No treatments can stop or reverse its progression, though some may temporarily improve symptoms.[2] Ahealthy diet,physical activity, andsocial engagement are generally beneficial in aging, and may help in reducing the risk of cognitive decline and Alzheimer's.[20] Affected people become increasingly reliant on others for assistance, often placing a burden oncaregivers.[24] The pressures can include social, psychological, physical, and economic elements.[24] Exercise programs may be beneficial with respect toactivities of daily living and can potentially improve outcomes.[25] Behavioral problems orpsychosis due to dementia are sometimes treated withantipsychotics, but this has an increased risk of early death.[26][27]
As of 2020, there were approximately 50 million people worldwide with Alzheimer's disease.[14] It most often begins in people over 65 years of age, although up to 10% of cases areearly-onset impacting those in their 30s to mid-60s.[28][4] It affects about 6% of people 65 years and older,[17] and women more often than men.[29] The disease is named after German psychiatrist and pathologistAlois Alzheimer, who first described it in 1906.[30] Alzheimer's financial burden on society is large, with an estimated global annual cost ofUS$1trillion.[14] Alzheimer's and related dementias are ranked as theseventh leading cause of death worldwide.[31]
Given the widespread impacts of Alzheimer's disease, both basic-science and health funders in many countries support Alzheimer's research at large scales. For example, the USNational Institutes of Health program for Alzheimer's research, the National Plan to Address Alzheimer's Disease, has a budget of US$3.98 billion for fiscal year 2026.[32] In theEuropean Union, the 2020Horizon Europe research programme awarded over €570 million for dementia-related projects.[33]
Signs and symptoms
The course of Alzheimer's is generally described in three stages, with a progressive pattern ofcognitive andfunctionalimpairment.[34][28] The three stages are described as early or mild, middle or moderate, and late or severe.[34] The disease is known to target thehippocampus which is associated withmemory, and this is responsible for the first symptoms of memory impairment. As the disease progresses so does the degree of memory impairment.[20]
The first symptoms are often mistakenly attributed toaging orstress.[35] Detailedneuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria fordiagnosis of Alzheimer's disease.[36] These early symptoms can affect the most complexactivities of daily living.[37] The most noticeable deficit isshort term memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information.[36]
Subtle problems with theexecutive functions ofattentiveness,planning, flexibility, andabstract thinking, or impairments insemantic memory (memory of meanings, and concept relationships) can also be symptomatic of the early stages of Alzheimer's disease.[36]Apathy anddepression can be seen at this stage, with apathy remaining as the most persistent symptom throughout the course of the disease.[38][39] People with objective signs of cognitive impairment, but not more severe symptoms, may be diagnosed withmild cognitive impairment (MCI). If memory loss is the predominant symptom of MCI, it is termedamnestic MCI and is frequently seen as aprodromal or early stage of Alzheimer's disease.[40] Amnestic MCI has a greater than 90% likelihood of being associated with Alzheimer's.[41]
Early stage
In people with Alzheimer's disease, the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small percentage, difficulties with language, executive functions,perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems.[42] Alzheimer's disease does not affect all memory capacities equally.Older memories of the person's life (episodic memory), facts learned (semantic memory), andimplicit memory (the memory of the body on how to do things, such as using a fork to eat or how to drink from a glass) are affected to a lesser degree than new facts or memories.[43][44]
Language problems are mainly characterised by a shrinkingvocabulary and decreased wordfluency, leading to a general impoverishment of oral andwritten language.[42][45] In this stage, the person with Alzheimer's is usually capable of communicating basic ideas adequately.[42][45][46] While performingfine motor tasks such as writing, drawing, or dressing, certain movement coordination and planning difficulties (apraxia) may be present; however, they are commonly unnoticed.[42] As the disease progresses, people with Alzheimer's disease can often continue to perform many tasks independently; however, they may need assistance or supervision with the most cognitively demanding activities.[42]
Middle stage
Progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities of daily living.[42] Speech difficulties become evident due to an inability torecall vocabulary, which leads to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also progressively lost.[42][46] Complex motor sequences become less coordinated as time passes and Alzheimer's disease progresses, so the risk of falling increases.[42] During this phase, memory problems worsen, and the person may fail to recognise close relatives.[42]Long-term memory, which was previously intact, becomes impaired.[42]
A normal brain on the left and a late-stage Alzheimer's brain on the right
During the final stage, known as the late-stage or severe stage, there is complete dependence on caregivers.[20][34][42] Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech.[42][46] Despite the loss of verbal language abilities, people can often understand and return emotional signals. Although aggressiveness can still be present, extremeapathy andexhaustion are much more common symptoms. People with Alzheimer's disease will ultimately not be able to perform even the simplest tasks independently;muscle mass and mobility deteriorates to the point where they are bedridden and unable to feed themselves. The cause of death is usually an external factor, such as infection ofpressure ulcers orpneumonia, not the disease itself.[42] In some cases, there is aparadoxical lucidity immediately before death, where there is an unexpected recovery of mental clarity.[49]
Causes
Alzheimer's disease is believed to occur when abnormal amounts ofamyloid beta (Aβ), accumulating extracellularly asamyloid plaques andtau proteins, or intracellularly asneurofibrillary tangles, form in the brain, affecting neuronal functioning and connectivity, resulting in a progressive loss of brain function.[50][51] This alteredprotein clearance ability is age-related, regulated by brain cholesterol,[52] and associated with other neurodegenerative diseases.[53][54]
The cause for most Alzheimer's cases is still mostly unknown,[14] except for 1–2% of cases where deterministic genetic differences have been identified.[18] Several competinghypotheses attempt to explain the underlying cause; the most predominant hypothesis is the amyloid beta (Aβ) hypothesis.[14]
Genetic
Late onset
Late-onset Alzheimer's is about 70%heritable.[55][56] Most cases of Alzheimer's are notfamilial, and so they are termed sporadic Alzheimer's disease.[57] Of the cases of sporadic Alzheimer's disease, most are classified as late onset where they are developed after the age of 65 years.[58]
The strongest genetic risk factor for sporadic Alzheimer's disease isAPOEε4.[19] APOEε4 is one of four alleles ofapolipoprotein E (APOE). APOE plays a major role in lipid-binding proteins in lipoprotein particles and theε4 allele disrupts this function.[59] Between 40% and 80% of people with Alzheimer's disease possess at least one APOEε4 allele.[60] The APOEε4 allele increases the risk of the disease by three times inheterozygotes and by 15 times inhomozygotes.[61] Like many human diseases, environmental effects and genetic modifiers result in incompletepenetrance. For example, NigerianYoruba people do not show the relationship between dose of APOEε4 and incidence or age-of-onset for Alzheimer's disease seen in other human populations.[62][63]
Only 1–2% of Alzheimer's cases areinherited due toautosomal dominant effects, as Alzheimer's is highly polygenic. When the disease is caused by autosomal dominant variants, it is known asearly onset familial Alzheimer's disease, which is rarer and has a faster rate of progression.[18] Less than 5% of sporadic Alzheimer's disease have an earlier onset,[18] and early-onset Alzheimer's is about 90% heritable.[55][56] Familial Alzheimer's disease usually implies two or more persons affected in one or more generations.[64][65][66]
Early onset familial Alzheimer's disease can be attributed to mutations in one of three genes: those encodingamyloid-beta precursor protein (APP) andpresenilinsPSEN1 andPSEN2.[41] Most mutations in the APP and presenilin genes increase the production of a small protein calledamyloid beta (Aβ)42, which is the main component ofamyloid plaques.[67] Some of the mutations merely alter the ratio between Aβ42 and the other major forms—particularly Aβ40—without increasing Aβ42 levels in the brain.[68] Two other genes associated with autosomal dominant Alzheimer's disease areABCA7 andSORL1.[69]
Alleles in theTREM2 gene have been associated with a three to five times higher risk of developing Alzheimer's disease.[70]
A Japanese pedigree of familial Alzheimer's disease was found to be associated with a deletion mutation of codon 693 of APP.[71] This mutation and its association with Alzheimer's disease was first reported in 2008,[72] and is known as the Osaka mutation. Only homozygotes with this mutation have an increased risk of developing Alzheimer's disease. This mutation accelerates Aβ oligomerization but the proteins do not form the amyloid fibrils that aggregate into amyloid plaques, suggesting that it is the Aβ oligomerization rather than the fibrils that may be the cause of this disease. Mice expressing this mutation have all the usual pathologies of Alzheimer's disease.[73]
Hypotheses
Misfolded protein
Tau protein abnormalities in neurons may contribute to onset of Alzheimer's disease
Two abnormal proteins define the pathology of Alzheimer's disease: amyloid beta protein (Aβ) in amyloid plaques and tau protein in neurofibrillary tangles.[1] These proteins share two features that promote their ability to cause disease: They both become abnormal by misfolding, that is, by assuming a shape that is rich inbeta sheets;[74] and they proliferate in the brain by theprion-like mechanism of seeded protein aggregation.[75][76] The presence of these abnormal proteins in Alzheimer's disease has spawned two hypotheses of theproteopathic origin of the disease: The amyloid (or Aβ) hypothesis, and the tau hypothesis.
Theamyloid hypothesis, also known as the "amyloid cascade hypothesis"[77][78] or "Aβ cascade hypothesis",[79] holds that the accumulation of misfolded Aβ in the brain is the fundamental cause of Alzheimer's disease. In the amyloid cascade, the buildup of abnormal Aβ leads to tauopathy and eventually the complex degenerative changes of advanced Alzheimer's disease.[80] Abnormal Aβ is thought to damage the brain by directly interacting with cells, and/or indirectly, for example by causingoxidative stress andneuroinflammation.[81]
The amyloid hypothesis is supported by evidence from genetics and biomarkers. Allautosomal dominant genetic causes of Alzheimer's disease affect either theamyloid precursor protein (APP) onchromosome 21 or the enzymes that generate Aβ, known aspresenilin 1 andpresenilin 2; in addition, people withtrisomy 21 (Down syndrome), most of whom have anextra copy of the gene for APP, almost universally develop the symptoms and neuropathology of Alzheimer's disease by 40 years of age.[10][82] Conversely, people with a rare mutation in the APP gene that reduces the production of Aβ and its tendency to aggregate are protected against Alzheimer's disease.[82] Additionally, a major genetic risk factor for Alzheimer's disease is a specificisoform ofapolipoprotein E,APOE4.[16] Of the three major isoforms (APOE2, APOE3 and APOE4), APOE4 is linked to the least efficient removal of Aβ by astrocytes, which promotes the buildup of Aβ in the brain. The most efficient clearance of Aβ is achieved by cells bearing the APOE2 isoform, which protects against Alzheimer's disease.[82] Evidence frombiomarkers such asimaging of protein deposits in the brain and measurement of brain-derived substances incerebrospinal fluid and blood implicates abnormalities of Aβ as the earliest and most robust disease-specific change in Alzheimer's disease.[83]
Thetau hypothesis proposes that abnormalities of thetau protein initiate the disease cascade, at least in cases ofidiopathic Alzheimer's disease.[84] The tau hypothesis is supported by the histopathological findings ofHeiko Braak and colleagues that tauopathy can be detected in certain neurons before Aβ plaques are evident.[84] Specifically, Alzheimer's starts with thehyperphosphorylation of tau in specific vulnerable neuronal populations such as thelocus coeruleus and projection neurons of theassociation cortex. There is agreement in the research community that tau contributes strongly to dementia in Alzheimer's disease, but tauopathy occurs in over 30 diseases besides Alzheimer's disease).[85] In addition, mutations of the gene for tau (MAPT) cause neurodegenerative disorders known as primary tauopathies, but these diseases occur in the absence of Aβ proteopathy.[82] Current evidence thus favors abnormal Aβ as the prime mover of Alzheimer's disease.[82][86] However, the Aβ hypothesis and tau hypothesis are not mutually exclusive, in that abnormalities of Aβ initiate the disease and tauopathy is required for its complete expression.[87][88]
Hormonal
Because women have a higher incidence of AD than men, it has been thought that estrogen deficiency during menopause is a risk factor.In a 2025 analysis of the Canadian Longitudinal Study on Aging earlier age at menopause was linked with lower cognitive performance.[89]
Infection
The possibility that infectious agents cause Alzheimer's disease has been considered since the early 20th century, whenOskar Fischer likened amyloid plaques to small masses (called 'Drusen') of a microbe calledactinomyces.[90] Since then, at least 15 different agents, including bacteria, viruses, fungi and protozoa, have been proposed to cause Alzheimer's disease.[91] No definitive evidence has been presented that a specific infectious agent is necessary and sufficient to cause Alzheimer's disease.[92] However, it is possible that microbial infections might act asrisk factors for the disease.[93] For example, human herpes viruses such asHSV1,HHV6 andHHV7 have been linked to the risk of Alzheimer's disease.[92] In addition, some pathogens have been reported to seed Aβ deposition in the brain,[92] and aggregated Aβ hasantimicrobial properties, suggesting that Aβ plaques might form when brain cells generate Aβ to fight infection.[93] Researchers caution that brain infections can cause dementia by mechanisms unrelated to Alzheimer's disease.[93][92]
Thecholinergic hypothesis proposes that the loss of neurons in thebasal forebrain, which produce the neurotransmitteracetylcholine, is a key event in the pathogenesis of Alzheimer's disease.[95] These cells supply acetylcholine to synapses in thelimbic system and cerebral cortex.[40][95] The cholinergic hypothesis led to the development of drugs that increase acetylcholine in the brains of Alzheimer patients.[95] The efficacy of these agents is limited, probably because many other neurotransmitter systems degenerate in Alzheimer's disease.[96]
Sleep
Sleep disturbances are seen as a possiblerisk factor for inflammation in Alzheimer's disease.[97] Sleep disruption was previously only seen as a consequence of Alzheimer's disease, but as of 2020[update], accumulating evidence suggests that this relationship may bebidirectional.[98][99]
Neuroinflammation, metal toxicity, smoking, and air pollution
Systemic markers of theinnate immune system are risk factors for late-onset Alzheimer's disease,[100] and misfolded Aβ and tau proteins both are associated withoxidative stress andneuroinflammation.[101] Chronic inflammation also is a feature of other neurodegenerative diseases, includingParkinson's disease, andALS.[102] The cellularhomeostasis ofbiometals such as ionic copper, iron, and zinc is disrupted in Alzheimer's disease, though it remains unclear whether this is produced by or causes the changes in proteins.[14][103] Smoking is a significant Alzheimer's disease risk factor.[1]Exposure to air pollution may be a contributing factor to the development of Alzheimer's disease.[14]
Age-related myelin decline
Retrogenesis is a medicalhypothesis that just as the fetus goes through a process ofneurodevelopment beginning withneurulation and ending withmyelination, the brains of people with Alzheimer's disease go through a reverseneurodegeneration process starting withdemyelination and death of axons (white matter) and ending with the death of grey matter.[104] Likewise the hypothesis is, that as infants go through states ofcognitive development, people with Alzheimer's disease go through the reverse process of progressivecognitive impairment.[105]
The association withceliac disease is unclear, with a 2019 study finding no increase in dementia overall in those with celiac disease while a 2018 review found an association with several types of dementia including Alzheimer's disease.[109][110]
Studies have reported a potential link between infection with certain viruses and developing Alzheimer's disease later in life.[111] Notably, a large scale study conducted on 6,245,282 patients has reported an increased risk of developingAlzheimer's disease following COVID-19 infection in cognitively normal individuals over 65.[112]
Some evidence suggests that some viral infections such asHerpes simplex virus 1 (HSV-1) may be associated with dementia, but there are conflicting results and the association with Alzheimer's is unclear as of 2024.[113][114][115]
Some researchers have proposed that Alzheimer's disease is Type 3 diabetes because of a number of correspondences with both Type 1 and Type 2 diabetes.[116]
The gross (macroscopic) appearance of the brain in Alzheimer's disease is variable. In many cases the corticalsulci are widened and thegyri are shrunken,[117] but the degree of corticalatrophy varies, and it can sometimes be difficult to discern, particularly in very old subjects.[118] The areas most affected by atrophy are the medialtemporal lobe including thehippocampal formation, theamygdala, thefrontal lobe and theparietal lobe; theoccipital lobe is relatively unaffected by atrophy.[117] The volume of the ventricles increases in parallel with cortical shrinkage.[117] Studies usingMRI andPET have documented reductions in the size of specific brain regions in people with Alzheimer's disease as they progress from mild cognitive impairment to Alzheimer's disease, and in comparison with similar images from healthy older adults.[119][120] These macroscopic changes in the brain can occur in other disorders and to some extent in normal aging; thus, they are not specific to Alzheimer's disease, which can be diagnosed with certainty only by microscopic examination of the brain.[118]
At themicroscopic level, the defining histopathologic characteristics of Alzheimer's disease are abundantAβplaques andneurofibrillary tangles in certain brain regions.[121] Both of these abnormalities are clearly visible by microscopy;[122][117] in the early stages of disease, tangles are present mainly in the medialtemporal lobe and plaques are present mainly in theneocortex, but as the disease progresses the lesions proliferate throughout much of the brain.[121] Although it was once thought that Alzheimer's disease can occur without neurofibrillary tangles in the neocortex,[123] newer methods have shown that dementia in these cases can be linked to acomorbid condition, often Lewy body disease.[85]
Aβ plaques are dense, mostlyinsoluble deposits ofamyloid beta peptide andcellular material outside and aroundneurons.[93] Neurofibrillary tangles are aggregates of the microtubule-associatedprotein tau which has become hyperphosphorylated and accumulates inside neurons.[124][121] Although many older individuals develop some plaques and tangles as a consequence of aging, the brains of people with Alzheimer's disease have a greater number of them in specific brain regions.[125][117]
The two defining proteopathies of Alzheimer's disease: Aβ plaques (brown) and neurofibrillary (tau) tangles (black). Abnormal, hyperphosphorylated tau occurs in neuronal cell bodies, in fine neuronal processes throughout the neuropil, and in swollen neurites within the plaques. Dualimmunohistochemical stain using antibodies to Aβ and tau proteins. Scale bar = 50microns (0.05 mm).
In addition to plaques and tangles, other neuropathological changes contribute to the clinicopathologic features of advanced Alzheimer's disease. These includecerebral Aβ-amyloid angiopathy (CAA),[126] inflammation,[127] and the loss of neurons[128] andsynapses.[129] The disappearance of neurons and their synapses is a particularly prominent correlate of dementia, although not all cells are affected equally. Selective vulnerability - that is, why certain neurons and synapses are affected and others spared - is an important unanswered question.[129][128]
In more than half of the cases examined neuropathologically, and especially in very old people, the pathology of Alzheimer's disease is accompanied by lesions that are characteristic of other brain disorders.[121] The most common of these comorbid conditions arevascular disease,Lewy body disease, andTDP-43 proteinopathy.[121][130] This mixed pathology can complicate both diagnosis and the evaluation of clinical trials,[121] which often target only one of several potential contributors to dementia.
Alzheimer's disease has been identified as aprotein misfolding disease, aproteopathy, caused by the accumulation of abnormally foldedAβ protein into amyloid plaques, andtau protein into neurofibrillary tangles in the brain.[131] Plaques are made up of smallpeptides, 39–43 amino acids in length, called Aβ. Aβ is a fragment derived from the largerAβ precursor protein (APP), atransmembrane protein that penetrates thecell's membrane. APP is critical to neuronal growth, survival, and post-injury repair.[131] In Alzheimer's disease, the enzymesgamma secretase andbeta secretase act together in aproteolytic process that divides APP into smaller fragments.[131] One of these fragments is Aβ, which misfolds and self-assembles intofibrils; these fibrils form clumps that deposit outside neurons in dense formations known as Aβ plaques.[131] Excitatory neurons are known to be major producers of Aβ that contribute to extracellular plaque deposition.[131]
Enzymes act on the amyloid-beta precursor protein and cut it into fragments. The beta-amyloid fragment is crucial in the formation of amyloid plaques in Alzheimer's disease.
Phosphorylated tau
Alzheimer's disease is also considered atauopathy due to the abnormal aggregation of thetau protein within cells. Every neuron has acytoskeleton, an internal support structure partly made up oforganelles calledmicrotubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of theaxon and back. The tau protein stabilises the microtubules whenphosphorylated, and it is therefore called amicrotubule-associated protein. In Alzheimer's disease, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system.[132] Pathogenic tau can also cause neuronal death throughtransposable element dysregulation.[133]Necroptosis has also been reported as a mechanism of cell death in brain cells affected with tau tangles.[134][135]
Disease mechanism
Exactly how disturbances of production and aggregation of the Aβpeptide give rise to the pathology of Alzheimer's disease is not known.[136][137] The amyloid hypothesis (also known as the 'amyloid cascade hypothesis') posits that the accumulation of abnormally shaped Aβ peptides is the central event triggering the sequence of changes that eventually lead to neurodegeneration and dementia.[138] Misfolded Aβ accumulates in the brain because it causes normal Aβ molecules to similarly misfold by aprion-like 'seeding' mechanism.[139][140][141] The aggregated Aβ takes the form of smalloligomers (which are particularly toxic to neurons[142][143][138]) andamyloid fibrils, the longpolymers that are the main components of Aβ plaques.[93] Some researchers have argued that the amyloid fibrils bind up smaller oligomers and thus protect brain cells from the injurious effects of the oligomers.[143] However, the plaques are not benign inasmuch as they are associated with abnormal neuronalprocesses and local inflammation.[121] Whatever the relative influence of Aβ oligomers and fibrils, the presence of aggregated Aβ is associated with the disruption of neuronal metabolism[144] and various other changes such as inflammation.[121][93] Aβ also selectively builds up inmitochondria in the cells of Alzheimer's-affected brains, and it inhibits certainenzyme functions and the utilisation ofglucose by neurons.[145]
Evidence supports Aβ as playing a central role in the pathogenesis of Alzheimer's disease, but as the disease progresses the brain undergoes a complex assortment of cellular and molecular changes, including (in addition to tauopathy) inflammation, oxidative/nitrative stress, DNA damage,epigenetic changes,excitotoxicity,endosomal/lysosomal failure,dysproteostasis,autophagy failure, lipid dysmetabolism, calcium ion (Ca2+)dyshomeostasis,post-translational protein modifications, neuronalcell cycle re-entry, mitochondrial failure, cytoskeletal disruption, glucose dysmetabolism, vascular orlymphatic impairments, andbiometal dyshomeostasis.[146] Iron dyshomeostasis is linked to disease progression in which an iron-dependent form of regulated cell death calledferroptosis could be involved. Products oflipid peroxidation are also elevated in the Alzheimer brain compared with controls.[147]
Various inflammatory processes andcytokines also play a role in the pathology of Alzheimer's disease.Inflammation is a general marker oftissue damage in any disease, and may be either secondary to tissue damage in Alzheimer's disease or a marker of animmunological response.[148] Cells that mediate neuroinflammation in Alzheimer's includemicroglia,astrocytes,oligodendrocytes,lymphocytes andmyeloid cells.[127] There is increasing evidence of a strong interaction between neurons and the immunological mechanisms in the brain. Obesity and systemic inflammation may interfere with immunological processes which promote disease progression.[149]Microglia are especially important actors in the Alzheimer's-related inflammation.[150] Microglia are the principal immunological cells of the central nervous system, serving as thetissue-resident macrophages of the brain; they are capable of recognizing and taking up Aβ through multiple pattern recognition receptors, making them central to amyloid clearance within the brain.[151] However, microglia can also be a major source of pro-inflammatory mediators which can be deleterious to neurological function.[151] Microglia are topographically associated with aberrant deposits of tau and Aβ within the brain, even when each pathologic component occurs in distinct brain regions.[152] Microglial activation has been documented in people with mild cognitive impairment, despite a lack of detectable binding of aPET tracer for Aβ in the brain, suggesting that microglial dysfunction may precede plaque deposition as an inciting event in AD.[153]
By the time the symptoms of Alzheimer's first appear, the complex degenerative mechanisms in the brain have been active for many years. Hence, the beneficial effect of therapeutics (specifically, the monoclonal antibodies that promote Aβ clearance) has ranged from nonexistent to modest.[156] Second-generation antibodies to Aβ have resulted in significant slowing of the progression of Alzheimer's disease,[157] but these have not yet stopped or reversed dementia. Hence, researchers increasingly believe that the best strategy is to prevent Alzheimer's by intervening before the brain has been irreversibly damaged.[158][159]
PET scan of the brain of a person with Alzheimer's disease showing a loss of function in the temporal lobe
Alzheimer's disease (AD) can only be definitively diagnosed with autopsy findings; in the absence of autopsy, clinical diagnoses of AD are "possible" or "probable", based on other findings.[22][23][160] Up to 23% of those clinically diagnosed with AD may be misdiagnosed and may have pathology suggestive of another condition with symptoms that mimic those of AD.[23]
AD is usually clinically diagnosed based on a person'smedical history, observations from friends or relatives, and behavioral changes. The presence of characteristicneuropsychological changes with impairments in at least two cognitive domains that are severe enough to affect a person's functional abilities are required for the diagnosis. Domains that may be impaired include memory (most commonly impaired), language,executive function,visuospatial functioning, or other areas of cognition. The neurocognitive changes must be a decline from a prior level of function and the diagnosis requires ruling out other common causes of neurocognitive decline.[161][162][163] Advancedmedical imaging withcomputed tomography (CT) ormagnetic resonance imaging (MRI), and withsingle-photon emission computed tomography (SPECT) orpositron emission tomography (PET), can be used to help exclude other cerebral pathology or subtypes of dementia.[164] On MRI or CT, Alzheimer's disease usually shows a generalised or focal cortical atrophy, which may be asymmetric. Atrophy of the hippocampus is also commonly seen. Brain imaging commonly also shows cerebrovascular disease, most commonly previous strokes (small or large territory strokes), and this is thought to be a contributing cause of many cases of dementia (up to 46% cases of dementia also have cerebrovascular disease on imaging).[161] FDG-PET scan is not required for the diagnosis but it is sometimes used when standard testing is unclear. FDG-PET shows a bilateral, asymmetric, temporal and parietal reduced activity.[161] Advanced imaging may predict conversion fromprodromal stages (mild cognitive impairment) to Alzheimer's disease.[165] FDA-approvedradiopharmaceutical diagnostic agents used in PET for Alzheimer's disease areflorbetapir (2012),flutemetamol (2013),florbetaben (2014), andflortaucipir (2020).[166] Because many insurance companies in the United States do not cover this procedure, its use in clinical practice is largely limited to clinical trials as of 2018[update].[167]
Assessment of intellectual functioning including memory testing can further characterise the state of the disease.[1] Medical organizations have created diagnostic criteria to ease and standardise the diagnostic process for practising physicians. Definitive diagnosis can only be confirmed withpost-mortem evaluations when brain material is available and can be examinedhistologically for senile plaques and neurofibrillary tangles.[167][168]
TheDSM-5 defines criteria for probable or possible AD for both major and mild neurocognitive disorder.[170][171][160] Major or mild neurocognitive disorder must be present along with at least one cognitive deficit for a diagnosis of either probable or possible AD.[170][172] For major neurocognitive disorder due to AD, probable Alzheimer's disease can be diagnosed if the individual has genetic evidence of AD[173] or if two or more acquired cognitive deficits, and a functional disability that is not from another disorder, are present.[174] Otherwise, possible AD can be diagnosed as the diagnosis follows an atypical route.[172] For mild neurocognitive disorder due to AD, probable Alzheimer's disease can be diagnosed if there is genetic evidence, whereas possible AD can be met if all of the following are present: no genetic evidence, decline in both learning and memory, two or more cognitive deficits, and a functional disability not from another disorder.[170][175]
The NIA-AA criteria are used mainly in research rather than in clinical assessments.[176] They define AD through three major stages: preclinical, mild cognitive impairment (MCI), and Alzheimer's dementia.[177][178] Diagnosis in the preclinical stage is complex and focuses on asymptomatic individuals;[178][179] the latter two stages describe individuals experiencing symptoms,[178] along with biomarkers,[180] predominantly those for neuronal injury (mainly tau-related) and amyloid beta deposition.[176][178] The core clinical criteria itself rests on the presence of cognitive impairment[178] without the presence of comorbidities.[181][182] The third stage is divided into probable and possible AD dementia.[182] In probable AD dementia there is steady impairment of cognition over time and a memory-related or non-memory-related cognitive dysfunction.[182] In possible AD dementia, another causal disease such ascerebrovascular disease is present.[182]
Techniques
Cognitive tests such as the mini–mental state examination (MMSE) can help in the diagnosis of Alzheimer's disease. In this test instructions are given to copy drawings like the one reported, remember some words, read, and subtract numbers serially.
Neuropsychological tests includingcognitive tests such as themini–mental state examination (MMSE), theMontreal Cognitive Assessment (MoCA) and the Mini-Cog are widely used to aid in diagnosis of the cognitive impairments in AD.[183] These tests may not always be accurate, as they lack sensitivity to mild cognitive impairment, and can be biased by language or attention problems;[183] more comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease.[184][185]
Further neurological examinations are crucial in thedifferential diagnosis of Alzheimer's disease and other diseases.[35] Interviews with family members are used in assessment; caregivers can supply important information on daily living abilities and on the decrease in the person'smental function.[186] A caregiver's viewpoint is particularly important, since a person with Alzheimer's disease is commonlyunaware of their deficits.[187] Many times, families have difficulties in the detection of initial dementia symptoms and may not communicate accurate information to a physician.[188]
Supplemental testing can rule out other potentially treatable diagnoses and help avoid misdiagnoses.[189] Common supplemental tests includeblood tests,thyroid function tests, as well as tests to assess vitaminB12 levels, rule outneurosyphilis and rule out metabolic problems (including tests forkidney function, electrolyte levels and fordiabetes).[189] MRI or CT scans might also be used to rule out other potential causes of the symptoms – including tumors or strokes.[183]Delirium and depression can be common among individuals and are important to rule out.[190]
Due to low accuracy, the C-PIB-PET scan is not recommended as an early diagnostic tool or for predicting the development of AD when people show signs of mild cognitive impairment (MCI).[194] The use of18F-FDG PET scans, as a single test, to identify people who may develop Alzheimer's disease is not supported by evidence.[195]
In May 2025, the US FDA approved a blood test by Fujirebio Diagnostics' Lumipulse G pTau217/ß-Amyloid 1-42 Plasma Ratio diagnostic device for the early detection of amyloid plaques associated with AD in adults aged 55 years and older who are exhibiting signs and symptoms of the disease.[196]
Prevention
Intellectual activities such as playingchess or regular social interaction have been linked to a reduced risk of Alzheimer's disease in epidemiological studies, although no causal relationship has been found.
There are nodisease-modifying treatments available to cure Alzheimer's disease and because of this, AD research has focused on interventions to prevent the onset and progression.[13] There is no evidence that supports any particular measure in preventing AD,[1] and studies of measures to prevent the onset or progression have produced inconsistent results. Epidemiological studies have proposed relationships between an individual's likelihood of developing AD and modifiable factors, such as medications, lifestyle, and diet. There are some challenges in determining whether interventions for AD act as a primary prevention method, preventing the disease itself, or a secondary prevention method, identifying the early stages of the disease.[197] These challenges include duration of intervention, different stages of disease at which intervention begins, and lack of standardization of inclusion criteria regarding biomarkers specific for AD.[197] Further research is needed to determine factors that can help prevent AD.[197]
Medication
Cardiovascular risk factors, such ashypercholesterolaemia,hypertension,diabetes, andsmoking, are associated with a higher risk of onset and worsened course of AD.[198][199] The use ofstatins to lowercholesterol may be of benefit in AD.[200]Antihypertensive andantidiabetic medications in individuals without overt cognitive impairment may decrease the risk of dementia by influencing cerebrovascularpathology.[1][201] More research is needed to examine the relationship with AD specifically; clarification of the direct role medications play versus other concurrent lifestyle changes (diet, exercise, smoking) is needed.[1]
Depression is associated with an increased risk for AD; management with antidepressant medications may provide a preventative measure.[5]
Historically, long-term usage ofnon-steroidal anti-inflammatory drugs (NSAIDs) were thought to be associated with a reduced likelihood of developing AD as it reduces inflammation, but NSAIDs do not appear to be useful as a treatment.[167] Additionally, because women have a higher incidence of AD than men, it was once thought thatestrogen deficiency duringmenopause was a risk factor, but there is a lack of evidence to show thathormone replacement therapy (HRT) in menopause decreases risk of cognitive decline.[202]
Certain lifestyle activities, such as physical and cognitive exercises, higher education and occupational attainment, cigarette smoking, stress, sleep, and the management of other comorbidities, including diabetes and hypertension, may affect the risk of developing AD.[5]
Physical exercise is associated with a decreased rate of dementia,[6] and is effective in reducing symptom severity in those with AD.[203][204] Memory and cognitive functions can be improved with aerobic exercises including brisk walking three times weekly for forty minutes.[205] It may also induceneuroplasticity of the brain.[206] Participating in mental exercises, such as reading, crossword puzzles, and chess have reported potential to be preventive.[5] Meeting theWHO recommendations for physical activity is associated with a lower risk of AD.[207]
Higher education and occupational attainment, and participation in leisure activities, contribute to a reduced risk of developing AD,[7] or of delaying the onset of symptoms. This is compatible with thecognitive reserve theory, which states that some life experiences result in more efficient neural functioning providing the individual a cognitive reserve that delays the onset of dementia manifestations.[7]Education delays the onset of Alzheimer's disease syndrome without changing the duration of the disease.[208]
Cessation in smoking may reduce risk of developing AD, specifically in those who carry theAPOE ɛ4 allele.[208][5] The increased oxidative stress caused by smoking results in downstream inflammatory or neurodegenerative processes that may increase risk of developing AD.[209] Avoidance of smoking, counseling and pharmacotherapies to quit smoking are used, and avoidance of environmental tobacco smoke is recommended.[5]
Alzheimer's disease is associated withsleep disorders but the precise relationship is unclear.[210][211] It was once thought that as people get older, the risk of developing sleep disorders and AD independently increase, but research suggests sleep disorders may be a risk factor for AD.[212] One theory is that the mechanisms to increase clearance of toxic substances, includingAβ, are active during sleep.[210][213] With decreased sleep, a person is increasing Aβ production and decreasing Aβ clearance, resulting in Aβ accumulation.[97][210][211] Receiving adequate sleep (approximately 7–8 hours) every night has become a potential lifestyle intervention to prevent the development of AD.[5]
Stress is a risk factor for the development of AD.[5] The mechanism by which stress predisposes someone to development of AD is unclear, but it is suggested that lifetime stressors may affect a person'sepigenome, leading to an overexpression or under expression of specific genes.[214] Although the relationship of stress and AD is unclear, strategies to reduce stress and relax the mind may be helpful strategies in preventing the progression or Alzheimer's disease.[215] Meditation, for instance, is a helpful lifestyle change to support cognition and well-being, though further research is needed to assess long-term effects.[206]
Management
There is no cure for AD;[216] available treatments offer relatively small symptomatic benefits but remainpalliative in nature.[14][217] Treatments can be divided into pharmaceutical, psychosocial, and caregiving.
Reduction in the activity of thecholinergic neurons is a well-known feature of AD.[221] Acetylcholinesterase inhibitors are employed to reduce the rate at which the body breaks downacetylcholine (ACh), thereby increasing the concentration of ACh in the brain and combating the loss of ACh caused by the death of cholinergic neurons.[222] Evidence supports medical efficacy in mild to moderate AD,[223][218] and somewhat in the advanced stage.[218] This does not extend to delaying symptom onset.[224]
An extract ofGinkgo biloba known asEGb 761 has been used for treating AD and other neuropsychiatric disorders.[230] Its use is approved throughout Europe.[231] TheWorld Federation of Biological Psychiatry guidelines lists EGb 761 with the same weight of evidence (level B) given to acetylcholinesterase inhibitors and memantine. EGb 761 is the only one that showed improvement of symptoms in both AD and vascular dementia. EGb 761 may have a role either on its own or as an add-on to other therapies.[230] A 2016 review concluded that the quality of evidence from clinical trials onG. biloba has been insufficient to warrant its use.[232] Further studies suggested that Ginkgoleaves contain pharmacologically more effective substances than those contained in EGb 761, which may allow for causal treatment of preclinical Alzheimer's dementia.[233] Chaperones from plant protein extracts play an important role in this context.[234]
Atypical antipsychotics are modestly useful in reducingaggression andpsychosis in people with AD, but their advantages are offset by serious adverse effects, such asstroke,movement difficulties or cognitive decline.[235] When used in the long-term, they have been reported to associate with increased mortality.[236] They are recommended in dementia only after first line therapies such as behavior modification have failed, and due to the risk of adverse effects, they should be used for the shortest amount of time possible.[161] Stopping antipsychotic use in this group of people appears to be safe.[237]
Twoantibodies have been approved to target amyloid beta –donanemab andlecanemab[242][243][244] – but as of 2025, their role in treatment is uncertain because of side effects, questions about efficacy, and cost.[245]
Psychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within behavior-, emotion-, cognition- or stimulation-oriented approaches.[needs update][250]
Behavioral interventions attempt to identify and reduce the antecedents and consequences of problem behaviors. This approach has not reported success in improving overall functioning,[251] but can help to reduce some specific problem behaviors, such asincontinence.[252] There is a lack of high quality data on the effectiveness of these techniques in other behavior problems such as wandering.[253][254]Music therapy is effective in reducing behavioral and psychological symptoms.[255]
Emotion-oriented interventions includereminiscence therapy,validation therapy, supportivepsychotherapy,sensory integration, also calledsnoezelen, andsimulated presence therapy. A Cochrane review has found no evidence that this is effective.[256] Reminiscence therapy (RT) involves the discussion of past experiences individually or in group, many times with the aid of photographs, household items, music and sound recordings, or other familiar items from the past. A 2018 review of the effectiveness of RT found that effects were inconsistent, small in size and of doubtful clinical significance, and varied by setting.[257] Simulated presence therapy (SPT) is based onattachment theories and involves playing a recording with voices of the closest relatives of the person with AD. There is partial evidence indicating that SPT may reducechallenging behaviors.[258]
The aim of cognition-oriented treatments, which include reality orientation andcognitive retraining, is the reduction ofcognitive deficits. Reality orientation consists of the presentation of information about time, place, or person to ease the understanding of the person about its surroundings and his or her place in them. On the other hand, cognitive retraining tries to improve impaired capacities by exercising mental abilities. Both have reported some efficacy improving cognitive capacities.[259]
Stimulation-oriented treatments includeart,music andpet therapies,exercise, and any other kind ofrecreational activities. Stimulation has modest support for improving behavior, mood, and, to a lesser extent, function. Nevertheless, as important as these effects are, the main support for the use of stimulation therapies is the change in the person's routine.[250]
Since AD has no cure and it gradually renders people incapable of tending to their own needs, caregiving is essentially the treatment and must be carefully managed over the course of the disease.
During the early and moderate stages, modifications to the living environment and lifestyle can increasesafety and reduce caretaker burden.[260][261] Examples of such modifications are the adherence to simplified routines, the placing of safety locks, the labeling of household items to cue the person with the disease or the use of modified daily life objects.[250][262][263] If eating becomes problematic, food will need to be prepared in smaller pieces or evenpuréed.[264] Whenswallowing difficulties arise, the use offeeding tubes may be required. In such cases, the medical efficacy and ethics of continuing feeding is an important consideration of the caregivers and family members.[265][266] The use of physical restraints is rarely indicated in any stage of the disease, although there are situations when they are necessary to prevent harm to the person with Alzheimer's disease or their caregivers.[250]
During the final stages of the disease, treatment is centred on relieving discomfort until death, often with the help ofhospice.[267]
Diet
Diet may be a modifiable risk factor for the development of Alzheimer's disease but more research needs to be conducted.[268] TheMediterranean diet, and theDASH diet are both associated with less cognitive decline.[269] A different approach has been to incorporate elements of both of these diets into one known as theMIND diet.[269] Results from large-scaleepidemiological studies and clinical trials have not demonstrated an independent role for most individual dietary components.[269]
Prognosis
The early stages of AD are difficult to diagnose. A definitive diagnosis is usually made once cognitive impairment compromises daily living activities, although the person may still be living independently. The symptoms will progress from mild cognitive problems, such as memory loss through increasing stages of cognitive and non-cognitive disturbances, eliminating any possibility of independent living, especially in the late stages of the disease.[42]
Life expectancy of people with AD is reduced.[270] The normal life expectancy for 60 to 70 years old is 23 to 15 years; for 90 years old it is 4.5 years.[271] Following AD diagnosis it ranges from 7 to 10 years for those in their 60s and early 70s (a loss of 13 to 8 years), to only about 3 years or less (a loss of 1.5 years) for those in their 90s.[270]
As of 1995, fewer than 3% of people live more than fourteen years after diagnosis.[272] Disease features significantly associated with reduced survival are an increased severity of cognitive impairment, decreased functional level, disturbances in the neurological examination, history offalls,malnutrition,dehydration andweight loss.[3] Other coincident diseases such asheart problems,diabetes, or history ofalcohol abuse are also related with shortened survival.[273][274][275] While the earlier the age at onset the higher the total survival years, life expectancy is particularly reduced when compared to the healthy population among those who are younger.[276]
Men have a less favorable survival prognosis than women.[277] even after controlling for age and some medical conditions.[non-primary source needed][278] As of 2025, the reasons for the higher mortality in men are unknown. It has been speculated that men have different dementia risk factors than women, liketraumatic brain injury.[278]
Aspiration pneumonia is the most frequent immediate cause of death brought by AD.[3] While the reasons behind the lower prevalence ofcancer in AD patients remain unclear, some researchers hypothesize that biological mechanisms shared by both diseases might play a role. However, this requires further investigation.[279]
Two main measures are used inepidemiological studies: incidence and prevalence.Incidence is the number of new cases per unit of person-time at risk (usually number of new cases per thousand person-years); whileprevalence is the total number of cases of the disease in the population at any given time.
Deaths per million persons in 2012 due to dementias including Alzheimer's disease
0–4
5–8
9–10
11–13
14–17
18–24
25–45
46–114
115–375
376–1266
Regarding incidence,cohortlongitudinal studies where a disease-free population is followed over the years have shown rates between 10 and 15 per thousand person-years for all dementias and 5–8 for AD in Spain and Italy,[280][281] which means that half of new dementia cases each year are Alzheimer's disease. Advancing age is a primary risk factor for the disease and incidence rates are not equal for all ages: every 5 years after the age of 65, the risk of acquiring the disease approximately doubles, increasing from 3 to as much as 69 per thousand person years.[280][281] The prevalence of AD in populations is dependent upon factors including incidence and survival. Since the incidence of AD increases with age, prevalence depends on the mean age of the population for which prevalence is given. In the United States in 2020, AD dementia prevalence was estimated to be 5.3% for those in the 60–74 age group, with the rate increasing to 13.8% in the 74–84 group and to 34.6% in those greater than 85.[282] Prevalence rates in some less developed regions around the globe are lower.[283][284] Both the prevalence and incidence rates of AD are steadily increasing, and the prevalence rate is estimated to triple by 2050 reaching 152 million, compared to the 50 million people with AD globally in 2020.[better source needed][14][285][better source needed][286]
Sex difference
Women with AD are more common than males.[29] This difference has been thought to be due to women's longer life spans. According to one study when adjusted for age, both sexes were affected by Alzheimer's at equal rates.[16] However, many studies have found even higher age-adjusted numbers for women, including the Framingham study which found women to have almost twice the lifetime risk of men.[29]
As of 2025 it is unknown why women are more commonly affected by AD, although many theories exist as mentioned in the section causes above.There are also observable differences in the disease course, astau protein accumulates faster in women than in men.[287] Also, presence ofAPOE4 increases AD risk more in women than in men.[288] Even if the same amount of AD pathology observed in a woman compared to a man, there is greater cognitive decline in a woman.[289]
This is relevant for therapy, like the timing of anti-tau treatments[287] ormenopausal hormone therapy: In the Canadian Longitudinal Study of Aging women on MHT had higher memory scores than those who were not on MHT.[89]
Ethnicity
In the United States, the risk of dying from AD in 2010 was 26% higher among the non-Hispanic white population than among the non-Hispanic black population, and the Hispanic population had a 30% lower risk than the non-Hispanic white population.[290] However, much AD research remains to be done in minority groups, such as theAfrican American,East Asian andHispanic/Latino populations.[291][292] Studies have reported that these groups are underrepresented in clinical trials and do not have the same risk of developing AD when carrying certain genetic risk factors (i.e. APOE4), compared to their caucasian counterparts.[292][293][294]
History
Alois Alzheimer's patientAuguste Deter in 1902. Hers was the first described case of what became known as Alzheimer's disease.
Theancient Greek and Roman philosophers andphysicians associated old age with increasingdementia.[30] It was not until 1901 that German psychiatristAlois Alzheimer identified the first case of what became known as Alzheimer's disease, named after him, in a fifty-year-old woman he calledAuguste D. He followed her case until she died in 1906 when he first reported publicly on it.[295] During the next five years, eleven similar cases were reported in themedical literature, some of them already using the term Alzheimer's disease.[30] The disease was first described as a distinctive disease byEmil Kraepelin after suppressing some of the clinical (delusions and hallucinations) and pathological features (arteriosclerotic changes) contained in the original report of Auguste D.[296] He includedAlzheimer's disease, also namedpreseniledementia by Kraepelin, as a subtype ofsenile dementia in the eighth edition of hisTextbook of Psychiatry, published on 15 July 1910.[297]
For most of the 20th century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of dementia. The terminology changed after 1977 when a conference on Alzheimer's disease concluded that the clinical andpathological manifestations of presenile and senile dementia were almost identical, although the authors also added that this did not rule out the possibility that they had different causes.[298] This eventually led to the diagnosis ofAlzheimer's disease independent of age.[299] The termsenile dementia of the Alzheimer type (SDAT) was used for a time to describe the condition in those over 65, with classical Alzheimer's disease being used to describe those who were younger. Eventually, the term Alzheimer's disease was formally adopted in medicalnomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, andneuropathology.[300]
Dementia, and specifically Alzheimer's disease, may be among the most costly diseases for societies worldwide.[304] As populations age, these costs will probably increase and become an importantsocial problem and economic burden.[305] Costs associated with AD include direct and indirect medical costs, which vary between countries depending on social care for a person with AD.[304][306][307] Direct costs include doctor visits, hospital care, medical treatments,nursing home care, specialised equipment, and household expenses.[304][305] Indirect costs include the cost of informal care and the loss inproductivity of informal caregivers.[305]
In the United States as of 2019[update], informal (family) care is estimated to constitute nearly three-fourths of caregiving for people with AD at a cost of US$234 billion per year and approximately 18.5 billion hours of care.[304] The cost to society worldwide to care for individuals with AD is projected to increase nearly ten-fold, and reach about US$9.1 trillion by 2050.[306]
Costs for those with more severe dementia or behavioral disturbances are higher and are related to the additional caregiving time to provide physical care.[307]
This section needs to beupdated. Please help update this article to reflect recent events or newly available information.(February 2022)
Individuals with Alzheimer's will require assistance in their lifetime, and care will most likely come in the form of a full-timecaregiver which is often a role that is taken on by the spouse or a close relative. Caregiving tends to include physical and emotional burdens as well as time and financial strain at times on the person administering the aid.[308][309] Alzheimer's disease is known for placing a great burden on caregivers which includes social, psychological, physical, or economic aspects.[24][310][311] Home care is usually preferred by both those people with Alzheimer's disease as well as their families.[312] This option also delays or eliminates the need for more professional and costly levels of care.[312][313] Nevertheless, two-thirds of nursing home residents have dementias.[250]
Dementia caregivers are subject to high rates of physical andmental disorders.[314] Factors associated with greater psychosocial problems of the primary caregivers include having an affected person at home, the caregiver being a spouse, demanding behaviors of the cared person such as depression, behavioral disturbances, hallucinations, sleep problems or walking disruptions andsocial isolation.[315][316] In the United States, the yearly cost of caring for a person with dementia ranges from $28,078-$56,022 per year for formal medical care and $36,667-$92,689 for informal care provided by a relative or friend (assuming market value replacement costs for the care provided by the informal caregiver) and $15,792-$71,813 in lost wages.[317]
Specific medications that may reduce the risk or progression of Alzheimer's disease include those that impactAβplaques, inflammation,APOE, neurotransmitter receptors, neurogenesis,growth factors or hormones.[332][333][334]
Between 1995 and 2021, more than 140 clinical trials costing $42.5B yielded no drugs. As of 2025, 182 clinical trials were testing 138 drugs against multiple targets.[336]
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