁹¹, R⁸⁶⁶, R⁹⁵³, C⁸⁰¹, or C⁸¹⁶ in the YWTD doman; (d) C¹⁰²¹, C¹⁰²⁶, C¹⁰³⁰, C¹⁰⁴⁰, C¹⁰⁴², C¹⁰⁵⁸, C¹⁰⁶⁰, and C¹⁰⁷¹ in the EGF domain; (e) S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹²⁹⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁴⁰, G¹⁴⁹³, G¹⁵³⁶, D¹⁰⁹⁸, D¹¹⁰², D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸², D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹, D¹²⁶⁷, E¹²⁶⁸, D¹²⁹⁷, Q¹³⁰¹, D¹³⁰⁷, E¹³⁰⁸, D¹³⁴⁵, D¹³⁴⁹, D¹³⁵⁵, E¹³⁵⁶, D¹³⁸⁹, D¹³⁹³, D¹³⁹⁹, E¹⁴⁰⁰, D¹⁴³⁹, D¹⁴⁴³, D¹⁴⁴⁹, E¹⁴⁵⁰, D¹⁴⁹², D¹⁴⁹⁶, D¹⁵⁰², E¹⁵⁰³, D¹⁵³⁵, D¹⁵³⁹, D¹⁵⁴⁵, E¹⁵⁴⁶, C¹⁰⁷⁸, C¹⁰⁸⁵, C¹⁰⁹⁰, C¹⁰⁹⁷, C¹¹⁰³, C¹¹¹², C¹¹¹⁷, C¹¹²⁵, C¹¹³¹, C¹¹³⁸, C¹¹⁴⁴, C¹¹⁵³, C¹¹⁵⁸, C¹¹⁶⁵, C¹¹⁷⁰, C¹¹⁷⁷, C¹¹⁸³, C¹¹⁹², C¹¹⁹⁹, C¹²⁰⁶, C¹²¹¹, C¹²¹⁸, C¹²²⁴, C¹²³⁵, C¹²³⁹, C¹²⁴⁴, C¹²⁴⁹, C¹²⁵⁶, C¹²⁶², C¹²⁷¹, C¹²⁷⁵, C¹²⁸³, C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁴⁴, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁵³, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁰, C¹⁵⁴⁹, D¹¹⁰⁵, D¹¹⁴⁶, D¹¹⁸⁵,

I¹⁶⁶⁹, L¹⁷⁶³, F¹⁷⁶⁵, V¹⁸⁵⁸, C¹⁸⁶⁰, V¹⁹⁴⁸, I¹⁹⁵⁰, V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², W¹⁷³⁵, P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, P¹⁹⁵⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹,

(g) F²¹⁷², A²¹⁷³, N²¹⁷⁴, S²¹⁷⁵, H²¹⁷⁶, Y²¹⁷⁷, D²¹⁹⁰, D²¹⁹¹, L²¹⁹², G²¹⁹³, E²¹⁹⁴, D²¹⁹⁵, D²¹⁹⁶, E²¹⁹⁷,

tail domain; (h) or any combination thereof. 172. The use of any one of claims 167-171, wherein the disease-associated mutation occurs at any one of positions:

YWTD domain; (d) C¹⁰²¹, C¹⁰²⁶, C¹⁰³⁰, C¹⁰⁴⁰, C¹⁰⁴², C¹⁰⁵⁸, C¹⁰⁶⁰, or C¹⁰⁷¹ in the EGF domain; (e) S¹¹⁰⁷, S¹¹⁴⁸, S¹¹⁸⁷, S¹²²⁸, S¹²⁶⁶, S¹³⁰⁶, S¹³⁵⁴, S¹³⁹⁸, S¹⁴⁴⁸, S¹⁵⁴⁴, W¹⁰⁹⁵, D¹¹⁰⁰, Y¹¹³⁶, E¹¹⁴¹, W¹¹⁷⁵, D¹¹⁸⁰, W¹²¹⁶, D¹²²¹, K¹²⁵⁴, L¹²⁵⁹, M¹²⁹⁴, I¹²⁹⁹, W¹³⁴², M¹³⁴⁷, W¹³⁸⁶, E¹³⁹¹, W¹⁴³⁶, Y¹⁴⁴¹, K¹⁴⁸⁹, H¹⁴⁹⁴, E¹⁵³², F¹⁵³⁷, Y¹⁰⁸³, I¹⁰⁹¹, F¹¹²³, I¹¹³², Y¹¹⁶³, I¹¹⁷¹, F¹²⁰⁴, I¹²¹², F¹²⁴², I¹²⁵⁰, F¹²⁸¹, L¹²⁹⁰, F¹³³⁰, I¹³³⁸, F¹³⁷⁴, I¹³⁸², Y¹⁴²⁴, V¹⁴³², F¹⁴⁷⁶, I¹⁴⁸⁵, F¹⁵¹⁹, I¹⁵²⁸, G¹⁰⁸⁸, G¹¹²⁹, G¹¹⁶⁸, G¹¹⁷⁹, G¹²⁰⁹, G¹²²⁰, G¹²⁴⁷, G¹²⁵⁸, G¹³³⁵, G¹³⁴⁶, G¹³⁷⁹, G¹⁴²⁹, G¹⁴⁹³, G¹⁵³⁶, D¹⁰⁹⁸, D¹¹⁰⁸, E¹¹⁰⁹, D¹¹³⁹, D¹¹⁴³, D¹¹⁴⁹, E¹¹⁵⁰, D¹¹⁷⁸, D¹¹⁸⁸, E¹¹⁸⁹, D¹²¹⁹, D¹²²³, D¹²²⁹, E¹²³⁰, D¹²⁵⁷, D¹²⁶¹,

C¹²⁸⁹, C¹²⁹⁶, C¹³⁰², C¹³¹⁵, C¹³²⁵, C¹³³², C¹³³⁷, C¹³⁵⁰, C¹³⁵⁹, C¹³⁶⁸, C¹³⁷⁶, C¹³⁸¹, C¹³⁸⁸, C¹³⁹⁴, C¹⁴⁰³, C¹⁴¹⁹, C¹⁴²⁶, C¹⁴³¹, C¹⁴³⁸, C¹⁴⁴⁴, C¹⁴⁷¹, C¹⁴⁷⁸, C¹⁴⁸⁴, C¹⁴⁹¹, C¹⁴⁹⁷, C¹⁵⁰⁶, C¹⁵¹⁴, C¹⁵²¹, C¹⁵²⁷, C¹⁵³⁴, C¹⁵⁴⁹, D¹¹⁴⁶, D¹¹⁸⁵, D¹²²⁶, D¹²⁶⁴, D¹³⁰⁴, D¹³⁵², D¹³⁹⁶, D¹⁴⁴⁶, D¹⁴⁹⁹, or D¹⁵⁴² in the CR domain; (f) L¹⁵⁶¹, W¹⁵⁶³, L¹⁶⁵⁹, L¹⁶⁶¹, I¹⁷⁵³, I¹⁷⁵⁵, L¹⁸⁴⁸, A¹⁸⁵⁰, L¹⁹³⁸, V¹⁹⁴⁰, L²⁰³⁰, I²⁰³², V¹⁵⁷¹, L¹⁵⁷³, I¹⁶⁶⁹, L¹⁷⁶³, F¹⁷⁶⁵, V¹⁸⁵⁸, C¹⁸⁶⁰, V¹⁹⁴⁸, I¹⁹⁵⁰, V²⁰³⁹, L²⁰⁴¹, V¹⁵⁹⁰, Y¹⁵⁹², V¹⁶⁸⁸, Y¹⁶⁹⁰, V¹⁷⁸⁰, L¹⁷⁸², I¹⁸⁷², Y¹⁸⁷⁴, V¹⁹⁶⁷, V¹⁹⁶⁹, I²⁰⁶¹, M²⁰⁶³, G¹⁷³⁰, G¹⁸²⁷, G²¹⁰⁴, V¹⁶²⁵, V¹⁶²⁷, V¹⁶²⁹, V¹⁷²¹, V¹⁷²³, A¹⁷²⁵, I¹⁸¹⁸, A¹⁸²⁰, A¹⁸²², F¹⁹⁰⁷, V¹⁹⁰⁹, V¹⁹¹¹, I²⁰⁰⁴, V²⁰⁰⁶, L²⁰⁰⁸, F²⁰⁹⁵, V²⁰⁹⁷, A²⁰⁹⁹, I¹⁶¹⁴, I¹⁷¹⁰, V¹⁸⁰⁷, V¹⁸⁹⁷, V¹⁸⁹⁹, Y¹⁹⁹¹, L¹⁹⁹³, F²⁰⁸², I²⁰⁸⁴, R¹⁵⁹³, W¹⁶⁰⁰, K¹⁶²⁶, H¹⁶³⁶, E¹⁶⁹⁰, W¹⁶⁹⁹, R¹⁷²², W¹⁷³⁵, P¹⁶⁵⁴, P¹⁷⁴⁹, P¹⁷⁵⁰, P¹⁸⁴³, P¹⁸⁴⁴, P¹⁹³⁴, P¹⁹³⁵, P²⁰²⁷, W¹⁵⁷⁵, W¹⁶⁷³, L¹⁷⁶⁷, W¹⁸⁶², W¹⁹⁵², W²⁰⁴³, P¹⁵⁷⁸, P¹⁶⁷⁶, P¹⁸⁶⁵, Y¹⁵⁸⁸, Y¹⁶⁸⁶, Y¹⁷⁷⁸, Y¹⁸⁷⁰, Y¹⁹⁶⁵, Y²⁰⁵⁹, L¹⁶¹⁷, L¹⁷¹³, L¹⁸¹⁰, L¹⁹⁹⁶, L²⁰⁸⁷, G¹⁶⁸¹, G¹⁷³², G¹⁹¹⁷, Y¹⁶²³, Y¹⁷¹⁹, Y¹⁸¹⁶, Y¹⁹⁰⁵, Y²⁰⁰², Y²⁰⁹³, P¹⁶¹⁹, P¹⁹⁹⁸,

(h) any combination thereof. 173. The use of any one of claims 167-172, wherein the neurological disease is a neurodegenerative disease, optionally wherein the neurodegenerative disease is selected from the group consisting of Parkinson’s Disease, Dementia, Pick’s Disease, Lewy Body Dementia, Huntington’s Disease, Alzheimer’s disease, Early-Onset Alzheimer’s disease, Late-Onset Alzheimer’s disease, and Familial Alzheimer’s disease. 174. The use of any one of claims 167-173, wherein the EGF domain is deleted. 175. The use of any one of claims 167-173, wherein the disease-associated mutation comprises an insertion of a cysteine residue in the EGF domain. 176. The use of any one of claims 167-175, wherein the disease associated mutation confers a moderate risk or a high risk of developing a neurological disease. 177. The use of any one of claims 167-176, wherein the small molecule therapy comprises administration of an aminoguanidine hydrazone or a retromer chaperone.

178. The use of any one of claims 167-177, wherein the gene therapy comprises administration of an engineered nucleic acid or a transgene encoding retromer protein VPS35, VPS26a, or VPS26b. 179. The use of any one of claims 167-178, wherein the gene therapy comprises administration of an inhibitory nucleic acid comprising sequence complementarity to a SORL1 mRNA transcript encoding the disease-associated mutation, wherein the inhibitory nucleic acid is an antisense oligonucleotide (ASO) or an interfering RNA. 180. The use of any one of claims 167-179, wherein the inhibitory nucleic acid comprises a sequence that hybridizes to a sequence comprising 10 or more nucleotides that are contiguous in any one of SEQ ID NOs: 60-108. 181. The use of claim 179 or 180, wherein the ASO is an exon-skipper or promotes exon inclusion. 182. The use of claim 181, wherein the ASO hybridizes to an exon splice repressor in exon 2 or exon 19 of a SORL1 gene. 183. The use of claim 182, wherein the ASO comprises 15 or more contiguous nucleotides set forth in any one of SEQ ID NOs: 121-126. 184. The use of claim 179 or 180, wherein the interfering RNA is a small-interfering RNA, a short-hairpin RNA, or a microRNA. 185. The use of any one of claims 167-184, wherein the gene therapy comprises administration of an engineered nucleic acid comprising a polynucleotide encoding a SORL1 variant. 186. The use of claim 185, wherein the SORL1 variant comprises: (a) at least two SORL1 FnIII domains, (b) a SORL1 transmembrane domain, and (c) a SORL1 cytoplasmic tail domain.

187. The use of claim 185 or 186, wherein the SORL1 variant comprises, three, four, five, or six FnIII domains. 188. The use of any one of claims 185-187, wherein at least one of the SORL1 variant FnIII domains comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 15-20, the SORL1 transmembrane domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 22, and/or the SORL1 cytoplasmic tail domain comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 23 or 127. 189. The use of any one of claims 185-188, wherein at least one of the SORL1 variant FnIII domains comprises the amino acid sequence set forth in any one of SEQ ID NOs: 15-20, the SORL1 transmembrane domain comprises the amino acid sequence set forth in SEQ ID NO: 22, and the SORL1 cytoplasmic tail domain comprises the amino acid sequence set forth in SEQ ID NO: 23 or 127. 190. The use of any one of claims 185-189, wherein the engineered nucleic acid comprises a nucleotide sequence which is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% identical to any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43-59. 191. The use of any one of claims 185-190, wherein the engineered nucleic acid comprises the nucleic acid sequence of any one of SEQ ID NOs: 1-12, 25-26, 29-32, 35-37, or 43-59. 192. The use of any one of claims 185-191, wherein the polynucleotide encoding the SORL1 variant is operably linked to at least one regulatory sequence. 193. The use of claim 192, wherein the at least one regulatory sequence comprises a promoter. 194. The use of any one of claims 185-193, wherein the engineered nucleic acid is provided in a transgene flanked by adeno-associated virus (AAV) inverted terminal repeats (ITRs) or long terminal repeats (LTRs).

195. The use of any one of claims 185-194, wherein the vector is provided in a lentivirus or a recombinant adeno-associated virus. 196. The use of any one of claims 167-195, wherein the gene-editing therapy comprises a Cas molecule and a guide RNA (gRNA) comprising a sequence that is complementary to a sequence in a SORL1 gene. 197. The use of claim 196, wherein the gRNA hybridizes to a sequence comprising 10 or more nucleotides that are contiguous in any one of SEQ ID NOs: 60-108 or a reverse complement thereof. 198. The use of claim 196 or 197, wherein the gRNA is a single-gRNA (sgRNA) and/or wherein the gRNA comprises one or more chemical modifications. 199. The use of any one of claims 196-198, wherein the Cas molecule is a Cas endonuclease, a Cas nickase, or a catalytically inactive Cas molecule. 200. The use of claim 199, wherein the Cas nickase or the catalytically inactive Cas molecule is fused to a cytosine deaminase, an adenosine deaminase, or a guanine deaminase. 201. The use of claim 200, wherein a fusion protein comprising the Cas molecule fused to the cytosine deaminase comprises a uracil glycosylase inhibitor. 202. The use of any one of claims 196-201, wherein the gene-editing therapy comprises a repair template, wherein the repair template comprises a heterologous nucleic acid flanked by a first homology that is complementary to a first sequence in a SORL1 gene and a second homology arm that is complementary to a second sequence in a SORL1 gene. 203. The use of claim 202, wherein the heterologous nucleic acid comprises a wild-type SORL1 gene sequence corresponding to the sequence encoding the disease-associated mutation in SORL1, the first sequence comprises 20 or more contiguous nucleotides in any one of SEQ ID NOs: 60-108, the second sequence comprises 20 or more contiguous nucleotides in any one of SEQ ID NOs: 60-108.

204. The use of claim 203, wherein the wild-type SORL1 sequence in the heterologous nucleic acid comprises any one of SEQ ID NOs: 61-108 or a portion thereof. 205. The use of any one of claims 196-204, wherein administering gene-editing therapy comprises administering a first polynucleotide encoding the Cas molecule and a second polynucleotide encoding the gRNA. 206. The use of claim 205, wherein administering the gene-editing therapy comprises administering a nucleic acid comprising the first polynucleotide and the second polynucleotide. 207. The use of claim 205 or 206, wherein the first polynucleotide and/or the second polynucleotide are provided in a recombinant lentivirus or a recombinant adeno-associated virus (rAAV). 208. The use of any one of claims 205-207, wherein the first polynucleotide is operably linked to at least one regulatory sequence and/or the second polynucleotide is operably linked to at least one regulatory sequence. 209. The use of any one of claims 202-204, wherein the repair template is operably linked to at least one regulatory sequence. 210. The use of any one of claims 167-209, wherein the gene-editing therapy corrects the sequence encoding the disease-associated mutation.