Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated inAlzheimer's disease andcardiovascular diseases.[5] It is encoded in humans by thegeneAPOE.
Apolipoproteins are not unique to mammals. Many terrestrial and marinevertebrates have versions of them.[12] It is believed thatAPOE arose via gene duplications ofAPOC1 before the fish–tetrapod split ca. 400 million years ago. Proteins similar in function have been found inchoanoflagellates, suggesting that they are a very old class of proteins predating the dawn of all living animals.[13]
The three major humanalleles (E4,E3,E2) arose after the primate–human split around 7.5 million years ago. These alleles are the by-product of non-synonymous mutations which led to changes in functionality. The first allele to emerge was E4. After the primate–human split, there were four amino acid changes in the human lineage, three of which had no effect on protein function (V174L, A18T, A135V). The fourth substitution (T61R) traded a threonine for an arginine altering the protein's functionality. This substitution occurred somewhere in the 6 million year gap between the primate–human split and theDenisovan–human split, since exactly the same substitutions were found in DenisovanAPOE.[14]
About 220,000 years ago, a cysteine to arginine substitution took place at amino acid 112 (Cys112Arg) of theAPOE4 gene, and this resulted in theE3 allele. Finally, 80,000 years ago, an arginine to cysteine substitution at amino acid 158 (Arg158Cys) of theAPOE3 gene created theE2 allele.[15][13]
Apoe-E is 299amino acids long and contains multipleamphipathicα-helices. According to crystallography studies, a hinge region connects the N- and C-terminal regions of the protein. The N-terminal region (residues 1–167) forms an anti-parallel four-helix bundle such that the non-polar sides face inside the protein. Meanwhile, the C-terminal domain (residues 206–299) contains three α-helices which form a large exposedhydrophobic surface and interact with those in the N-terminal helix bundle domain throughhydrogen bonds and salt-bridges. The C-terminal region also contains alow density lipoprotein receptor (LDLR)-binding site.[18]
APOE ispolymorphic,[19][20] with three majoralleles (epsilon 2, epsilon 3, and epsilon 4):APOE-ε2 (cys112, cys158),APOE-ε3 (cys112, arg158), andAPOE-ε4 (arg112, arg158).[5][21][22] Although these allelic forms differ from each other by only one or two amino acids at positions 112 and 158,[23][24][25] these differences alter APOE structure and function.
There are several low-frequency polymorphisms of APOE. APOE5 comes in two subtypes E5f and E5s, based on migration rates. APOE5 E5f and APOE7 combined were found in 2.8% of Japanese males.[26][unreliable medical source] APOE7 is a mutation of APOE3 with two lysine residues replacing glutamic acid residues at positions 244 and 245.[27]
This variant of the apoprotein binds poorly to cell surface receptors while ε3 and ε4 bind well.[28] ε2 is associated with both increased and decreased risk foratherosclerosis. Individuals with an ε2/ε2 combination may clear dietary fat slowly and be at greater risk for early vascular disease and thegenetic disordertype III hyperlipoproteinemia—94.4% of people with such disease are ε2/ε2.[29][30][31] ε2 has also been implicated inParkinson's disease,[32] but this finding was not replicated in a larger population association study.[33]
Much remains to be learned about the APOE isoforms, including the interaction of other protective genes.[66] so caution is advised before making determinant statements about the influence of APOE polymorphisms on cognition, development of Alzheimer's disease, cardiovascular disease, telomere shortening, etc. Many of the studies cited that purport these adverse outcomes are from single studies that have not been replicated and the research is based on unchecked assumptions about this isoform. As of 2007, there was no evidence that APOE polymorphisms influence cognition in younger age groups (other than possible better visual working memory in younger APOE4 age groups), nor that the APOE4 isoform places individuals at increased risk for any infectious disease.[67]
However, the association between the APOE4 allele and Alzheimer's disease has been shown to be weaker in minority groups differently compared to their Caucasian counterparts.[9]Hispanics/Latinos andAfrican Americans who were homozygous for the APOE4 allele had 2.2 and 5.7 times the odds, respectively of developing Alzheimer's disease.[68][9] The homozygous APOE4 allele has an even stronger effect inEast Asian populations, with Japanese populations have 33 times the odds compared to the heterozygous population.[69] Caucasians who were homozygous for the allele had 12.5 times the odds.[68][9]
As a component of the lipoprotein lipid transport system, APOE facilitates the transport oflipids, fat-solublevitamins, andcholesterol via the blood. It interacts with the LDL receptor to facilitate endocytosis of VLDL remnants. It is synthesized principally in theliver, but has also been found in other tissues such as thebrain,kidneys, andspleen.[21] APOE synthesized in the liver associates withHDL which can then distribute it to newly formedVLDL orchylomicron particles to facilitate their eventual uptake by the liver.
In the nervous system, non-neuronal cell types, most notablyastroglia andmicroglia, are the primary producers of APOE, while neurons preferentially express the receptors for APOE.[70] There are seven currently identified mammalianreceptors for APOE which belong to the evolutionarily conserved LDLR family.[71]
APOE was initially recognized for its importance in lipoproteinmetabolism andcardiovascular disease. Defects in APOE result infamilial dysbetalipoproteinemia aka type IIIhyperlipoproteinemia (HLP III), in which increased plasmacholesterol and triglycerides are the consequence of impaired clearance ofchylomicron,VLDL andLDL.[72][7] More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including Alzheimer's disease (AD),immunoregulation, andcognition.[5] Though the exact mechanisms remain to be elucidated, isoform 4 of APOE, encoded by an APOE allele, has been associated with increased calcium ion levels and apoptosis following mechanical injury.[73]
In the field of immune regulation, a growing number of studies point to APOE's interaction with many immunological processes, including suppressingT cell proliferation,macrophage functioning regulation, lipid antigen presentation facilitation (byCD1)[74] tonatural killer T cell as well as modulation ofinflammation andoxidation.[75] APOE is produced by macrophages and APOE secretion has been shown to be restricted to classical monocytes in PBMC, and the secretion of APOE by monocytes is down regulated by inflammatory cytokines and upregulated by TGF-beta.[76]
As of 2012, the E4 variant was the largest known genetic risk factor for late-onset sporadicAlzheimer's disease (AD) in a variety of ethnic groups.[77] However, the E4 variant does not correlate with risk in every population. Nigerian people have the highest observed frequency of theAPOE4 allele in world populations,[78] but AD is rare among them.[78][79] This may be due to their low cholesterol levels.[78][79][80][81] Caucasian and Japanese carriers of two E4 alleles have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles. This may be caused by an interaction withamyloid.[82] Interestingly, there is a sex specific effect, as presence of APOE4 increases AD risk more in women than in men.[83]Alzheimer's disease is characterized by build-ups of aggregates of the peptidebeta-amyloid, the breakdown of which Apolipoprotein E enhances, both within and between cells. Theisoform APOE-ε4 is not as effective as the others at promoting this breakdown, resulting in increased vulnerability to AD in individuals with that gene variation.[84]
The amyloid hypothesis of Alzheimer's disease has been questioned, and a 2021 article inScience claimed that "Just as removing smoke does not extinguish a fire, reducing amyloid plaques may not affect the course of Alzheimer's disease."[85] The role that the E4 variant carries can still be fully explained even in the absence of a valid amyloid hypothesis given the fact thatreelin signaling emerges to be one of the key processes involved in Alzheimer's disease[86] and the E4 variant is shown to interact withApoER2, one of the neuronal reelin receptors, thereby obstructing reelin signaling.[86]
Although 40–65% of AD patients have at least one copy of the ε4 allele,APOE4 is not a determinant of the disease. At least one-third of patients with AD areAPOE4 negative and someAPOE4 homozygotes never develop the disease. Yet those with two ε4 alleles have up to 20 times the risk of developing AD.[87] There is also evidence that theAPOE2 allele may serve a protective role in AD.[88] Thus, the genotype most at risk for Alzheimer's disease and at an earlier age is APOE4,4. Using genotype APOE3,3 as a benchmark (with the persons who have this genotype regarded as having a risk level of 1.0) and for white populations only, individuals with genotype APOE4,4 have anodds ratio of 14.9 of developing Alzheimer's disease. Individuals with the APOE3,4 genotype face an odds ratio of 3.2, and people with a copy of the 2 allele and the 4 allele (APOE2,4), have an odds ratio of 2.6. Persons with one copy each of the 2 allele and the 3 allele (APOE2,3) have an odds ratio of 0.6. Persons with two copies of the 2 allele (APOE2,2) also have an odds ratio of 0.6.[89]
Estimated worldwide human allele frequencies of APOE in Caucasian population[89]
Allele
ε2
ε3
ε4
General frequency
8.4%
77.9%
13.7%
AD frequency
3.9%
59.4%
36.7%
While ApoE4 has been found to greatly increase the odds that an individual will develop Alzheimer's, a 2002 study concluded, that in persons with any combination of APOE alleles, high serum total cholesterol and high blood pressure in mid-life are independent risk factors which together can nearly triple the risk that the individual will later develop AD.[81] Projecting from their data, some researchers have suggested that lowering serum cholesterol levels may reduce a person's risk for Alzheimer's disease, even if they have two ApoE4 alleles, thus reducing the risk from nine or ten times the odds of getting AD down to just two times the odds.[81]
Women are more likely to develop AD than men across most ages and APOE genotypes. Premorbid women with the ε4 allele have significantly more neurological dysfunction than men.[90]
APOE-ε4 increases the risk not only for AD but also for dementia in pure alpha-synucleinopathies.[91] The influence ofAPOE-ε4 on hippocampal atrophy was suggested to be more predominant early in the course of AD at milder stages prior to more widespreadneurodegeneration.[46]
With the approval of the first disease-modifying therapies for Alzheimer's disease based on monoclonal antibodies against amyloid-beta, which delay disease progression, APOE genotyping has also become important in assessing a patient's risk of side effects under therapy. In November 2024, theCommittee for Medicinal Products for Human Use of theEuropean Medicines Agency following a re-examination procedure, adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Leqembi, intended for the treatment of early Alzheimer's disease in apolipoprotein E ε4 (ApoE ε4) non-carriers or heterozygotes.[92][93] The applicant for this medicinal product is Eisai GmbH.[92]
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