Alzheimer's disease

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"Alzheimer" redirects here. For the namesake of the disease, see Alois Alzheimer. For other uses, see Alzheimer (disambiguation).

Alzheimer's disease
Other namesAlzheimer's dementia
Trisomy 21[10]
MedicationAcetylcholinesterase inhibitors, NMDA receptor antagonists[11]
PrognosisLife expectancy 3–12 years[11][12][13]
Frequency50 million (2020)[14]
Named afterAlois Alzheimer

Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens.[2] It is the cause of 60–70% of cases of dementia.[2][15] The most common early symptom is difficulty in remembering recent events.[1] As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, self-neglect, and behavioral issues.[2] As a person's condition declines, they often withdraw from family and society.[16] Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the average life expectancy following diagnosis is three to twelve years.[11][12][13]

The causes of Alzheimer's disease remain poorly understood.

normal brain aging.[16] Examination of brain tissue is needed for a definite diagnosis, but this can only take place after death.[21][22]

No treatments can stop or reverse its progression, though some may temporarily improve symptoms.[2] A healthy diet, physical activity, and social engagement are generally beneficial in aging, and may help in reducing the risk of cognitive decline and Alzheimer's.[19] Affected people become increasingly reliant on others for assistance, often placing a burden on caregivers.[23] The pressures can include social, psychological, physical, and economic elements.[23] Exercise programs may be beneficial with respect to activities of daily living and can potentially improve outcomes.[24] Behavioral problems or psychosis due to dementia are sometimes treated with antipsychotics, but this has an increased risk of early death.[25][26]

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 are early-onset impacting those in their 30s to mid-60s.[27][4] It affects about 6% of people 65 years and older,[16] and women more often than men.[28] The disease is named after German psychiatrist and pathologist Alois Alzheimer, who first described it in 1906.[29] Alzheimer's financial burden on society is large, with an estimated global annual cost of US$1 trillion.[14] It is ranked as the seventh leading cause of death worldwide.[30]

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 US National 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.[31] In the European Union, the 2020 Horizon Europe research programme awarded over €570 million for dementia-related projects.[32]

Signs and symptoms

The course of Alzheimer's is generally described in three stages, with a progressive pattern of

cognitive and functional impairment.[33][27] The three stages are described as early or mild, middle or moderate, and late or severe.[33] The disease is known to target the hippocampus which is associated with memory, and this is responsible for the first symptoms of memory impairment. As the disease progresses so does the degree of memory impairment.[19]

First symptoms

Stages of atrophy in Alzheimer's

The first symptoms are often mistakenly attributed to

short term memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information.[35]

Subtle problems with the

prodromal or early stage of Alzheimer's disease.[39] Amnestic MCI has a greater than 90% likelihood of being associated with Alzheimer's.[40]

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.[41] Alzheimer's disease does not affect all memory capacities equally. Older memories of the person's life (episodic memory), facts learned (semantic memory), and implicit 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.[42][43]

Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, leading to a general impoverishment of oral and written language.[41][44] In this stage, the person with Alzheimer's is usually capable of communicating basic ideas adequately.[41][44][45] While performing fine motor tasks such as writing, drawing, or dressing, certain movement coordination and planning difficulties (apraxia) may be present; however, they are commonly unnoticed.[41] 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.[41]

Middle stage

Progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities of daily living.[41] Speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also progressively lost.[41][45] Complex motor sequences become less coordinated as time passes and Alzheimer's disease progresses, so the risk of falling increases.[41] During this phase, memory problems worsen, and the person may fail to recognise close relatives.[41] Long-term memory, which was previously intact, becomes impaired.[41]

Behavioral and

neuropsychiatric changes become more prevalent. Common manifestations are wandering, irritability and emotional lability, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving.[41] Sundowning can also appear.[46] Approximately 30% of people with Alzheimer's disease develop illusionary misidentifications and other delusional symptoms.[41] Subjects also lose insight of their disease process and limitations (anosognosia).[41] Urinary incontinence can develop.[41] These symptoms create stress for relatives and caregivers, which can be reduced by moving the person from home care to other long-term care facilities.[41][47]

Late stage

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.

paradoxical lucidity immediately before death, where there is an unexpected recovery of mental clarity.[48]

Causes

Alzheimer's disease is believed to occur when abnormal amounts of amyloid beta (Aβ), accumulating extracellularly as amyloid plaques and tau proteins, or intracellularly as neurofibrillary tangles, form in the brain, affecting neuronal functioning and connectivity, resulting in a progressive loss of brain function.[49][50] This altered protein clearance ability is age-related, regulated by brain cholesterol,[51] and associated with other neurodegenerative diseases.[52][53]

The cause for most Alzheimer's cases is still mostly unknown,

hypotheses attempt to explain the underlying cause; the most predominant hypothesis is the amyloid beta (Aβ) hypothesis.[14]

In the 1970s, the

APOE4, is a major genetic risk factor for Alzheimer's disease.[15] While apolipoproteins enhance the breakdown of amyloid beta, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain.[56]

Genetic

Late onset

Late-onset Alzheimer's is about 70%

familial, and so they are termed sporadic Alzheimer's disease.[60] Of the cases of sporadic Alzheimer's disease, most are classified as late onset where they are developed after the age of 65 years.[61]

The strongest genetic risk factor for sporadic Alzheimer's disease is

homozygotes.[64] Like many human diseases, environmental effects and genetic modifiers result in incomplete penetrance. For example, Nigerian Yoruba 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.[65][66]

Early onset

Further information: Early-onset Alzheimer's disease

Only 1–2% of Alzheimer's cases are

inherited due to autosomal dominant effects, as Alzheimer's is highly polygenic. When the disease is caused by autosomal dominant variants, it is known as early onset familial Alzheimer's disease, which is rarer and has a faster rate of progression.[17] Less than 5% of sporadic Alzheimer's disease have an earlier onset,[17] and early-onset Alzheimer's is about 90% heritable.[57][58] Familial Alzheimer's disease usually implies two or more persons affected in one or more generations.[67][68][69]

Early onset familial Alzheimer's disease can be attributed to mutations in one of three genes: those encoding

PSEN2.[40] Most mutations in the APP and presenilin genes increase the production of a small protein called amyloid beta (Aβ)42, which is the main component of amyloid plaques.[70] Some of the mutations merely alter the ratio between Aβ42 and the other major forms—particularly Aβ40—without increasing Aβ42 levels in the brain.[71] Two other genes associated with autosomal dominant Alzheimer's disease are ABCA7 and SORL1.[72]

Alleles in the TREM2 gene have been associated with a three to five times higher risk of developing Alzheimer's disease.[73]

A Japanese pedigree of familial Alzheimer's disease was found to be associated with a deletion mutation of codon 693 of APP.[74] This mutation and its association with Alzheimer's disease was first reported in 2008,[75] 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.[76]

Hypotheses

Amyloid beta and tau protein

Tau protein abnormalities in neurons may contribute to onset of Alzheimer's disease

The

paired helical filaments. Eventually, they form neurofibrillary tangles inside neurons.[77] When this occurs, the microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system.[77]

A number of studies connect the misfolded amyloid beta and tau proteins associated with the pathology of Alzheimer's disease, as bringing about

Spirochete infections have also been linked to dementia.[14] DNA damages accumulate in Alzheimer's diseased brains; reactive oxygen species may be the major source of this DNA damage.[80]

Sleep

Sleep disturbances are seen as a possible risk factor for inflammation in Alzheimer's disease.[81] Sleep disruption was previously only seen as a consequence of Alzheimer's disease, but as of 2020, accumulating evidence suggests that this relationship may be bidirectional.[82][83]

Metal toxicity, smoking, neuroinflammation and air pollution

The cellular

Exposure to air pollution may be a contributing factor to the development of Alzheimer's disease.[14]

Retrogenesis is a medical

demyelination and death of axons (white matter) and ending with the death of grey matter.[86] Likewise the hypothesis is, that as infants go through states of cognitive development, people with Alzheimer's disease go through the reverse process of progressive cognitive impairment.[87]

According to one theory, dysfunction of

hyperphosphorylation.[88][89] Comorbidities between the demyelinating disease, multiple sclerosis, and Alzheimer's disease have been reported.[90]

Other hypotheses

See also:
celiac 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.[91][92]

Studies have shown a potential link between infection with certain viruses and developing Alzheimer's disease later in life.[93] Notably, a large scale study conducted on 6,245,282 patients has shown an increased risk of developing Alzheimer's disease following COVID-19 infection in cognitively normal individuals over 65.[94]

Some evidence suggests that some viral infections such as Herpes 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.[95][96][97]

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.[98]

Pathophysiology

Neuropathology

CA3 area of the hippocampus, showing an amyloid plaque (top right), neurofibrillary tangles (bottom left), and granulovacuolar degeneration bodies
(bottom center)

Alzheimer's disease is characterised by loss of

cingulate gyrus.[99] Degeneration is also present in brainstem nuclei particularly the locus coeruleus in the pons.[100] Studies using MRI and PET have documented reductions in the size of specific brain regions in people with Alzheimer's disease as they progressed from mild cognitive impairment to Alzheimer's disease, and in comparison with similar images from healthy older adults.[101][102]

Both

insoluble deposits of amyloid beta peptide and cellular material outside and around neurons. Neurofibrillary tangles are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves. 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 such as the temporal lobe.[106] Lewy bodies are not rare in the brains of people with Alzheimer's disease.[107]

Biochemistry

Main article: Biochemistry of Alzheimer's disease

Amyloid beta

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.

Alzheimer's disease has been identified as a

tau protein into neurofibrillary tangles in the brain.[77] Plaques are made up of small peptides, 39–43 amino acids in length, called amyloid beta. Amyloid beta is a fragment from the larger amyloid-beta precursor protein (APP) a transmembrane protein that penetrates the cell's membrane. APP is critical to neuron growth, survival, and post-injury repair.[77] In Alzheimer's disease, gamma secretase and beta secretase act together in a proteolytic process which causes APP to be divided into smaller fragments.[77] Although commonly researched as neuronal proteins, APP and its processing enzymes are abundantly expressed by other brain cells. One of these fragments gives rise to fibrils of amyloid beta, which then form clumps that deposit outside neurons in dense formations known as amyloid plaques.[77] Excitatory neurons are known to be the major producers of amyloid beta that contribute to major extracellular plaque deposition.[77]

Phosphorylated tau

Alzheimer's disease is also considered a

microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilises the microtubules when phosphorylated, and is therefore called a microtubule-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.[108] Pathogenic tau can also cause neuronal death through transposable element dysregulation.[109] Necroptosis has also been reported as a mechanism of cell death in brain cells affected with tau tangles.[110][111]

Disease mechanism

Exactly how disturbances of production and aggregation of the beta-amyloid

amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces programmed cell death (apoptosis).[114] It is also known that Aβ selectively builds up in the mitochondria in the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilisation of glucose by neurons.[115]

Evidence supports Aβ as playing a central role in the pathogenesis of AD, but it does not completely explain the condition, as individuals may have normal cognition and very high Aβ burden in their brains at an advanced age,[medical citation needed] and the beneficial effect of therapeutics (such as monoclonal antibodies) promoting Aβ clearance has ranged from nonexistent to modest.[116]

Iron dyshomeostasis is linked to disease progression, an iron-dependent form of regulated cell death called ferroptosis could be involved. Products of lipid peroxidation are also elevated in AD brain compared with controls.[117]

Various inflammatory processes and

immunological response.[118] There is increasing evidence of a strong interaction between the neurons and the immunological mechanisms in the brain. Obesity and systemic inflammation may interfere with immunological processes which promote disease progression.[119]

Alterations in the distribution of different

neurotrophic factors and in the expression of their receptors such as the brain-derived neurotrophic factor (BDNF) have been described in Alzheimer's disease.[120][121]

Evidence has accrued for microglia as central actors in the mechanism of AD.[122] Microglia are topographically associated with pTau and Aβ within the brain, even when each pathologic component occurs in distinct brain regions,[123] and microglial activation has been documented in those with mild cognitive impairment, despite a lack of tracer uptake, suggesting that microglial dysfunction may precede plaque deposition as an inciting event in AD.[124] Microglia are the principal immunological cells of the central nervous system, serving as the tissue-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.[125] However, microglia can also be a major source of pro-inflammatory mediators which can be deleterious to neurological function.[125]

Diagnosis

See also: Early-onset Alzheimer's disease § Diagnosis
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.[21][22][126] 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.[22]

AD is usually clinically diagnosed based on a person's

florbetaben (2014), and flortaucipir (2020).[132] 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.[133]

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 with post-mortem evaluations when brain material is available and can be examined histologically for senile plaques and neurofibrillary tangles.[133][134]

Criteria

There are three sets of criteria for the clinical diagnoses of the spectrum of Alzheimer's disease: the 2013 fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5); the National Institute on Aging-Alzheimer's Association (NIA-AA) definition as revised in 2011; and the International Working Group criteria as revised in 2010.[40][133]

Eight intellectual domains are most commonly impaired in AD—

executive functional abilities, as listed in the fourth text revision of the DSM (DSM-IV-TR).[135]

The DSM-5 defines criteria for probable or possible AD for both major and mild neurocognitive disorder.[136][137][126] Major or mild neurocognitive disorder must be present along with at least one cognitive deficit for a diagnosis of either probable or possible AD.[136][138] For major neurocognitive disorder due to AD, probable Alzheimer's disease can be diagnosed if the individual has genetic evidence of AD[139] or if two or more acquired cognitive deficits, and a functional disability that is not from another disorder, are present.[140] Otherwise, possible AD can be diagnosed as the diagnosis follows an atypical route.[141] 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.[136][142]

The NIA-AA criteria are used mainly in research rather than in clinical assessments.[143] They define AD through three major stages: preclinical, mild cognitive impairment (MCI), and Alzheimer's dementia.[144][145] Diagnosis in the preclinical stage is complex and focuses on asymptomatic individuals;[145][146] the latter two stages describe individuals experiencing symptoms,[145] along with biomarkers,[147] predominantly those for neuronal injury (mainly tau-related) and amyloid beta deposition.[143][145] The core clinical criteria itself rests on the presence of cognitive impairment[145] without the presence of comorbidities.[148][149] The third stage is divided into probable and possible AD dementia.[149] In probable AD dementia there is steady impairment of cognition over time and a memory-related or non-memory-related cognitive dysfunction.[149] In possible AD dementia, another causal disease such as cerebrovascular disease is present.[149]

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 shown, remember some words, read, and subtract numbers serially.

Neuropsychological tests including cognitive tests such as the mini–mental state examination (MMSE), the Montreal Cognitive Assessment (MoCA) and the Mini-Cog are widely used to aid in diagnosis of the cognitive impairments in AD.[150] These tests may not always be accurate, as they lack sensitivity to mild cognitive impairment, and can be biased by language or attention problems;[150] more comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease.[151][152]

Further neurological examinations are crucial in the

mental function.[153] A caregiver's viewpoint is particularly important, since a person with Alzheimer's disease is commonly unaware of their deficits.[154] Many times, families have difficulties in the detection of initial dementia symptoms and may not communicate accurate information to a physician.[155]

Supplemental testing can rule out other potentially treatable diagnoses and help avoid misdiagnoses.[156] Common supplemental tests include blood tests, thyroid function tests, as well as tests to assess vitamin B12 levels, rule out neurosyphilis and rule out metabolic problems (including tests for kidney function, electrolyte levels and for diabetes).[156] MRI or CT scans might also be used to rule out other potential causes of the symptoms – including tumors or strokes.[150] Delirium and depression can be common among individuals and are important to rule out.[157]

Psychological tests for depression are used, since depression can either be concurrent with AD (see Depression of Alzheimer disease), an early sign of cognitive impairment,[158] or even the cause.[159][160]

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).[161] The use of 18F-FDG PET scans, as a single test, to identify people who may develop Alzheimer's disease is not supported by evidence.[162]

Prevention

Intellectual activities such as playing chess 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 no disease-modifying treatments available to cure Alzheimer's disease and because of this, AD research has focused on interventions to prevent the onset and progression.[163] 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.[164] 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.[164] Further research is needed to determine factors that can help prevent AD.[164]

Medication

Cardiovascular risk factors, such as

Antihypertensive and antidiabetic medications in individuals without overt cognitive impairment may decrease the risk of dementia by influencing cerebrovascular pathology.[1][168] 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 of

hormone replacement therapy (HRT) in menopause decreases risk of cognitive decline.[169]

Lifestyle

Further information: Neurobiological effects of physical exercise

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.[170] Memory and cognitive functions can be improved with aerobic exercises including brisk walking three times weekly for forty minutes.[171] It may also induce neuroplasticity of the brain.[172] Participating in mental exercises, such as reading, crossword puzzles, and chess have shown potential to be preventive.[5] Meeting the WHO recommendations for physical activity is associated with a lower risk of AD.[173]

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 the cognitive 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.[174]

Cessation in smoking may reduce risk of developing AD, specifically in those who carry the

APOE ɛ4 allele.[175][5] The increased oxidative stress caused by smoking results in downstream inflammatory or neurodegenerative processes that may increase risk of developing AD.[176] 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 with sleep disorders but the precise relationship is unclear.[177][178] 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.[179] One theory is that the mechanisms to increase clearance of toxic substances, including Aβ, are active during sleep.[177][180] With decreased sleep, a person is increasing Aβ production and decreasing Aβ clearance, resulting in Aβ accumulation.[181][177][178] 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's epigenome, leading to an overexpression or under expression of specific genes.[182] 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.[183] Meditation, for instance, is a helpful lifestyle change to support cognition and well-being, though further research is needed to assess long-term effects.[172]

Management

There is no cure for AD;[184] available treatments offer relatively small symptomatic benefits but remain palliative in nature.[14][185] Treatments can be divided into pharmaceutical, psychosocial, and caregiving.

Pharmaceutical

Three-dimensional molecular model of donepezil, an acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease symptoms
Molecular structure of memantine, a medication approved for advanced Alzheimer's disease symptoms

Medications used to treat the cognitive symptoms of AD rather than the underlying cause include: four acetylcholinesterase inhibitors (tacrine, rivastigmine, galantamine, and donepezil) and memantine, an NMDA receptor antagonist. The acetylcholinesterase inhibitors are intended for those with mild to severe AD, whereas memantine is intended for those with moderate or severe Alzheimer's disease.[133] The benefit from their use is small.[186][187][188][15]

Reduction in the activity of the cholinergic neurons is a well-known feature of AD.[189] Acetylcholinesterase inhibitors are employed to reduce the rate at which acetylcholine (ACh) is broken down, thereby increasing the concentration of ACh in the brain and combating the loss of ACh caused by the death of cholinergic neurons.[190] There is evidence for the efficacy of these medications in mild to moderate AD,[191][186] and some evidence for their use in the advanced stage.[186] The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of Alzheimer's disease.[192] The most common side effects are nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately 10–20% of users, are mild to moderate in severity, and can be managed by slowly adjusting medication doses.[193] Less common secondary effects include muscle cramps, decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid production.[191]

glutamatergic system by blocking NMDA receptors and inhibiting their overstimulation by glutamate.[194][195] Memantine has been shown to have a small benefit in the treatment of moderate to severe AD.[196] Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue.[197][198] The combination of memantine and donepezil[199] has been shown to be "of statistically significant but clinically marginal effectiveness".[200]

An extract of Ginkgo biloba known as EGb 761 has been used for treating AD and other neuropsychiatric disorders.[201] Its use is approved throughout Europe.[202] The World 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 if other therapies prove ineffective.[201] A 2016 review concluded that the quality of evidence from clinical trials on Ginkgo biloba has been insufficient to warrant its use for treating AD.[203]

Atypical antipsychotics are modestly useful in reducing aggression and psychosis in people with AD, but their advantages are offset by serious adverse effects, such as stroke, movement difficulties or cognitive decline.[204] When used in the long-term, they have been shown to associate with increased mortality.[205] 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.[127] Stopping antipsychotic use in this group of people appears to be safe.[206]

Psychosocial

Psychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within behavior-, emotion-, cognition- or stimulation-oriented approaches.[needs update][207]

Behavioral interventions attempt to identify and reduce the antecedents and consequences of problem behaviors. This approach has not shown success in improving overall functioning,[208] but can help to reduce some specific problem behaviors, such as incontinence.[209] There is a lack of high quality data on the effectiveness of these techniques in other behavior problems such as wandering.[210][211] Music therapy is effective in reducing behavioral and psychological symptoms.[212]

Emotion-oriented interventions include

challenging behaviors.[215]

The aim of cognition-oriented treatments, which include reality orientation and

cognitive 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 shown some efficacy improving cognitive capacities.[216]

Stimulation-oriented treatments include art, music and pet therapies, exercise, and any other kind of recreational 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.[207]

Caregiving

Further information:
Caring for people with dementia and Palliative care

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 increase safety and reduce caretaker burden.[217][218] 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.[207][219][220] If eating becomes problematic, food will need to be prepared in smaller pieces or even puréed.[221] When swallowing difficulties arise, the use of feeding 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.[222][223] 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.[207]

During the final stages of the disease, treatment is centred on relieving discomfort until death, often with the help of hospice.[224]

Diet

Diet may be a modifiable risk factor for the development of Alzheimer's disease but more research needs to be conducted.[225] The Mediterranean diet, and the DASH diet are both associated with less cognitive decline.[226] A different approach has been to incorporate elements of both of these diets into one known as the MIND diet.[226] Results from large-scale epidemiological studies and clinical trials have not demonstrated an independent role for most individual dietary components.[226]

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.[41]

Life expectancy of people with AD is reduced.[227] The normal life expectancy for 60 to 70 years old is 23 to 15 years; for 90 years old it is 4.5 years.[228] 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.[227]

Fewer than 3% of people live more than fourteen years after diagnosis.

diabetes, or history of alcohol abuse are also related with shortened survival.[230][231][232] 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.[233] Men have a less favourable survival prognosis than women.[needs update][229][234]

Aspiration pneumonia is the most frequent immediate cause of death brought by AD.[3] While the reasons behind the lower prevalence of cancer in AD patients remain unclear, some researchers hypothesize that biological mechanisms shared by both diseases might play a role. However, this requires further investigation.[235]

Epidemiology

See also:
Alzheimer's Disease in the East Asian Population

Two main measures are used in epidemiological 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); while prevalence 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,

East Asian and Hispanic/Latino populations.[239][240] Studies have shown 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.[240][241][242]

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.

better source needed][247]

History

Alois Alzheimer's patient Auguste Deter in 1902. Hers was the first described case of what became known as Alzheimer's disease.

The

Auguste D. He followed her case until she died in 1906 when he first reported publicly on it.[248] During the next five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer's disease.[29] The disease was first described as a distinctive disease by Emil Kraepelin after suppressing some of the clinical (delusions and hallucinations) and pathological features (arteriosclerotic changes) contained in the original report of Auguste D.[249] He included Alzheimer's disease, also named presenile dementia by Kraepelin, as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published on 15 July 1910.[250]

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 and

pathological 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.[251] This eventually led to the diagnosis of Alzheimer's disease independent of age.[252] The term senile 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 medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology.[253]

The

brain tissue is required for a definitive diagnosis. Good statistical reliability and validity have been shown between the diagnostic criteria and definitive histopathological confirmation.[256]

Society and culture

See also:
Alzheimer's disease organizations

Social costs

Dementia, and specifically Alzheimer's disease, may be among the most costly diseases for societies worldwide.

nursing home care, specialised equipment, and household expenses.[257][258] Indirect costs include the cost of informal care and the loss in productivity of informal caregivers.[258]

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.[257] 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.[259]

Costs for those with more severe dementia or behavioral disturbances are higher and are related to the additional caregiving time to provide physical care.[260]

Caregiving burden

Further information:
Caregiving and dementia

Individuals with Alzheimer's will require assistance in their lifetime, and care will most likely come in the form of a full-time caregiver 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.[261][262] Alzheimer's disease is known for placing a great burden on caregivers which includes social, psychological, physical, or economic aspects.[23][263][264] Home care is usually preferred by both those people with Alzheimer's disease as well as their families.[265] This option also delays or eliminates the need for more professional and costly levels of care.[265][266] Nevertheless, two-thirds of nursing home residents have dementias.[207]

Dementia caregivers are subject to high rates of physical and mental disorders.[267] 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 and social isolation.[268][269] 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.[270]

coping strategies either individually or in group have demonstrated their efficacy in improving caregivers' psychological health.[23][271]

Media

Main article: Alzheimer's disease in the media

Alzheimer's disease has been portrayed in films such as:

Memories of Tomorrow (Ashita no Kioku) (2006), based on Hiroshi Ogiwara's novel of the same name;[275] Away from Her (2006), based on Alice Munro's short story The Bear Came over the Mountain;[276] Still Alice (2014), about a Columbia University professor who has early onset Alzheimer's disease, based on Lisa Genova's 2007 novel of the same name and featuring Julianne Moore in the title role. Documentaries on Alzheimer's disease include Malcolm and Barbara: A Love Story (1999) and Malcolm and Barbara: Love's Farewell (2007), both featuring Malcolm Pointon.[277][278][279]

Alzheimer's disease has also been portrayed in music by English musician the Caretaker in releases such as Persistent Repetition of Phrases (2008), An Empty Bliss Beyond This World (2011), and Everywhere at the End of Time (2016–2019).[280][281][282] Paintings depicting the disorder include the late works by American artist William Utermohlen, who drew self-portraits from 1995 to 2000 as an experiment of showing his disease through art.[283][284]

Research directions

See also:
Anti-amyloid drugs

Antibodies may have the ability to alter the disease course by targeting amyloid beta with immunotherapy medications such as donanemab and lecanemab.[285][286][287]

Lecanemab was approved via the FDA accelerated approval process,[288][289][290][291] and was converted to traditional approval in July 2023, after further testing, along with the addition of a boxed warning about amyloid-related imaging abnormalities.[292][293] As of early August 2024, lecanemab was approved for sale in Japan, South Korea, China, Hong Kong and Israel although it was recommended against approval by an advisory body of the European Union on July 26, citing its side effects.[294]

Donanemab was approved by the FDA in July 2024.[295] Anti-amyloid drugs also cause brain shrinkage.[296] The cholinesterase inhibitor benzgalantamine was approved by the FDA in July 2024.[297]

Specific medications that may reduce the risk or progression of Alzheimer's disease have been studied.

Aβ plaques, inflammation, APOE, neurotransmitter receptors, neurogenesis, growth factors or hormones.[298][299][300]

Machine learning algorithms with electronic health records are being studied as a way to predict Alzheimer's disease earlier.[301]

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