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Alzheimer's disease (AD) is a
neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...
and the cause of 60–70% of cases of
dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems with language,
disorientation Orientation is a function of the mind involving awareness of three dimensions: time, place and person. Problems with orientation lead to ''dis''orientation, and can be due to various conditions. It ranges from an inability to coherently understand ...
(including easily getting lost),
mood swing A mood swing is an extreme or sudden change of mood. Such changes can play a positive or a disruptive part in promoting problem solving and in producing flexible forward planning. When mood swings are severe, they may be categorized as part ...
s, loss of
motivation Motivation is an mental state, internal state that propels individuals to engage in goal-directed behavior. It is often understood as a force that explains why people or animals initiate, continue, or terminate a certain behavior at a particul ...
,
self-neglect Self-neglect is a behavioral condition in which an individual neglects to attend to their basic needs, such as personal hygiene, appropriate clothing, feeding, or tending appropriately to any illness, medical conditions they have. More generally, ...
, and behavioral issues. As a person's condition declines, they often withdraw from family and society. 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. The causes of Alzheimer's disease remain poorly understood. There are many environmental and genetic
risk factor In epidemiology, a risk factor or determinant is a variable associated with an increased risk of disease or infection. Due to a lack of harmonization across disciplines, determinant, in its more widely accepted scientific meaning, is often use ...
s associated with its development. The strongest genetic risk factor is from an
allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...
of
apolipoprotein E Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene ''APOE''. Apo-E belongs to a family ...
. Other risk factors include a history of
head injury A head injury is any injury that results in trauma to the skull or brain. The terms ''traumatic brain injury'' and ''head injury'' are often used interchangeably in the medical literature. Because head injuries cover such a broad scope of inju ...
,
clinical depression Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...
, and
high blood pressure Hypertension, also known as high blood pressure, is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms itself. It is, however, a major ri ...
. The progression of the disease is largely characterised by the accumulation of malformed protein deposits in the
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...
, called
amyloid plaques Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of amyloid beta (Aβ) protein that present mainly in the grey matter of the brain. Degeneration (medical), Degenerative neuronal ...
and
neurofibrillary tangles Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary Biomarker (medicine), biomarker of Alzheimer's disease. Their presence is also found in numerous other disea ...
. These misfolded protein aggregates interfere with normal cell function, and over time lead to irreversible degeneration of neurons and loss of synaptic connections in the
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
. A probable diagnosis is based on the history of the illness and
cognitive test Cognitive tests are assessments of the cognitive capabilities of humans and other animals. Tests administered to humans include various forms of IQ tests; those administered to animals include the mirror test (a test of visual self-awareness) and ...
ing, with
medical imaging Medical imaging is the technique and process of imaging the interior of a body for clinical analysis and medical intervention, as well as visual representation of the function of some organs or tissues (physiology). Medical imaging seeks to revea ...
and
blood test A blood test is a medical laboratory, laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a hypodermic needle, or via fingerprick. Multiple tests for specific blood components, such as a glucose ...
s to rule out other possible causes. Initial symptoms are often mistaken for normal brain aging. Examination of brain tissue is needed for a definite diagnosis, but this can only take place after death. No treatments can stop or reverse its progression, though some may temporarily improve symptoms. A
healthy diet A healthy diet is a diet that maintains or improves overall health. A healthy diet provides the body with essential nutrition: fluid, macronutrients such as protein, micronutrients such as vitamins, and adequate fibre and food energy. A he ...
,
physical activity Physical activity is defined as any voluntary movement produced by skeletal muscles that requires energy expenditure.Global Recommendations on Physical Activity for Health, 2009. World Health Organization. Geneva, Switzerland. Accessed 13/07/2018 ...
, and
social engagement Social engagement (also social involvement, social participation) refers to one's degree of participation in a community or society. Definitions The term "social engagement" is commonly used to refer to one's participation in the activities o ...
are generally beneficial in aging, and may help in reducing the risk of cognitive decline and Alzheimer's. Affected people become increasingly reliant on others for assistance, often placing a burden on
caregivers A caregiver, carer or support worker is a paid or unpaid person who helps an individual with activities of daily living. Caregivers who are members of a care recipient's family or social network, who may have specific professional training, are o ...
. The pressures can include social, psychological, physical, and economic elements. Exercise programs may be beneficial with respect to
activities of daily living Activities of daily living (ADLs) is a term used in healthcare to refer to an individual's daily self-care activities. Health professionals often use a person's ability or inability to perform ADLs as a measure of their Performance status, functi ...
and can potentially improve outcomes. Behavioral problems or
psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...
due to dementia are sometimes treated with
antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...
s, but this has an increased risk of early death. As of 2020, there were approximately 50 million people worldwide with Alzheimer's disease. 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. It affects about 6% of people 65 years and older, and women more often than men. The disease is named after German psychiatrist and pathologist
Alois Alzheimer Alois Alzheimer ( , , ; 14 June 1864 – 19 December 1915) was a German psychiatrist, neuropathologist and colleague of Emil Kraepelin. He is credited with identifying the first published case of "presenile dementia", which Kraepelin later ide ...
, who first described it in 1906. Alzheimer's financial burden on society is large, with an estimated global annual cost of trillion. It is ranked as the seventh leading cause of death worldwide. 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 The National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. It was founded in 1887 and is part of the United States Department of Health and Human Service ...
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. In the
European Union The European Union (EU) is a supranational union, supranational political union, political and economic union of Member state of the European Union, member states that are Geography of the European Union, located primarily in Europe. The u ...
, the 2020
Horizon Europe Horizon Europe is a seven-year European Union scientific research initiative to help develop a sustainable and livable society in Europe. It is the ninth of the Framework Programmes for Research and Technological Development (FP9), and the succe ...
research programme awarded over €570 million for dementia-related projects.


Signs and symptoms

The course of Alzheimer's is generally described in three stages, with a progressive pattern of
cognitive Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...
and functional impairment. The three stages are described as early or mild, middle or moderate, and late or severe. The disease is known to target the
hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...
which is associated with
memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembe ...
, and this is responsible for the first symptoms of memory impairment. As the disease progresses so does the degree of memory impairment.


First symptoms

The first symptoms are often mistakenly attributed to
aging Ageing (or aging in American English) is the process of becoming Old age, older until death. The term refers mainly to humans, many other animals, and fungi; whereas for example, bacteria, perennial plants and some simple animals are potentiall ...
or stress. Detailed
neuropsychological test Neuropsychological tests are specifically designed tasks that are used to measure a psychological function known to be linked to a particular brain structure or pathway. Tests are used for cognitive neuropsychology, research into brain function a ...
ing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for
diagnosis Diagnosis (: diagnoses) is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in a lot of different academic discipline, disciplines, with variations in the use of logic, analytics, and experience, to determine " ...
of Alzheimer's disease. These early symptoms can affect the most complex
activities of daily living Activities of daily living (ADLs) is a term used in healthcare to refer to an individual's daily self-care activities. Health professionals often use a person's ability or inability to perform ADLs as a measure of their Performance status, functi ...
. The most noticeable deficit is short term memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information. Subtle problems with the
executive functions In cognitive science and neuropsychology, executive functions (collectively referred to as executive function and cognitive control) are a set of cognitive processes that support goal-directed behavior, by regulating thoughts and actions thro ...
of attentiveness,
planning Planning is the process of thinking regarding the activities required to achieve a desired goal. Planning is based on foresight, the fundamental capacity for mental time travel. Some researchers regard the evolution of forethought - the cap ...
, flexibility, and
abstract thinking Abstraction is a process where general rules and concepts are derived from the use and classifying of specific examples, literal ( real or concrete) signifiers, first principles, or other methods. "An abstraction" is the outcome of this process ...
, or impairments in
semantic memory Semantic memory refers to general world knowledge that humans have accumulated throughout their lives. This general knowledge (Semantics, word meanings, concepts, facts, and ideas) is intertwined in experience and dependent on culture. New concep ...
(memory of meanings, and concept relationships) can also be symptomatic of the early stages of Alzheimer's disease.
Apathy Apathy, also referred to as indifference, is a lack of feeling, emotion, interest, or concern about something. It is a state of indifference, or the suppression of emotions such as concern, excitement, motivation, or passion. An apathetic i ...
and depression can be seen at this stage, with apathy remaining as the most persistent symptom throughout the course of the disease. People with objective signs of cognitive impairment, but not more severe symptoms, may be diagnosed with
mild cognitive impairment Mild cognitive impairment (MCI) is a diagnosis that reflects an intermediate stage of cognitive impairment that is often, but not always, a transitional phase from cognitive changes in normal aging to those typically found in dementia, especially ...
(MCI). If memory loss is the predominant symptom of MCI, it is termed amnestic MCI and is frequently seen as a
prodromal In medicine, a prodrome is an early Medical sign, sign or symptom (or set of signs and symptoms, referred to as prodromal symptoms) that often indicates the onset of a disease before more diagnostically specific signs and symptoms develop. More spe ...
or early stage of Alzheimer's disease. Amnestic MCI has a greater than 90% likelihood of being associated with Alzheimer's.


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 Perception () is the organization, identification, and interpretation of sensory information in order to represent and understand the presented information or environment. All perception involves signals that go through the nervous syste ...
(
agnosia Agnosia is a neurological disorder characterized by an inability to process sensory information. Often there is a loss of ability to recognize objects, persons, sounds, shapes, or smells while the specific sense is neither defective nor i ...
), or execution of movements (
apraxia Apraxia is a motor disorder caused by damage to the brain (specifically the posterior parietal cortex or corpus callosum), which causes difficulty with motor planning to perform tasks or movements. The nature of the damage determines the di ...
) are more prominent than memory problems. Alzheimer's disease does not affect all memory capacities equally. Older memories of the person's life (
episodic memory Episodic memory is the memory of everyday events (such as times, location geography, associated emotions, and other contextual information) that can be explicitly stated or conjured. It is the collection of past personal experiences that occurred ...
), facts learned (
semantic memory Semantic memory refers to general world knowledge that humans have accumulated throughout their lives. This general knowledge (Semantics, word meanings, concepts, facts, and ideas) is intertwined in experience and dependent on culture. New concep ...
), and
implicit memory In psychology, implicit memory is one of the two main types of long-term human memory. It is acquired and used unconsciously, and can affect thoughts and behaviours. One of its most common forms is procedural memory, which allows people to perf ...
(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. Language problems are mainly characterised by a shrinking
vocabulary A vocabulary (also known as a lexicon) is a set of words, typically the set in a language or the set known to an individual. The word ''vocabulary'' originated from the Latin , meaning "a word, name". It forms an essential component of languag ...
and decreased word
fluency Fluency (also called volubility and eloquency) refers to continuity, smoothness, rate, and effort in speech production. It is also used to characterize language production, language ability or language proficiency. In speech language patholog ...
, leading to a general impoverishment of oral and
written language A written language is the representation of a language by means of writing. This involves the use of visual symbols, known as graphemes, to represent linguistic units such as phonemes, syllables, morphemes, or words. However, written language is ...
. In this stage, the person with Alzheimer's is usually capable of communicating basic ideas adequately. While performing fine motor tasks such as writing, drawing, or dressing, certain movement coordination and planning difficulties (
apraxia Apraxia is a motor disorder caused by damage to the brain (specifically the posterior parietal cortex or corpus callosum), which causes difficulty with motor planning to perform tasks or movements. The nature of the damage determines the di ...
) may be present; however, they are commonly unnoticed. 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.


Middle stage

Progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities of daily living. Speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions (
paraphasia Paraphasia is a type of language output error commonly associated with aphasia and characterized by the production of unintended syllables, words, or phrases during the effort to speak. Paraphasic errors are most common in patients with fluent for ...
s). Reading and writing skills are also progressively lost. Complex motor sequences become less coordinated as time passes and Alzheimer's disease progresses, so the risk of falling increases. During this phase, memory problems worsen, and the person may fail to recognise close relatives.
Long-term memory Long-term memory (LTM) is the stage of the Atkinson–Shiffrin memory model in which informative knowledge is held indefinitely. It is defined in contrast to sensory memory, the initial stage, and short-term or working memory, the second stage ...
, which was previously intact, becomes impaired. Behavioral and neuropsychiatric changes become more prevalent. Common manifestations are wandering,
irritability Irritability is the excitatory ability that living organisms have to respond to changes in their environment. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimul ...
and
emotional lability In medicine and psychology, emotional lability is a Medical sign, sign or symptom typified by exaggerated changes in mood or affect (psychology), affect in quick succession. Sometimes the emotions expressed outwardly are very different from how th ...
, leading to crying, outbursts of unpremeditated
aggression Aggression is behavior aimed at opposing or attacking something or someone. Though often done with the intent to cause harm, some might channel it into creative and practical outlets. It may occur either reactively or without provocation. In h ...
, or resistance to caregiving.
Sundowning Sundowning, or sundown syndrome, is a neurological phenomenon wherein people with delirium or some form of dementia experience increased confusion and restlessness beginning in the late afternoon and early evening. It is most commonly associated ...
can also appear. Approximately 30% of people with Alzheimer's disease develop illusionary misidentifications and other
delusion A delusion is a fixed belief that is not amenable to change in light of conflicting evidence. As a pathology, it is distinct from a belief based on false or incomplete information, confabulation, dogma, illusion, hallucination, or some other m ...
al symptoms. Subjects also lose insight of their disease process and limitations (
anosognosia Anosognosia is a condition in which a person with a disability is cognitively unaware of having it due to an underlying physical condition. Anosognosia results from physiological damage to brain structures, typically to the parietal lobe or a di ...
).
Urinary incontinence Urinary incontinence (UI), also known as involuntary urination, is any uncontrolled leakage of urine. It is a common and distressing problem, which may have a significant effect on quality of life. Urinary incontinence is common in older women ...
can develop. These symptoms create stress for relatives and caregivers, which can be reduced by moving the person from
home care Homecare (home care, in-home care, care at home), also known as domiciliary care, personal care, community care, or social care, is health care or supportive care provided in the individual home where the patient or client is living, generally focu ...
to other long-term care facilities.


Late stage

During the final stage, known as the late-stage or severe stage, there is complete dependence on caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. Despite the loss of verbal language abilities, people can often understand and return emotional signals. Although aggressiveness can still be present, extreme
apathy Apathy, also referred to as indifference, is a lack of feeling, emotion, interest, or concern about something. It is a state of indifference, or the suppression of emotions such as concern, excitement, motivation, or passion. An apathetic i ...
and exhaustion are much more common symptoms. People with Alzheimer's disease will ultimately not be able to perform even the simplest tasks independently;
muscle mass Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the voluntary muscular system and typically are attached by tendons to bo ...
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 of
pressure ulcer Pressure ulcers, also known as pressure sores, bed sores or pressure injuries, are localised ulcer (dermatology), damage to the skin and/or underlying tissue that usually occur over a Bone, bony prominence as a result of usually long-term pres ...
s or
pneumonia Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...
, not the disease itself. In some cases, there is a paradoxical lucidity immediately before death, where there is an unexpected recovery of mental clarity.


Causes

Alzheimer's disease is believed to occur when abnormal amounts of
amyloid beta Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor prot ...
(Aβ), accumulating extracellularly as
amyloid plaques Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of amyloid beta (Aβ) protein that present mainly in the grey matter of the brain. Degeneration (medical), Degenerative neuronal ...
and
tau protein The tau proteins (abbreviated from tubulin associated unit) form a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintainin ...
s, or intracellularly as
neurofibrillary tangle Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary Biomarker (medicine), biomarker of Alzheimer's disease. Their presence is also found in numerous other disea ...
s, form in the brain, affecting neuronal functioning and connectivity, resulting in a progressive loss of brain function. This altered protein clearance ability is age-related, regulated by brain cholesterol, and associated with other neurodegenerative diseases. The cause for most Alzheimer's cases is still mostly unknown, except for 1–2% of cases where deterministic genetic differences have been identified. Several competing
hypotheses A hypothesis (: hypotheses) is a proposed explanation for a phenomenon. A scientific method, scientific hypothesis must be based on observations and make a testable and reproducible prediction about reality, in a process beginning with an educ ...
attempt to explain the underlying cause; the most predominant hypothesis is the amyloid beta (Aβ) hypothesis.


Genetic


Late onset

Late-onset Alzheimer's is about 70%
heritable Heredity, also called inheritance or biological inheritance, is the passing on of Phenotypic trait, traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cell (biology), cells or orga ...
. Most cases of Alzheimer's are not familial, and so they are termed sporadic Alzheimer's disease. Of the cases of sporadic Alzheimer's disease, most are classified as late onset where they are developed after the age of 65 years. The strongest genetic risk factor for sporadic Alzheimer's disease is APOEε4. APOEε4 is one of four alleles of
apolipoprotein E Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene ''APOE''. Apo-E belongs to a family ...
(APOE). APOE plays a major role in lipid-binding proteins in lipoprotein particles and the ε4 allele disrupts this function. Between 40% and 80% of people with Alzheimer's disease possess at least one APOEε4 allele. The APOEε4 allele increases the risk of the disease by three times in
heterozygotes Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...
and by 15 times in
homozygotes Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...
. Like many human diseases, environmental effects and genetic modifiers result in incomplete
penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the pr ...
. 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.


Early onset

Only 1–2% of Alzheimer's cases are inherited due to
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
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. Less than 5% of sporadic Alzheimer's disease have an earlier onset, and early-onset Alzheimer's is about 90% heritable. Familial Alzheimer's disease usually implies two or more persons affected in one or more generations. Early onset familial Alzheimer's disease can be attributed to mutations in one of three genes: those encoding
amyloid-beta precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse formation, ...
(APP) and
presenilin Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early ons ...
s
PSEN1 Presenilin-1 (PS-1) is a presenilin protein that in humans is encoded by the ''PSEN1'' gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid bet ...
and
PSEN2 Presenilin-2 is a protein that (in humans) is encoded by the ''PSEN2'' gene. Function Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins ( PSEN1; PSEN2) or the amyloid precursor ...
. Most mutations in the APP and presenilin genes increase the production of a small protein called
amyloid beta Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor prot ...
(Aβ)42, which is the main component of
amyloid plaques Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of amyloid beta (Aβ) protein that present mainly in the grey matter of the brain. Degeneration (medical), Degenerative neuronal ...
. Some of the mutations merely alter the ratio between Aβ42 and the other major forms—particularly Aβ40—without increasing Aβ42 levels in the brain. Two other genes associated with autosomal dominant Alzheimer's disease are ABCA7 and SORL1.
Allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...
s in the TREM2 gene have been associated with a three to five times higher risk of developing Alzheimer's disease. A Japanese pedigree of familial Alzheimer's disease was found to be associated with a deletion mutation of codon 693 of APP. This mutation and its association with Alzheimer's disease was first reported in 2008, 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.


Hypotheses


Misfolded protein

The tau hypothesis proposes that
tau protein The tau proteins (abbreviated from tubulin associated unit) form a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintainin ...
abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau as
paired helical filament Tauopathies are a class of neurodegenerative diseases characterized by the aggregation of abnormal tau protein. Hyperphosphorylation of tau proteins causes them to dissociate from microtubules and form insoluble aggregates called neurofibrillary t ...
s. Eventually, they form
neurofibrillary tangle Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary Biomarker (medicine), biomarker of Alzheimer's disease. Their presence is also found in numerous other disea ...
s inside neurons. When this occurs, the
microtubule Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nanometer, nm and have an inner diameter bet ...
s disintegrate, destroying the structure of the cell's
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
which collapses the neuron's transport system. Misfolded amyloid beta and tau proteins are associated with the disease, bringing about
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
that leads to
neuroinflammation Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury,Ebert SE, Jensen P, Ozenne B, Armand S, Svarer C, Stenbaek DS ''et al.'' Molecular imaging of ...
. This chronic inflammation is a feature of other neurodegenerative diseases including
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
, and
ALS Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or—in the United States—Lou Gehrig's disease (LGD), is a rare, terminal neurodegenerative disorder that results in the progressive loss of both upper and low ...
.


Infection

Spirochete infections have been linked to dementia.


DNA damage

DNA damages accumulate in affected brains;
reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
may be the major source of this DNA damage.


Amyloid

The amyloid hypothesis claimed that extracellular amyloid beta (Aβ) deposits are the fundamental cause. Support comes from the location of the gene for the
amyloid precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many biological tissue, tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of s ...
(APP) on
chromosome 21 Chromosome 21 is one of the 23 pairs of chromosomes in humans. Chromosome 21 is both the smallest human autosome and chromosome, with 46.7 million base pairs (the building material of DNA) representing about 1.5 percent of the total DNA in cell ...
, together with the fact that people with
trisomy 21 A trisomy is a type of polysomy in which there are three instances of a particular chromosome, instead of the normal two. A trisomy is a type of aneuploidy (an abnormal number of chromosomes). Description and causes Most organisms that repro ...
( Down syndrome) who have an extra gene copy almost universally exhibit at least early symptoms by age 40. A specific
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
of
apolipoprotein Apolipoproteins are proteins that bind lipids (oil-soluble substances such as fats, cholesterol and fat soluble vitamins) to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph. The lipid components of lipoprotei ...
, APOE4, is a major genetic risk factor. While apolipoproteins enhance the breakdown of amyloid beta, some isoforms are less effective at this task (such as APOE4), leading to amyloid buildup in the brain.


Cholinergic

The cholinergic hypothesis proposed that reduced synthesis of the neurotransmitter
acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...
was involved. The loss of cholinergic neurons in the
limbic system The limbic system, also known as the paleomammalian cortex, is a set of brain structures located on both sides of the thalamus, immediately beneath the medial temporal lobe of the cerebrum primarily in the forebrain.Schacter, Daniel L. 2012. ''P ...
and cerebral cortex is a key feature.


Sleep

Sleep disturbances are seen as a possible
risk factor In epidemiology, a risk factor or determinant is a variable associated with an increased risk of disease or infection. Due to a lack of harmonization across disciplines, determinant, in its more widely accepted scientific meaning, is often use ...
for inflammation in Alzheimer's disease. Sleep disruption was previously only seen as a consequence of Alzheimer's disease, but , accumulating evidence suggests that this relationship may be bidirectional.


Metal toxicity, smoking, neuroinflammation and air pollution

The cellular
homeostasis In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...
of biometals 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. Smoking is a significant Alzheimer's disease risk factor. Systemic markers of the
innate immune system The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates (the other being the adaptive immune system). The innate immune system is an alternate defense strategy and is the dominant immune s ...
are risk factors for late-onset Alzheimer's disease. Exposure to air pollution may be a contributing factor to the development of Alzheimer's disease.


Age-related myelin decline

Retrogenesis is a medical
hypothesis A hypothesis (: hypotheses) is a proposed explanation for a phenomenon. A scientific hypothesis must be based on observations and make a testable and reproducible prediction about reality, in a process beginning with an educated guess o ...
that just as the fetus goes through a process of
neurodevelopment The development of the nervous system in humans, or neural development, or neurodevelopment involves the studies of embryology, developmental biology, and neuroscience. These describe the cellular and molecular mechanisms by which the complex ...
beginning with
neurulation Neurulation refers to the folding process in vertebrate embryos, which includes the transformation of the neural plate into the neural tube. The embryo at this stage is termed the neurula. The process begins when the notochord induces the formati ...
and ending with
myelination Myelination, or myelinogenesis, is the formation and development of myelin sheaths in the nervous system, typically initiated in late prenatal neurodevelopment and continuing throughout postnatal development. The term ''myelinogenesis'' is also ...
, the brains of people with Alzheimer's disease go through a reverse
neurodegeneration A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their cell death, death. Neurodegenerative diseases include amyotrophic lateral sc ...
process starting with demyelination and death of axons (white matter) and ending with the death of grey matter. Likewise the hypothesis is, that as infants go through states of
cognitive development Cognitive development is a field of study in neuroscience and psychology focusing on a child's development in terms of information processing, conceptual resources, perceptual skill, language learning, and other aspects of the developed adult bra ...
, people with Alzheimer's disease go through the reverse process of progressive cognitive impairment. According to one theory, dysfunction of
oligodendrocytes Oligodendrocytes (), also known as oligodendroglia, are a type of neuroglia whose main function is to provide the myelin sheath to neuronal axons in the central nervous system (CNS). Myelination gives metabolic support to, and insulates the axon ...
and their associated
myelin Myelin Sheath ( ) is a lipid-rich material that in most vertebrates surrounds the axons of neurons to insulate them and increase the rate at which electrical impulses (called action potentials) pass along the axon. The myelinated axon can be lik ...
during aging contributes to
axon An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...
damage, which in turn generates in amyloid production and tau
hyperphosphorylation Protein phosphorylation is a reversible post-translational modification of proteins in which an amino acid residue is phosphorylated by a protein kinase by the addition of a covalently bound phosphate group. Phosphorylation alters the structural ...
. Comorbidities between the demyelinating disease,
multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
, and Alzheimer's disease have been reported.


Other hypotheses

The association with
celiac disease Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine. Patients develop intolerance to gluten, which is present in foods such as wheat, rye, spel ...
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. Studies have reported a potential link between infection with certain viruses and developing Alzheimer's disease later in life. Notably, a large scale study conducted on 6,245,282 patients has reported an increased risk of developing Alzheimer's disease following COVID-19 infection in cognitively normal individuals over 65. 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. 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.


Pathophysiology


Neuropathology

Alzheimer's disease is characterised by loss of
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s and
synapse In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...
s in the
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...
and certain subcortical regions. This loss results in gross
atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), malnutrition, poor nourishment, poor circulatory system, circulation, loss of hormone, ...
of the affected regions, including degeneration in the
temporal lobe The temporal lobe is one of the four major lobes of the cerebral cortex in the brain of mammals. The temporal lobe is located beneath the lateral fissure on both cerebral hemispheres of the mammalian brain. The temporal lobe is involved in pr ...
and
parietal lobe The parietal lobe is one of the four Lobes of the brain, major lobes of the cerebral cortex in the brain of mammals. The parietal lobe is positioned above the temporal lobe and behind the frontal lobe and central sulcus. The parietal lobe integra ...
, and parts of the
frontal cortex The frontal lobe is the largest of the four major lobes of the brain in mammals, and is located at the front of each cerebral hemisphere (in front of the parietal lobe and the temporal lobe). It is parted from the parietal lobe by a groove betw ...
and
cingulate gyrus The cingulate cortex is a part of the brain situated in the medial aspect of the cerebral cortex. The cingulate cortex includes the entire cingulate gyrus, which lies immediately above the corpus callosum, and the continuation of this in the cin ...
. Degeneration is also present in
brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is conti ...
nuclei particularly the
locus coeruleus The locus coeruleus () (LC), also spelled locus caeruleus or locus ceruleus, is a nucleus in the pons of the brainstem involved with physiological responses to stress and panic. It is a part of the reticular activating system in the reticular ...
in the
pons The pons (from Latin , "bridge") is part of the brainstem that in humans and other mammals, lies inferior to the midbrain, superior to the medulla oblongata and anterior to the cerebellum. The pons is also called the pons Varolii ("bridge of ...
. Studies using
MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...
and
PET A pet, or companion animal, is an animal kept primarily for a person's company or entertainment rather than as a working animal, livestock, or a laboratory animal. Popular pets are often considered to have attractive/ cute appearances, inte ...
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. Both plaques and
neurofibrillary tangle Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary Biomarker (medicine), biomarker of Alzheimer's disease. Their presence is also found in numerous other disea ...
s are clearly visible by
microscopy Microscopy is the technical field of using microscopes to view subjects too small to be seen with the naked eye (objects that are not within the resolution range of the normal eye). There are three well-known branches of microscopy: optical mic ...
in brains of those with Alzheimer's disease, especially in the
hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...
. However, Alzheimer's disease may occur without neurofibrillary tangles in the
neocortex The neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian cerebral cortex involved in higher-order brain functions such as sensory perception, cognition, generation of motor commands, ...
. Plaques are dense, mostly
insoluble In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solub ...
deposits of
amyloid beta Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor prot ...
peptide and cellular material outside and around
neurons A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
.
Neurofibrillary tangles Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary Biomarker (medicine), biomarker of Alzheimer's disease. Their presence is also found in numerous other disea ...
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 The temporal lobe is one of the four major lobes of the cerebral cortex in the brain of mammals. The temporal lobe is located beneath the lateral fissure on both cerebral hemispheres of the mammalian brain. The temporal lobe is involved in pr ...
. Lewy bodies are not rare in the brains of people with Alzheimer's disease.


Biochemistry


Amyloid beta

Alzheimer's disease has been identified as a protein misfolding disease, a
proteopathy In medicine, proteinopathy ( 'pref''. protein -pathy 'suff''. disease proteinopathies ''pl''.; proteinopathic ''adj''), or proteopathy, protein conformational disorder, or protein misfolding disease, is a class of diseases in which certain prote ...
, caused by the accumulation of abnormally folded
amyloid beta Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor prot ...
protein into amyloid plaques, and
tau protein The tau proteins (abbreviated from tubulin associated unit) form a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintainin ...
into neurofibrillary tangles in the brain. Plaques are made up of small
peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...
s, 39–43 
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s in length, called amyloid beta. Amyloid beta is a fragment from the larger
amyloid-beta precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse formation, ...
(APP) a
transmembrane protein A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently un ...
that penetrates the cell's membrane. APP is critical to neuron growth, survival, and post-injury repair. In Alzheimer's disease,
gamma secretase Gamma secretase is a multi-subunit protease complex, an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. The most ...
and beta secretase act together in a
proteolytic Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Protein degradation is a major regulatory mechanism of gene expression and contributes substantially to shaping mammalian proteomes. Uncatalysed, the hydrolysis o ...
process which causes APP to be divided into smaller fragments. 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 Fibrils () are structural biological materials found in nearly all living organisms. Not to be confused with fibers or filaments, fibrils tend to have diameters ranging from 10 to 100 nanometers (whereas fibers are micro to milli-scale stru ...
of amyloid beta, which then form clumps that deposit outside neurons in dense formations known as amyloid plaques. Excitatory neurons are known to be the major producers of amyloid beta that contribute to major extracellular plaque deposition.


Phosphorylated tau

Alzheimer's disease is also considered a
tauopathy Tauopathies are a class of neurodegenerative diseases characterized by the aggregation of abnormal tau protein. Hyperphosphorylation of tau proteins causes them to dissociate from microtubules and form insoluble aggregates called neurofibrillary ...
due to abnormal aggregation of the
tau protein The tau proteins (abbreviated from tubulin associated unit) form a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintainin ...
. Every neuron has a
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
, an internal support structure partly made up of structures called
microtubules Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27  nm and have an inner diameter between 11 an ...
. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the
axon An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...
and back. A protein called ''tau'' stabilises the microtubules when
phosphorylated In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...
, and is therefore called a
microtubule-associated protein In cell biology, microtubule-associated proteins (MAPs) are proteins that interact with the microtubules of the cellular cytoskeleton. MAPs are integral to the stability of the cell and its internal structures and the transport of components withi ...
. 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. Pathogenic tau can also cause neuronal death through
transposable element A transposable element (TE), also transposon, or jumping gene, is a type of mobile genetic element, a nucleic acid sequence in DNA that can change its position within a genome. The discovery of mobile genetic elements earned Barbara McClinto ...
dysregulation. Necroptosis has also been reported as a mechanism of cell death in brain cells affected with tau tangles.


Disease mechanism

Exactly how disturbances of production and aggregation of the beta-amyloid
peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...
give rise to the pathology of Alzheimer's disease is not known. The amyloid hypothesis traditionally points to the accumulation of beta-amyloid peptides as the central event triggering neuron degeneration. Accumulation of aggregated
amyloid fibril Amyloids are aggregates of proteins characterised by a fibrillar morphology of typically 7–13 Nanometer, nm in diameter, a beta sheet, β-sheet Secondary structure of proteins, secondary structure (known as cross-β) and ability to be Staining ...
s, which are believed to be the toxic form of the protein responsible for disrupting the cell's
calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...
ion
homeostasis In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...
, induces
programmed cell death Programmed cell death (PCD) sometimes referred to as cell, or cellular suicide is the death of a cell (biology), cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usual ...
(
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
). It is also known that Aβ selectively builds up in the
mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
in the cells of Alzheimer's-affected brains, and it also inhibits certain
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
functions and the utilisation of
glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
by neurons. 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, and the beneficial effect of therapeutics (such as monoclonal antibodies) promoting Aβ clearance has ranged from nonexistent to modest. Iron dyshomeostasis is linked to disease progression, an iron-dependent form of regulated cell death called ferroptosis could be involved. Products of
lipid peroxidation Lipid peroxidation, or lipid oxidation, is a complex chemical process that leads to oxidative degradation of lipids, resulting in the formation of peroxide and hydroperoxide derivatives.{{Cite journal , last1=Ayala , first1=Antonio , last2=Muñoz ...
are also elevated in AD brain compared with controls. Various inflammatory processes and
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
s may also have a role in the pathology of Alzheimer's disease.
Inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
is a general marker of tissue damage in any disease, and may be either secondary to tissue damage in Alzheimer's disease or a marker of an immunological response. 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. Alterations in the distribution of different
neurotrophic factor Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their trop ...
s and in the expression of their receptors such as the
brain-derived neurotrophic factor Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the can ...
(BDNF) have been described in Alzheimer's disease. Evidence has accrued for
microglia Microglia are a type of glia, glial cell located throughout the brain and spinal cord of the central nervous system (CNS). Microglia account for about around 5–10% of cells found within the brain. As the resident macrophage cells, they act as t ...
as central actors in the mechanism of AD. Microglia are topographically associated with pTau and Aβ within the brain, even when each pathologic component occurs in distinct brain regions, 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. 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. However, microglia can also be a major source of pro-inflammatory mediators which can be deleterious to neurological function.


Diagnosis

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. 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. AD is usually clinically diagnosed based on a person's
medical history The medical history, case history, or anamnesis (from Greek: ἀνά, ''aná'', "open", and μνήσις, ''mnesis'', "memory") of a patient is a set of information the physicians collect over medical interviews. It involves the patient, and ev ...
, observations from friends or relatives, and behavioral changes. The presence of characteristic
neuropsychological Neuropsychology is a branch of psychology concerned with how a person's cognition and behavior are related to the brain and the rest of the nervous system. Professionals in this branch of psychology focus on how injuries or illnesses of the brai ...
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 In cognitive science and neuropsychology, executive functions (collectively referred to as executive function and cognitive control) are a set of cognitive processes that support goal-directed behavior, by regulating thoughts and actions thro ...
, 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. Advanced
medical imaging Medical imaging is the technique and process of imaging the interior of a body for clinical analysis and medical intervention, as well as visual representation of the function of some organs or tissues (physiology). Medical imaging seeks to revea ...
with
computed tomography A computed tomography scan (CT scan), formerly called computed axial tomography scan (CAT scan), is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers or ...
(CT) or
magnetic resonance imaging Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and ...
(MRI), and with
single-photon emission computed tomography Single-photon emission computed tomography (SPECT, or less commonly, SPET) is a nuclear medicine tomography, tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera ...
(SPECT) or
positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...
(PET), can be used to help exclude other cerebral pathology or subtypes of dementia. 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). 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. Advanced imaging may predict conversion from
prodromal In medicine, a prodrome is an early Medical sign, sign or symptom (or set of signs and symptoms, referred to as prodromal symptoms) that often indicates the onset of a disease before more diagnostically specific signs and symptoms develop. More spe ...
stages (mild cognitive impairment) to Alzheimer's disease. FDA-approved
radiopharmaceutical Radiopharmaceuticals, or medicinal radiocompounds, are a group of pharmaceutical drugs containing radioactive isotopes. Radiopharmaceuticals can be used as diagnostic and therapeutic agents. Radiopharmaceuticals emit radiation themselves, which ...
diagnostic agents used in PET for Alzheimer's disease are florbetapir (2012), flutemetamol (2013), florbetaben (2014), and flortaucipir (2020). Because many insurance companies in the United States do not cover this procedure, its use in clinical practice is largely limited to clinical trials . Assessment of intellectual functioning including memory testing can further characterise the state of the disease. 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 An autopsy (also referred to as post-mortem examination, obduction, necropsy, or autopsia cadaverum) is a surgical procedure that consists of a thorough examination of a corpse by dissection to determine the cause, mode, and manner of death ...
evaluations when brain material is available and can be examined
histologically Histology, also known as microscopic anatomy or microanatomy, is the branch of biology that studies the microscopic anatomy of biological tissue (biology), tissues. Histology is the microscopic counterpart to gross anatomy, which looks at large ...
for senile plaques and neurofibrillary tangles.


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 The ''Diagnostic and Statistical Manual of Mental Disorders'' (''DSM''; latest edition: ''DSM-5-TR'', published in March 2022) is a publication by the American Psychiatric Association (APA) for the classification of mental disorders using a com ...
'' (
DSM-5 The ''Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition'' (DSM-5), is the 2013 update to the '' Diagnostic and Statistical Manual of Mental Disorders'', the taxonomic and diagnostic tool published by the American Psychiat ...
); the
National Institute on Aging The National Institute on Aging (NIA) is a division of the U.S. National Institutes of Health (NIH), located in Bethesda, Maryland. The NIA itself is headquartered in Baltimore, Maryland. The NIA leads a broad scientific effort to understand ...
-
Alzheimer's Association The Alzheimer's Association is a nonprofit voluntary health organization that focuses on Alzheimer's disease care, support and research. History Jerome H. Stone founded the Alzheimer's Association with the help of several family support groups ...
(NIA-AA) definition as revised in 2011; and the International Working Group criteria as revised in 2010. Eight intellectual domains are most commonly impaired in AD—
memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembe ...
,
language Language is a structured system of communication that consists of grammar and vocabulary. It is the primary means by which humans convey meaning, both in spoken and signed language, signed forms, and may also be conveyed through writing syste ...
, perceptual skills,
attention Attention or focus, is the concentration of awareness on some phenomenon to the exclusion of other stimuli. It is the selective concentration on discrete information, either subjectively or objectively. William James (1890) wrote that "Atte ...
,
motor skill A motor skill is a function that involves specific movements of the motor system, body's muscles to perform a certain task. These tasks could include walking, running, or riding a bike. In order to perform this skill, the body's nervous system, m ...
s,
orientation Orientation may refer to: Positioning in physical space * Map orientation, the relationship between directions on a map and compass directions * Orientation (housing), the position of a building with respect to the sun, a concept in building des ...
,
problem solving Problem solving is the process of achieving a goal by overcoming obstacles, a frequent part of most activities. Problems in need of solutions range from simple personal tasks (e.g. how to turn on an appliance) to complex issues in business an ...
and
executive function In cognitive science and neuropsychology, executive functions (collectively referred to as executive function and cognitive control) are a set of cognitive processes that support goal-directed behavior, by regulating thoughts and actions thro ...
al abilities, as listed in the fourth text revision of the DSM (DSM-IV-TR). The
DSM-5 The ''Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition'' (DSM-5), is the 2013 update to the '' Diagnostic and Statistical Manual of Mental Disorders'', the taxonomic and diagnostic tool published by the American Psychiat ...
defines criteria for probable or possible AD for both major and mild neurocognitive disorder. Major or mild neurocognitive disorder must be present along with at least one cognitive deficit for a diagnosis of either probable or possible AD. For major neurocognitive disorder due to AD, probable Alzheimer's disease can be diagnosed if the individual has genetic evidence of AD or if two or more acquired cognitive deficits, and a functional disability that is not from another disorder, are present. Otherwise, possible AD can be diagnosed as the diagnosis follows an atypical route. 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. The NIA-AA criteria are used mainly in research rather than in clinical assessments. They define AD through three major stages: preclinical, mild cognitive impairment (MCI), and Alzheimer's dementia. Diagnosis in the preclinical stage is complex and focuses on asymptomatic individuals; the latter two stages describe individuals experiencing symptoms, along with biomarkers, predominantly those for neuronal injury (mainly tau-related) and amyloid beta deposition. The core clinical criteria itself rests on the presence of cognitive impairment without the presence of comorbidities. The third stage is divided into probable and possible AD dementia. In probable AD dementia there is steady impairment of cognition over time and a memory-related or non-memory-related cognitive dysfunction. In possible AD dementia, another causal disease such as
cerebrovascular disease Cerebrovascular disease includes a variety of medical conditions that affect the blood vessels of the brain and the cerebral circulation. Arteries supplying oxygen and nutrients to the brain are often damaged or deformed in these disorders. Th ...
is present.


Techniques

Neuropsychological test Neuropsychological tests are specifically designed tasks that are used to measure a psychological function known to be linked to a particular brain structure or pathway. Tests are used for cognitive neuropsychology, research into brain function a ...
s including
cognitive test Cognitive tests are assessments of the cognitive capabilities of humans and other animals. Tests administered to humans include various forms of IQ tests; those administered to animals include the mirror test (a test of visual self-awareness) and ...
s such as the
mini–mental state examination The mini–mental state examination (MMSE) or Folstein test is a 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. It is commonly used in medicine and allied health to screen for d ...
(MMSE), the
Montreal Cognitive Assessment The Montreal Cognitive Assessment (MoCA) is a widely used screening assessment for detecting cognitive impairment. It was created in 1996 by Ziad Nasreddine in Montreal, Quebec. It was validated in the setting of mild cognitive impairment (MC ...
(MoCA) and the Mini-Cog are widely used to aid in diagnosis of the cognitive impairments in AD. These tests may not always be accurate, as they lack sensitivity to mild cognitive impairment, and can be biased by language or attention problems; more comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease. Further neurological examinations are crucial in the
differential diagnosis In healthcare, a differential diagnosis (DDx) is a method of analysis that distinguishes a particular disease or condition from others that present with similar clinical features. Differential diagnostic procedures are used by clinicians to di ...
of Alzheimer's disease and other diseases. Interviews with family members are used in assessment; caregivers can supply important information on daily living abilities and on the decrease in the person's
mental function Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, i ...
. A caregiver's viewpoint is particularly important, since a person with Alzheimer's disease is commonly unaware of their deficits. Many times, families have difficulties in the detection of initial dementia symptoms and may not communicate accurate information to a physician. Supplemental testing can rule out other potentially treatable diagnoses and help avoid misdiagnoses. Common supplemental tests include
blood test A blood test is a medical laboratory, laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a hypodermic needle, or via fingerprick. Multiple tests for specific blood components, such as a glucose ...
s,
thyroid function tests Thyroid function tests (TFTs) is a collective term for blood tests used to check the function of the thyroid. TFTs may be requested if a patient is thought to suffer from hyperthyroidism (overactive thyroid) or hypothyroidism (underactive thyroid) ...
, as well as tests to assess vitamin B12 levels, rule out
neurosyphilis Neurosyphilis is the infection of the central nervous system by '' Treponema pallidum'', the bacterium that causes the sexually transmitted infection syphilis. In the era of modern antibiotics, the majority of neurosyphilis cases have been report ...
and rule out metabolic problems (including tests for
kidney function Assessment of kidney function occurs in different ways, using the presence of symptoms and medical sign, signs, as well as measurements using urine tests, blood tests, and medical imaging. Renal physiology, Functions of a healthy kidney include ...
, electrolyte levels and for
diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
). MRI or CT scans might also be used to rule out other potential causes of the symptoms – including tumors or strokes.
Delirium Delirium (formerly acute confusional state, an ambiguous term that is now discouraged) is a specific state of acute confusion attributable to the direct physiological consequence of a medical condition, effects of a psychoactive substance, or ...
and depression can be common among individuals and are important to rule out. 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, or even the cause. 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). 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. 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.


Prevention

There are no
disease-modifying treatment A disease-modifying treatment, disease-modifying drug, or disease-modifying therapy is a treatment that delays, slows or reverses the progression of a disease by targeting its underlying cause. They are distinguished from symptomatic treatments th ...
s available to cure Alzheimer's disease and because of this, AD research has focused on interventions to prevent the onset and progression. There is no evidence that supports any particular measure in preventing AD, 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. 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. Further research is needed to determine factors that can help prevent AD.


Medication

Cardiovascular risk factors, such as
hypercholesterolaemia Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia (high levels of lipids in the blood), hyperlipoproteinemia (high levels of lipoproteins in the blood), ...
,
hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
,
diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
, and
smoking Smoking is a practice in which a substance is combusted, and the resulting smoke is typically inhaled to be tasted and absorbed into the bloodstream of a person. Most commonly, the substance used is the dried leaves of the tobacco plant, whi ...
, are associated with a higher risk of onset and worsened course of AD. The use of
statin Statins (or HMG-CoA reductase inhibitors) are a class of medications that lower cholesterol. They are prescribed typically to people who are at high risk of cardiovascular disease. Low-density lipoprotein (LDL) carriers of cholesterol play ...
s to lower
cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...
may be of benefit in AD.
Antihypertensive Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infa ...
and
antidiabetic Drugs used in diabetes treat types of diabetes mellitus by decreasing glucose levels in the blood. With the exception of insulin, most GLP-1 receptor agonists ( liraglutide, exenatide, and others), and pramlintide, all diabetes medications a ...
medications in individuals without overt cognitive impairment may decrease the risk of dementia by influencing cerebrovascular
pathology Pathology is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...
. 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. Depression is associated with an increased risk for AD; management with antidepressant medications may provide a preventative measure. Historically, long-term usage of non-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. Additionally, because women have a higher incidence of AD than men, it was once thought that estrogen deficiency during
menopause Menopause, also known as the climacteric, is the time when Menstruation, menstrual periods permanently stop, marking the end of the Human reproduction, reproductive stage for the female human. It typically occurs between the ages of 45 and 5 ...
was a risk factor, but there is a lack of evidence to show that hormone replacement therapy (HRT) in menopause decreases risk of cognitive decline.


Lifestyle

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. Physical exercise is associated with a decreased rate of dementia, and is effective in reducing symptom severity in those with AD. Memory and cognitive functions can be improved with aerobic exercises including brisk walking three times weekly for forty minutes. It may also induce
neuroplasticity Neuroplasticity, also known as neural plasticity or just plasticity, is the ability of neural networks in the brain to change through neurogenesis, growth and reorganization. Neuroplasticity refers to the brain's ability to reorganize and rewir ...
of the brain. Participating in mental exercises, such as reading, crossword puzzles, and chess have reported potential to be preventive. Meeting the
WHO The World Health Organization (WHO) is a specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Geneva, Switzerland, and has 6 regional offices and 15 ...
recommendations for physical activity is associated with a lower risk of AD. Higher education and occupational attainment, and participation in leisure activities, contribute to a reduced risk of developing AD, or of delaying the onset of symptoms. This is compatible with the
cognitive reserve Cognitive reserve is the mind's and brain's resistance to damage of the brain. The mind's resilience is evaluated behaviorally, whereas the neuropathological damage is evaluated histologically, although damage may be estimated using blood-based ma ...
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.
Education Education is the transmission of knowledge and skills and the development of character traits. Formal education occurs within a structured institutional framework, such as public schools, following a curriculum. Non-formal education als ...
delays the onset of Alzheimer's disease syndrome without changing the duration of the disease. Cessation in smoking may reduce risk of developing AD, specifically in those who carry the APOE ɛ4 allele. The increased oxidative stress caused by smoking results in downstream inflammatory or neurodegenerative processes that may increase risk of developing AD. Avoidance of smoking, counseling and pharmacotherapies to quit smoking are used, and avoidance of environmental tobacco smoke is recommended. Alzheimer's disease is associated with
sleep disorders A sleep disorder, or somnipathy, is a medical disorder affecting an individual's sleep patterns, sometimes impacting physical, mental, social, and emotional functioning. Polysomnography and actigraphy are tests commonly ordered for diagnosing sle ...
but the precise relationship is unclear. 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. One theory is that the mechanisms to increase clearance of toxic substances, including , are active during sleep. With decreased sleep, a person is increasing Aβ production and decreasing Aβ clearance, resulting in Aβ accumulation. Receiving adequate sleep (approximately 7–8 hours) every night has become a potential lifestyle intervention to prevent the development of AD. Stress is a risk factor for the development of AD. 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 In biology, the epigenome of an organism is the collection of chemical changes to its DNA and histone proteins that affects when, where, and how the DNA is expressed; these changes can be passed down to an organism's offspring via transgenerat ...
, leading to an overexpression or under expression of specific genes. 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. Meditation, for instance, is a helpful lifestyle change to support cognition and well-being, though further research is needed to assess long-term effects.


Management

There is no cure for AD; available treatments offer relatively small symptomatic benefits but remain
palliative Palliative care (from Latin root "to cloak") is an interdisciplinary medical care-giving approach aimed at optimizing quality of life and mitigating or reducing suffering among people with serious, complex, and often terminal illnesses. Man ...
in nature. Treatments can be divided into pharmaceutical, psychosocial, and caregiving.


Pharmaceutical


Symptomatic treatment

Medications used to treat the cognitive symptoms of AD rather than the underlying cause include: four
acetylcholinesterase inhibitor Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine into choline and acetate, thereby increasing both the level an ...
s ( tacrine,
rivastigmine Rivastigmine, sold under the brand name Exelon among others, is an acetylcholinesterase inhibitor used for the treatment of dementia associated with Alzheimer's disease and with Parkinson's disease. Rivastigmine can be administered orally or v ...
,
galantamine Galantamine is a type of acetylcholinesterase inhibitor. It is an alkaloid extracted from the bulbs and flowers of ''Galanthus nivalis'' (common snowdrop), '' Galanthus caucasicus'' (Caucasian snowdrop), '' Galanthus woronowii'' (Voronov's snow ...
, and
donepezil Donepezil, sold under the brand name Aricept among others, is a medication used to treat dementia of the Alzheimer's type. It appears to result in a small benefit in mental function and ability to function. Use, however, has not been shown to ...
) and
memantine Memantine, sold under the brand name Namenda among others, is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth. Common side effects include headache, constipation, sleepiness, and dizz ...
, an
NMDA receptor antagonist NMDA receptor antagonists are a class of drugs that work to receptor antagonist, antagonize, or inhibit the action of, the NMDA, ''N''-Methyl-D-aspartate receptor (NMDA receptor, NMDAR). They are commonly used as anesthetics for humans and anima ...
. 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. The benefit from their use is small. Reduction in the activity of the
cholinergic Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word " choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cation ...
neurons is a well-known feature of AD. Acetylcholinesterase inhibitors are employed to reduce the rate at which the body breaks down
acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...
(ACh), thereby increasing the concentration of ACh in the brain and combating the loss of ACh caused by the death of cholinergic neurons. Evidence supports medical efficacy in mild to moderate AD, and somewhat in the advanced stage. This does not extend to delaying symptom onset.
Glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
is an excitatory
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...
, although in excess can lead to
cell Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...
death through a process called
excitotoxicity In excitotoxicity, neuron, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamic acid, glutamate become pathologically high, resulting in excessive stimulation of cell surface recept ...
which consists of the overstimulation of glutamate
receptors Receptor may refer to: *Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds ...
. Excitotoxicity also occurs in other neurological diseases such as
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
and
multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
.
Memantine Memantine, sold under the brand name Namenda among others, is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth. Common side effects include headache, constipation, sleepiness, and dizz ...
is a noncompetitive
NMDA receptor antagonist NMDA receptor antagonists are a class of drugs that work to receptor antagonist, antagonize, or inhibit the action of, the NMDA, ''N''-Methyl-D-aspartate receptor (NMDA receptor, NMDAR). They are commonly used as anesthetics for humans and anima ...
first used as an anti-
influenza Influenza, commonly known as the flu, is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These sympto ...
agent. It acts on the glutamatergic system by blocking
NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...
s and inhibiting their overstimulation by glutamate. Memantine has been reported to have a small benefit in the treatment of moderate to severe AD. The combination of memantine and donepezil has been reported to be "of
statistically significant In statistical hypothesis testing, a result has statistical significance when a result at least as "extreme" would be very infrequent if the null hypothesis were true. More precisely, a study's defined significance level, denoted by \alpha, is the ...
but clinically marginal effectiveness". An extract of ''
Ginkgo biloba ''Ginkgo biloba'', commonly known as ginkgo or gingko ( ), also known as the maidenhair tree, is a species of gymnosperm tree native to East Asia. It is the last living species in the order Ginkgoales, which first appeared over 290 million year ...
'' known as ''EGb 761'' has been used for treating AD and other neuropsychiatric disorders. Its use is approved throughout Europe. 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 to other therapies. A 2016 review concluded that the quality of evidence from clinical trials on ''G. biloba'' has been insufficient to warrant its use.
Atypical antipsychotic The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as tranquilizers and neurol ...
s are modestly useful in reducing
aggression Aggression is behavior aimed at opposing or attacking something or someone. Though often done with the intent to cause harm, some might channel it into creative and practical outlets. It may occur either reactively or without provocation. In h ...
and
psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...
in people with AD, but their advantages are offset by serious adverse effects, such as
stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
, movement difficulties or cognitive decline. When used in the long-term, they have been reported to associate with increased mortality. Se
lay summary
January 2009.
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. Stopping antipsychotic use in this group of people appears to be safe. Benzgalantamine is a cholinesterase inhibitor.


= Side effects

= The most common
side effects In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually used ...
are
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
and
vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
, 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. Less common secondary effects include muscle
cramp A cramp is a sudden, involuntary, painful skeletal muscle contraction or overshortening associated with electrical activity. While generally temporary and non-damaging, they can cause significant pain and a paralysis-like immobility of the aff ...
s, decreased
heart rate Heart rate is the frequency of the cardiac cycle, heartbeat measured by the number of contractions of the heart per minute (''beats per minute'', or bpm). The heart rate varies according to the body's Human body, physical needs, including the nee ...
(
bradycardia Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathological processes, it is commonly a physiological response to cardiovascular conditioning or due ...
), decreased
appetite Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to reg ...
and weight, and increased
gastric acid Gastric acid or stomach acid is the acidic component – hydrochloric acid – of gastric juice, produced by parietal cells in the gastric glands of the stomach lining. In humans, the pH is between one and three, much lower than most other a ...
production. Reported adverse events with memantine are infrequent and mild, including
hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...
s,
confusion In psychology, confusion is the quality or emotional state of being bewildered or unclear. The term "acute mental confusion"
,
dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...
,
headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
and
fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...
.


Antibodies

Two
antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
have been approved to target amyloid beta: donanemab and lecanemab. Lecanemab is approved in the US, including a
boxed warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administratio ...
about amyloid-related imaging abnormalities. As of early August 2024, lecanemab was approved for sale in
Japan Japan is an island country in East Asia. Located in the Pacific Ocean off the northeast coast of the Asia, Asian mainland, it is bordered on the west by the Sea of Japan and extends from the Sea of Okhotsk in the north to the East China Sea ...
,
South Korea South Korea, officially the Republic of Korea (ROK), is a country in East Asia. It constitutes the southern half of the Korea, Korean Peninsula and borders North Korea along the Korean Demilitarized Zone, with the Yellow Sea to the west and t ...
,
China China, officially the People's Republic of China (PRC), is a country in East Asia. With population of China, a population exceeding 1.4 billion, it is the list of countries by population (United Nations), second-most populous country after ...
,
Hong Kong Hong Kong)., Legally Hong Kong, China in international treaties and organizations. is a special administrative region of China. With 7.5 million residents in a territory, Hong Kong is the fourth most densely populated region in the wor ...
and
Israel Israel, officially the State of Israel, is a country in West Asia. It Borders of Israel, shares borders with Lebanon to the north, Syria to the north-east, Jordan to the east, Egypt to the south-west, and the Mediterranean Sea to the west. Isr ...
although not by an advisory body of the European Union on July 26, citing side effects. Donanemab is approved in the US.


Psychosocial

Psychosocial The psychosocial approach looks at individuals in the context of the combined influence that psychological factors and the surrounding social environment have on their physical and mental wellness and their ability to function. This approach is ...
interventions are used as an adjunct to pharmaceutical treatment and can be classified within behavior-, emotion-, cognition- or stimulation-oriented approaches. Behavioral interventions attempt to identify and reduce the antecedents and consequences of problem behaviors. This approach has not reported success in improving overall functioning, but can help to reduce some specific problem behaviors, such as
incontinence Incontinence or Incontinent may refer to: * Urinary incontinence, the most commonly occurring type of incontinence, the involuntary excretion of urine *Fecal incontinence Fecal incontinence (FI), or in some forms, encopresis, is a lack of con ...
. There is a lack of high quality data on the effectiveness of these techniques in other behavior problems such as wandering.
Music therapy Music therapy, an allied health profession, "is the clinical and evidence-based use of music interventions to accomplish individualized goals within a therapeutic relationship by a credentialed professional who has completed an approved music t ...
is effective in reducing behavioral and psychological symptoms. Emotion-oriented interventions include reminiscence therapy,
validation therapy Validation therapy was developed by Naomi Feil for older people with cognitive impairments and dementia. Feil's own approach classifies individuals with cognitive impairment as having one of four stages in a continuum of dementia. These stages ar ...
, supportive
psychotherapy Psychotherapy (also psychological therapy, talk therapy, or talking therapy) is the use of Psychology, psychological methods, particularly when based on regular Conversation, personal interaction, to help a person change behavior, increase hap ...
, sensory integration, also called
snoezelen Snoezelen () or controlled multisensory environment (MSE) is a therapy for people with autism and other developmental disabilities, dementia or brain injury. It consists of placing the person in a soothing and stimulating environment, called the ...
, and simulated presence therapy. A Cochrane review has found no evidence that this is effective. 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. Simulated presence therapy (SPT) is based on attachment 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 reduce challenging behaviors. The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining, is the reduction of
cognitive deficit Cognitive impairment is an inclusive term to describe any characteristic that acts as a barrier to the cognition process or different areas of cognition. Cognition, also known as cognitive function, refers to the mental processes of how a person ...
s. 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. Stimulation-oriented treatments include
art Art is a diverse range of cultural activity centered around ''works'' utilizing creative or imaginative talents, which are expected to evoke a worthwhile experience, generally through an expression of emotional power, conceptual ideas, tec ...
,
music Music is the arrangement of sound to create some combination of Musical form, form, harmony, melody, rhythm, or otherwise Musical expression, expressive content. Music is generally agreed to be a cultural universal that is present in all hum ...
and
pet A pet, or companion animal, is an animal kept primarily for a person's company or entertainment rather than as a working animal, livestock, or a laboratory animal. Popular pets are often considered to have attractive/ cute appearances, inte ...
therapies,
exercise Exercise or workout is physical activity that enhances or maintains fitness and overall health. It is performed for various reasons, including weight loss or maintenance, to aid growth and improve strength, develop muscles and the cardio ...
, 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.


Caregiving

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 Safety is the state of being protected from harm or other danger. Safety can also refer to the control of recognized hazards in order to achieve an acceptable level of risk. Meanings The word 'safety' entered the English language in the 1 ...
and reduce caretaker burden. 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. If eating becomes problematic, food will need to be prepared in smaller pieces or even
purée A purée (or mash) is cooked food, usually vegetables, fruits or legumes, that has been ground, pressed, blended or sieved to the consistency of a creamy paste or liquid. Purées of specific foods are often known by specific names, e.g., appl ...
d. When swallowing difficulties arise, the use of
feeding tube A feeding tube is a medical device used to provide nutrition to people who cannot obtain nutrition by mouth, are unable to swallow safely, or need nutritional supplementation. The state of being fed by a feeding tube is called gavage, enteral f ...
s may be required. In such cases, the medical efficacy and ethics of continuing feeding is an important consideration of the caregivers and family members. 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. During the final stages of the disease, treatment is centred on relieving discomfort until death, often with the help of
hospice Hospice care is a type of health care that focuses on the palliation of a terminally ill patient's pain and symptoms and attending to their emotional and spiritual needs at the end of life. Hospice care prioritizes comfort and quality of life b ...
.


Diet

Diet may be a modifiable risk factor for the development of Alzheimer's disease but more research needs to be conducted. The
Mediterranean diet The Mediterranean diet is a concept first proposed in 1975 by the American biologist Ancel Keys and chemist Margaret Keys. The diet took inspiration from the eating habits and traditional food typical of Crete, much of the rest of Greece, and s ...
, and the
DASH diet The Dietary Approaches to Stop Hypertension (DASH) diet is a diet to control hypertension promoted by the U.S.-based National Heart, Lung, and Blood Institute, part of the National Institutes of Health (NIH), an agency of the United States Depart ...
are both associated with less cognitive decline. A different approach has been to incorporate elements of both of these diets into one known as the MIND diet. Results from large-scale
epidemiological Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and Risk factor (epidemiology), determinants of health and disease conditions in a defined population, and application of this knowledge to prevent dise ...
studies and clinical trials have not demonstrated an independent role for most individual dietary components.


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.
Life expectancy Human life expectancy is a statistical measure of the estimate of the average remaining years of life at a given age. The most commonly used measure is ''life expectancy at birth'' (LEB, or in demographic notation ''e''0, where '' ...
of people with AD is reduced. The normal life expectancy for 60 to 70 years old is 23 to 15 years; for 90 years old it is 4.5 years. 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. Fewer than 3% of people live more than fourteen years after diagnosis. Disease features significantly associated with reduced survival are an increased severity of cognitive impairment, decreased functional level, disturbances in the neurological examination, history of falls,
malnutrition Malnutrition occurs when an organism gets too few or too many nutrients, resulting in health problems. Specifically, it is a deficiency, excess, or imbalance of energy, protein and other nutrients which adversely affects the body's tissues a ...
,
dehydration In physiology, dehydration is a lack of total body water that disrupts metabolic processes. It occurs when free water loss exceeds intake, often resulting from excessive sweating, health conditions, or inadequate consumption of water. Mild deh ...
and
weight loss Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...
. Other coincident diseases such as
heart problems Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina pectoris, angina, myocardial infarction, heart attack), heart failure, ...
,
diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
, or history of
alcohol abuse Alcohol abuse encompasses a spectrum of alcohol-related substance abuse. This spectrum can range from being mild, moderate, or severe. This can look like consumption of more than 2 drinks per day on average for men, or more than 1 drink per ...
are also related with shortened survival. 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. Men have a less favourable survival prognosis than women.
Aspiration pneumonia Aspiration pneumonia is a type of lung infection that is due to a relatively large amount of material from the stomach or mouth entering the lungs. Signs and symptoms often include fever and cough of relatively rapid onset. Complications may incl ...
is the most frequent immediate cause of death brought by AD. While the reasons behind the lower prevalence of
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
in AD patients remain unclear, some researchers hypothesize that biological mechanisms shared by both diseases might play a role. However, this requires further investigation.


Epidemiology

Two main measures are used in
epidemiological Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and Risk factor (epidemiology), determinants of health and disease conditions in a defined population, and application of this knowledge to prevent dise ...
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 In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...
is the total number of cases of the disease in the population at any given time. Regarding incidence,
cohort Cohort or cohortes may refer to: Cohort Sociological * Cohort (military unit), the basic tactical unit of a Roman legion * Cohort (educational group), a group of students working together through the same academic curriculum Scientific * Cohort ...
longitudinal studies A longitudinal study (or longitudinal survey, or panel study) is a research design that involves repeated observations of the same variables (e.g., people) over long periods of time (i.e., uses longitudinal data). It is often a type of observation ...
(studies where a disease-free population is followed over the years) provide rates between 10 and 15 per thousand person-years for all dementias and 5–8 for AD, 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. Females with AD are more common than males, but this difference is likely due to women's longer life spans. When adjusted for age, both sexes are affected by Alzheimer's at equal rates. 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. However, much AD research remains to be done in minority groups, such as the
African American African Americans, also known as Black Americans and formerly also called Afro-Americans, are an Race and ethnicity in the United States, American racial and ethnic group that consists of Americans who have total or partial ancestry from an ...
,
East Asian East Asia is a geocultural region of Asia. It includes China, Japan, Mongolia, North Korea, South Korea, and Taiwan, plus two special administrative regions of China, Hong Kong and Macau. The economies of Economy of China, China, Economy of Ja ...
and Hispanic/Latino populations. 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. 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. Prevalence rates in some less developed regions around the globe are lower. 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.


History

The ancient Greek and Roman philosophers and
physician A physician, medical practitioner (British English), medical doctor, or simply doctor is a health professional who practices medicine, which is concerned with promoting, maintaining or restoring health through the Medical education, study, Med ...
s associated old age with increasing
dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
. It was not until 1901 that German psychiatrist
Alois Alzheimer Alois Alzheimer ( , , ; 14 June 1864 – 19 December 1915) was a German psychiatrist, neuropathologist and colleague of Emil Kraepelin. He is credited with identifying the first published case of "presenile dementia", which Kraepelin later ide ...
identified the first case of what became known as Alzheimer's disease, named after him, in a fifty-year-old woman he called Auguste D. He followed her case until she died in 1906 when he first reported publicly on it. During the next five years, eleven similar cases were reported in the
medical literature Medical literature is the scientific literature of medicine: articles in journals and texts in books devoted to the field of medicine. Many references to the medical literature include the health care literature generally, including that of denti ...
, some of them already using the term Alzheimer's disease. The disease was first described as a distinctive disease by
Emil Kraepelin Emil Wilhelm Georg Magnus Kraepelin (; ; 15 February 1856 – 7 October 1926) was a German psychiatrist. H. J. Eysenck's Encyclopedia of Psychology identifies him as the founder of modern scientific psychiatry, psychopharmacology and psychiatric ...
after suppressing some of the clinical (delusions and hallucinations) and pathological features (arteriosclerotic changes) contained in the original report of Auguste D. He included ''Alzheimer's disease'', also named ''presenile''
dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
by Kraepelin, as a subtype of ''senile dementia'' in the eighth edition of his ''Textbook of Psychiatry'', published on 15 July 1910. 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 Pathology is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...
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. This eventually led to the diagnosis of ''Alzheimer's disease'' independent of age. 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 Nomenclature (, ) is a system of names or terms, or the rules for forming these terms in a particular field of arts or sciences. (The theoretical field studying nomenclature is sometimes referred to as ''onymology'' or ''taxonymy'' ). The principl ...
to describe individuals of all ages with a characteristic common symptom pattern, disease course, and
neuropathology Neuropathology is the study of disease of nervous system tissue, usually in the form of either small surgical biopsies or whole-body autopsies. Neuropathologists usually work in a department of anatomic pathology, but work closely with the clini ...
. The
National Institute of Neurological and Communicative Disorders and Stroke The National Institute of Neurological Disorders and Stroke (NINDS) is a part of the U.S. National Institutes of Health (NIH). It conducts and funds research on brain and nervous system disorders and has a budget of just over US$2.03 billion. The ...
(NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA, now known as the
Alzheimer's Association The Alzheimer's Association is a nonprofit voluntary health organization that focuses on Alzheimer's disease care, support and research. History Jerome H. Stone founded the Alzheimer's Association with the help of several family support groups ...
) established the most commonly used NINCDS-ADRDA Alzheimer's Criteria for diagnosis in 1984, extensively updated in 2007. These criteria require that the presence of cognitive impairment, and a suspected dementia syndrome, be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable Alzheimer's disease. A
histopathologic Histopathology (compound of three Greek language, Greek words: 'tissue', 'suffering', and ''-logy, -logia'' 'study of') is the light microscope, microscopic examination of Tissue (biology), tissue in order to study the manifestations of dis ...
confirmation including a
microscopic The microscopic scale () is the scale of objects and events smaller than those that can easily be seen by the naked eye, requiring a lens or microscope to see them clearly. In physics, the microscopic scale is sometimes regarded as the scale betwe ...
examination of
brain tissue The human brain is the central organ of the nervous system, and with the spinal cord, comprises the central nervous system. It consists of the cerebrum, the brainstem and the cerebellum. The brain controls most of the activities of the bod ...
is required for a definitive diagnosis. Good
statistical reliability In statistics and psychometrics, reliability is the overall consistency of a measure. A measure is said to have a high reliability if it produces similar results under consistent conditions:It is the characteristic of a set of test scores that r ...
and validity have been reported between the diagnostic criteria and definitive histopathological confirmation.


Society and culture


Social costs

Dementia, and specifically Alzheimer's disease, may be among the most costly diseases for societies worldwide. As populations age, these costs will probably increase and become an important social problem and economic burden. Costs associated with AD include direct and indirect medical costs, which vary between countries depending on social care for a person with AD. Direct costs include doctor visits, hospital care, medical treatments,
nursing home care A nursing home is a facility for the residential care of older people, senior citizens, or disabled people. Nursing homes may also be referred to as care homes, skilled nursing facilities (SNF), or long-term care facilities. Often, these terms ...
, specialised equipment, and household expenses. Indirect costs include the cost of informal care and the loss in
productivity Productivity is the efficiency of production of goods or services expressed by some measure. Measurements of productivity are often expressed as a ratio of an aggregate output to a single input or an aggregate input used in a production proce ...
of informal caregivers. In the United States , 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. 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. Costs for those with more severe dementia or behavioral disturbances are higher and are related to the additional caregiving time to provide physical care.


Caregiving burden

Individuals with Alzheimer's will require assistance in their lifetime, and care will most likely come in the form of a full-time
caregiver A caregiver, carer or support worker is a paid or unpaid person who helps an individual with activities of daily living. Caregivers who are members of a care recipient's family or social network, who may have specific professional training, are o ...
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. Alzheimer's disease is known for placing a great burden on caregivers which includes social, psychological, physical, or economic aspects. Home care is usually preferred by both those people with Alzheimer's disease as well as their families. This option also delays or eliminates the need for more professional and costly levels of care. Nevertheless, two-thirds of nursing home residents have dementias.
Dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
caregivers are subject to high rates of physical and mental disorders. 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 Social isolation is a state of complete or near-complete lack of contact between an individual and society. It differs from loneliness, which reflects temporary and involuntary lack of contact with other humans in the world. Social isolation c ...
. 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.
Cognitive behavioral therapy Cognitive behavioral therapy (CBT) is a form of psychotherapy that aims to reduce symptoms of various mental health conditions, primarily depression, PTSD, and anxiety disorders. Cognitive behavioral therapy focuses on challenging and chang ...
and the teaching of
coping strategies Coping refers to conscious or unconscious strategies used to reduce and manage unpleasant emotions. Coping strategies can be cognitions or behaviors and can be individual or social. To cope is to deal with struggles and difficulties in life. It ...
either individually or in group have demonstrated their efficacy in improving caregivers' psychological health.


Media

Alzheimer's disease has been portrayed in films such as: '' Iris'' (2001), based on John Bayley's memoir of his wife
Iris Murdoch Dame Jean Iris Murdoch ( ; 15 July 1919 – 8 February 1999) was an Irish and British novelist and philosopher. Murdoch is best known for her novels about good and evil, sexual relationships, morality, and the power of the unconscious. Her fi ...
; '' The Notebook'' (2004), based on
Nicholas Sparks Nicholas Charles Sparks (born December 31, 1965) is an American novelist, screenwriter, and film producer. He has published twenty-three novels, all ''New York Times'' bestsellers, and two works of nonfiction, with over 115 million copies sold ...
's 1996 novel of the same name; '' A Moment to Remember'' (2004); '' Thanmathra'' (2005); '' Memories of Tomorrow (Ashita no Kioku)'' (2006), based on Hiroshi Ogiwara's novel of the same name; '' Away from Her'' (2006), based on
Alice Munro Alice Ann Munro ( ; ; 10 July 1931 – 13 May 2024) was a Canadian short story writer who was awarded the Nobel Prize in Literature in 2013. Her work tends to move forward and backward in time, with integrated short story cycles. Munro's ...
's
short story A short story is a piece of prose fiction. It can typically be read in a single sitting and focuses on a self-contained incident or series of linked incidents, with the intent of evoking a single effect or mood. The short story is one of the old ...
'' The Bear Came over the Mountain''; '' Still Alice'' (2014), about a
Columbia University Columbia University in the City of New York, commonly referred to as Columbia University, is a Private university, private Ivy League research university in New York City. Established in 1754 as King's College on the grounds of Trinity Churc ...
professor who has early onset Alzheimer's disease, based on Lisa Genova's 2007 novel of the same name and featuring
Julianne Moore Julie Anne Smith (born December 3, 1960), known professionally as Julianne Moore, is an American actress and children's author. Prolific in film since the early 1990s, she is known for her portrayals of emotionally troubled women in independent ...
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. 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'' (20162019). Paintings depicting the disorder include the late works by American artist
William Utermohlen William Charles Utermohlen (December 5, 1933 – March 21, 2007) was an American figurative artist known for his late-period self-portraits completed after his diagnosis of probable Alzheimer's disease. He was diagnosed in 1995, having had pro ...
, who drew self-portraits from 1995 to 2000 as an experiment of showing his disease through art.


Research

Specific medications that may reduce the risk or progression of Alzheimer's disease include those that impact plaques, inflammation,
APOE Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene ''APOE''. Apo-E belongs to a family ...
, neurotransmitter receptors, neurogenesis,
growth factor A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for ...
s or hormones.
Machine learning Machine learning (ML) is a field of study in artificial intelligence concerned with the development and study of Computational statistics, statistical algorithms that can learn from data and generalise to unseen data, and thus perform Task ( ...
algorithms with
electronic health record An electronic health record (EHR) is the systematized collection of electronically stored patient and population health information in a digital format. These records can be shared across different health care settings. Records are shared thro ...
s are studied as a way to predict Alzheimer's disease earlier. 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.


References


External links

* * {{Authority control Alzheimer's disease Aging-associated diseases Ailments of unknown cause Amyloidosis Aphasias Cognitive disorders Dementia Diseases named after discoverers Herpes simplex virus–associated diseases Learning disabilities Unsolved problems in neuroscience Wikipedia medicine articles ready to translate Wikipedia neurology articles ready to translate