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Alzheimer's disease (AD) is a
neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. 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, from delirium to intoxication. Typically, disorient ...
(including easily getting lost), mood swings, loss of motivation,
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 medical conditions they have. More generally, any lack ...
, 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 typical life expectancy following diagnosis is three to nine years. The cause of Alzheimer's disease is poorly understood. There are many environmental and genetic risk factors associated with its development. The strongest genetic risk factor is from an allele of
APOE Apolipoprotein E (APOE) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular disease. APOE belongs to a family of fat-binding proteins called apolipoproteins. ...
. 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. Introd ...
, and high blood pressure. The disease process is largely associated with
amyloid plaques Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of mic ...
,
neurofibrillary tangle Neurofibrillary tangles (NFTs) are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease. Their presence is also found in numerous other diseases known as tauopathies. Little is k ...
s, and loss of neuronal connections in the brain. 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 rev ...
and
blood test A blood test is a 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 test or a choleste ...
s to rule out other possible causes. Initial symptoms are often mistaken for normal aging. Examination of brain tissue is needed for a definite diagnosis, but this can only take place after death. Good nutrition, physical activity, and engaging socially are known to be of benefit generally in aging, and these may help in reducing the risk of cognitive decline and Alzheimer's; in 2019 clinical trials were underway to look at these possibilities. There are no medications or supplements that have been shown to decrease risk. No treatments stop or reverse its progression, though some may temporarily improve symptoms. Affected people increasingly rely on others for assistance, often placing a burden on the
caregiver A caregiver or carer is a paid or unpaid member of a person's social network who helps them with activities of daily living. Since they have no specific professional training, they are often described as informal caregivers. Caregivers most commo ...
. The pressures can include social, psychological, physical, and economic elements. Exercise programs may be beneficial with respect to
activities of daily living Activity may refer to: * Action (philosophy), in general * Human activity: human behavior, in sociology behavior may refer to all basic human actions, economics may study human economic activities and along with cybernetics and psychology may st ...
and can potentially improve outcomes. Behavioral problems or
psychosis Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior t ...
due to dementia are often treated with
antipsychotic Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of oth ...
s, but this is not usually recommended, as there is little benefit and 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 affecting 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 and neuropathologist and a colleague of Emil Kraepelin. Alzheimer is credited with identifying the first published case of "presenile dementia", which Kraep ...
, who first described it in 1906. Alzheimer's financial burden on society is large, with an estimated global annual cost of trillion. Alzheimer's disease is currently ranked as the seventh leading cause of death in the United States.


Signs and symptoms

The course of Alzheimer's is generally described in three stages, with a progressive pattern of
cognitive Cognition refers to "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, though ...
and
functional Functional may refer to: * Movements in architecture: ** Functionalism (architecture) ** Form follows function * Functional group, combination of atoms within molecules * Medical conditions without currently visible organic basis: ** Functional sy ...
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 which is associated with memory, and this is responsible for the first symptoms of memory impairment. As the disease progresses so does the degree of memory impairment.


First symptoms

The first symptoms are often mistakenly attributed to
aging Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. I ...
or stress. Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for diagnosis of Alzheimer's disease. These early symptoms can affect the most complex
activities of daily living Activity may refer to: * Action (philosophy), in general * Human activity: human behavior, in sociology behavior may refer to all basic human actions, economics may study human economic activities and along with cybernetics and psychology may st ...
. 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 of attentiveness, planning, flexibility, and
abstract thinking Abstraction in its main sense is a conceptual process wherein general rules and concepts are derived from the usage and classification of specific examples, literal ("real" or "concrete") signifiers, first principles, or other methods. "An abstr ...
, or impairments in semantic memory (memory of meanings, and concept relationships) can also be symptomatic of the early stages of Alzheimer's disease.
Apathy Apathy 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 individual has an absence of interes ...
and depression can be seen at this stage, with apathy remaining as the most persistent symptom throughout the course of the disease. Mild cognitive impairment (MCI) is often found to be a transitional stage between normal aging and dementia. MCI can present with a variety of symptoms, and when memory loss is the predominant symptom, it is termed
amnestic MCI Mild cognitive impairment (MCI) is a neurocognitive disorder which involves cognitive impairments beyond those expected based on an individual's age and education but which are not significant enough to interfere with instrumental activities ...
and is frequently seen as a
prodromal In medicine, a prodrome is an early sign or symptom (or set of signs and symptoms) that often indicates the onset of a disease before more diagnostically specific signs and symptoms develop. It is derived from the Greek word ''prodromos'', mean ...
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 system ...
(
agnosia Agnosia is the 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 not defective nor is there any significant memory loss. It is usually ...
), 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 disorder ...
) 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), facts learned ( semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat or how to drink from a glass) are affected to a lesser degree than new facts or memories. Language problems are mainly characterised by a shrinking
vocabulary A vocabulary is a set of familiar words within a person's language. A vocabulary, usually developed with age, serves as a useful and fundamental tool for communication and acquiring knowledge. Acquiring an extensive vocabulary is one of the la ...
and decreased word fluency, leading to a general impoverishment of oral and
written language A written language is the representation of a spoken or gestural language by means of a writing system. Written language is an invention in that it must be taught to children, who will pick up spoken language or sign language by exposure even i ...
. 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) may be present, but they are commonly unnoticed. As the disease progresses, people with Alzheimer's disease can often continue to perform many tasks independently, but 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 ( paraphasias). 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 short-term and working memory, which persist for only about 18 to 30 seconds. Long-te ...
, which was previously intact, becomes impaired. Behavioral and
neuropsychiatric Neuropsychiatry or Organic Psychiatry is a branch of medicine that deals with psychiatry as it relates to neurology, in an effort to understand and attribute behavior to the interaction of neurobiology and social psychology factors. Within neurop ...
changes become more prevalent. Common manifestations are wandering, irritability and emotional lability, leading to crying, outbursts of unpremeditated
aggression Aggression is overt or covert, often harmful, social interaction with the intention of inflicting damage or other harm upon another individual; although it can be channeled into creative and practical outlets for some. It may occur either reacti ...
, or resistance to caregiving.
Sundowning Sundowning, or sundown syndrome, is a neurological phenomenon associated with increased confusion and restlessness in people with delirium or some form of dementia. It is most commonly associated with Alzheimer's disease but also found in those w ...
can also appear. Approximately 30% of people with Alzheimer's disease develop illusionary misidentifications and other delusional 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 or psychological (e.g., PTSD, Stockholm syndrome, schizophrenia, bipolar disorder, dementia) condition. Anosognosia c ...
). Urinary incontinence can develop. These symptoms create stress for relatives and caregivers, which can be reduced by moving the person from
home care Homecare (also spelled as home care) is health care or supportive care provided by a professional caregiver in the individual home where the patient or client is living, as opposed to care provided in group accommodations like clinics or nursing ho ...
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 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 individual has an absence of interes ...
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 muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscle ...
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 damage to the skin and/or underlying tissue that usually occur over a bony prominence as a result of usually long-term pressure, or pressure in combi ...
s or pneumonia, not the disease itself.


Causes

Proteins fail to function normally. This disrupts the work of the brain cells affected and triggers a toxic cascade, ultimately leading to cell death and later brain shrinkage. Alzheimer's disease is believed to occur when abnormal amounts of
amyloid beta Amyloid beta (Aβ or Abeta) 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 precursor protein (APP), which is ...
(Aβ), accumulating extracellularly as
amyloid plaques Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of mic ...
and tau proteins, or intracellularly as
neurofibrillary tangle Neurofibrillary tangles (NFTs) are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease. Their presence is also found in numerous other diseases known as tauopathies. Little is k ...
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. Advances in brain imaging techniques allow researchers to see the development and spread of abnormal amyloid and tau proteins in the living brain, as well as changes in brain structure and function. Beta-amyloid is a fragment of a larger protein. When these fragments cluster together, a toxic effect appears on neurons and disrupt cell-to-cell communication. Larger deposits called amyloid plaques are thus further formed. Tau proteins are responsible in neuron's internal support and transport system to carry nutrients and other essential materials. In Alzheimer's disease, the shape of tau proteins is altered and thus organize themselves into structures called neurofibrillary tangles. The tangles disrupt the transport system and are toxic to cells. 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 attempt to explain the underlying cause; the two predominant hypotheses are the amyloid beta (Aβ) hypothesis and the cholinergic hypothesis. The oldest hypothesis, on which most drug therapies are based, is the cholinergic hypothesis, which proposes that Alzheimer's disease is caused by reduced synthesis of the neurotransmitter
acetylcholine Acetylcholine (ACh) is an organic chemical 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. Parts ...
. The loss of
cholinergic neuron A cholinergic neuron is a nerve cell which mainly uses the neurotransmitter acetylcholine (ACh) to send its messages. Many neurological systems are cholinergic. Cholinergic neurons provide the primary source of acetylcholine to the cerebral corte ...
s noted in the limbic system and cerebral cortex, is a key feature in the progression of Alzheimer's. The 1991 amyloid hypothesis postulated that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease. Support for this postulate 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 tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse forma ...
(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 48 million base pairs (the building material of DNA) representing about 1.5 percent of the total DNA in cells. M ...
, 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 reprodu ...
(Down syndrome) who have an extra gene copy almost universally exhibit at least the earliest symptoms of Alzheimer's disease by 40 years of age. 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 or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some is ...
of apolipoprotein,
APOE4 Apolipoprotein E (APOE) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular disease. APOE belongs to a family of fat-binding proteins called apolipoproteins. ...
, is a major genetic risk factor for Alzheimer's disease. While apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain.


Genetic

Only 1–2% of Alzheimer's cases are inherited (
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...
). These types are known as early onset familial Alzheimer's disease, can have a very early onset, and a faster rate of progression. 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 formati ...
(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 onse ...
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 beta ...
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 or Abeta) 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 precursor protein (APP), which is ...
(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 the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of mic ...
. Some of the mutations merely alter the ratio between Aβ42 and the other major forms—particularly Aβ40—without increasing Aβ42 levels. Two other genes associated with autosomal dominant Alzheimer's disease are
ABCA7 ATP-binding cassette sub-family A member 7 is a protein that in humans is encoded by the ''ABCA7'' gene. Function The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transpo ...
and
SORL1 Sortilin-related receptor, L(DLR class) A repeats containing is a protein that in humans is encoded by the SORL1 gene. SORL1 (also known as SORLA, SORLA1, or LR11) is a neuronal apolipoprotein E receptor, the gene for which is predominantly expre ...
. Most cases of Alzheimer's are not inherited and are termed sporadic Alzheimer's disease, in which environmental and genetic differences may act as risk factors. Most cases of sporadic Alzheimer's disease in contrast to familial Alzheimer's disease are late-onset Alzheimer's disease (LOAD) developing after the age of 65 years. Less than 5% of sporadic Alzheimer's disease have an earlier onset. The strongest genetic risk factor for sporadic Alzheimer's disease is APOEε4. APOEε4 is one of four alleles of
apolipoprotein E Apolipoprotein E (APOE) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular disease. APOE belongs to a family of fat-binding proteins called apolipoproteins. ...
(APOE). APOE plays a major role in lipid-binding proteins in lipoprotein particles and the epsilon4 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 and by 15 times in homozygotes. 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 (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is t ...
. For example, certain Nigerian populations do not show the relationship between dose of APOEε4 and incidence or age-of-onset for Alzheimer's disease seen in other human populations.
Allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chro ...
s in the
TREM2 Triggering receptor expressed on myeloid cells 2 (TREM2) is a protein that in humans is encoded by the ''TREM2'' gene. TREM2 is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia, which are immune cell ...
gene have been associated with a 3 to 5 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.


Other hypotheses

The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau as
paired helical filament Tauopathy belongs to a class of neurodegenerative diseases involving the aggregation of tau protein into neurofibrillary or gliofibrillary tangles in the human brain. Tangles are formed by hyperphosphorylation of the microtubule protein known a ...
s. Eventually, they form
neurofibrillary tangle Neurofibrillary tangles (NFTs) are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease. Their presence is also found in numerous other diseases known as tauopathies. Little is k ...
s inside nerve cell bodies. When this occurs, the microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system. A number of studies connect the misfolded amyloid beta and tau proteins associated with the pathology of Alzheimer's disease, as 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 r ...
that leads to chronic inflammation. Sustained inflammation (neuroinflammation) is also a feature of other neurodegenerative diseases including Parkinson's disease, and
ALS Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
.
Spirochete infection A spirochaete () or spirochete is a member of the phylum Spirochaetota (), (synonym Spirochaetes) which contains distinctive diderm (double-membrane) gram-negative bacteria, most of which have long, helically coiled (corkscrew-shaped or s ...
s have also been linked to dementia. DNA damages accumulate in AD brains; reactive oxygen species may be the major source of this DNA damage. Sleep disturbances are seen as a possible risk factor for inflammation in Alzheimer's disease. Sleep problems have been seen as a consequence of Alzheimer's disease but studies suggest that they may instead be a causal factor. Sleep disturbances are thought to be linked to persistent inflammation. The cellular
homeostasis In biology, homeostasis (British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and i ...
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 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. One hypothesis posits that dysfunction of oligodendrocytes and their associated myelin during aging contributes to axon damage, which then causes amyloid production and tau hyper-phosphorylation as a side effect. Retrogenesis is a medical hypothesis 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 to describe the cellular and molecular mechanisms by which the complex nervous ...
beginning with neurulation and ending with
myelination Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...
, the brains of people with Alzheimer's disease go through a reverse
neurodegeneration A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
process starting with
demyelination A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This damage impairs the conduction of signals in the affected nerves. In turn, the reduction in conduction ability causes deficiency i ...
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 Cognitive deficit is an inclusive term to describe any characteristic that acts as a barrier to the cognition process. The term may describe * deficits in overall intelligence (as with intellectual disabilities), * specific and restricted defici ...
. 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, where individuals develop intolerance to gluten, present in foods such as wheat, rye and barle ...
is unclear, with a 2019 study finding no increase in dementia overall in those with CD, while a 2018 review found an association with several types of dementia including Alzheimer's disease.


Pathophysiology


Neuropathology

Alzheimer's disease is characterised by loss of neurons and synapses 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. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting of ...
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), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply t ...
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, 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 ...
. Degeneration is also present in brainstem nuclei particularly the locus coeruleus in the pons. Studies using
MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
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 appearances, intelligence, ...
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
Amyloid beta (Aβ or Abeta) 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 precursor protein (APP), which is ...
plaques and
neurofibrillary tangle Neurofibrillary tangles (NFTs) are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease. Their presence is also found in numerous other diseases known as tauopathies. Little is k ...
s are clearly visible by
microscopy Microscopy is the technical field of using microscopes to view objects and areas of objects that cannot 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 mic ...
in brains of those with Alzheimer's disease, especially in the hippocampus. However, Alzheimer's disease may occur without neurofibrillary tangles in the neocortex. 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 solubi ...
deposits of
beta-amyloid Amyloid beta (Aβ or Abeta) 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 precursor protein (APP), which is ...
peptide and cellular material outside and around neurons. Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves. Although many older individuals develop some plaques and tangles as a consequence of aging, the brains of people with Alzheimer's disease have a greater number of them in specific brain regions such as the temporal lobe.
Lewy bodies Lewy bodies are the inclusion bodies – abnormal aggregations of protein – that develop inside nerve cells affected by Parkinson's disease (PD), the Lewy body dementias (Parkinson's disease dementia and dementia with Lewy bodies (DLB)), and ...
are not rare in the brains of people with Alzheimer's disease.


Biochemistry

Alzheimer's disease has been identified as a protein misfolding disease, a proteopathy, caused by the accumulation of abnormally folded
amyloid beta Amyloid beta (Aβ or Abeta) 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 precursor protein (APP), which is ...
protein into amyloid plaques, and tau protein into neurofibrillary tangles in the brain. Plaques are made up of small peptides, 39–43 
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s in length, called amyloid beta (Aβ). 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 formati ...
(APP) a transmembrane protein that penetrates the neuron'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, itself 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. Th ...
and
beta secretase Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is enco ...
act together in a
proteolytic Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called prote ...
process which causes APP to be divided into smaller fragments. One of these fragments gives rise to fibrils of amyloid beta, which then form clumps that deposit outside neurons in dense formations known as
amyloid plaques Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of mic ...
. Alzheimer's disease is also considered a
tauopathy Tauopathy belongs to a class of neurodegenerative diseases involving the aggregation of tau protein into neurofibrillary or gliofibrillary tangles in the human brain. Tangles are formed by hyperphosphorylation of the microtubule protein known ...
due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, 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 a ...
. 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 spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action p ...
and back. A protein called ''tau'' stabilises the microtubules when
phosphorylated In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...
, 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 within ...
. In Alzheimer's disease, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating
neurofibrillary tangle Neurofibrillary tangles (NFTs) are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease. Their presence is also found in numerous other diseases known as tauopathies. Little is k ...
s and disintegrating the neuron's transport system. Pathogenic tau can also cause neuronal death through
transposable element A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Transp ...
dysregulation.


Disease mechanism

Exactly how disturbances of production and aggregation of the beta-amyloid peptide 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 7–13 nm in diameter, a beta sheet (β-sheet) secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the hum ...
s, which are believed to be the toxic form of the protein responsible for disrupting the cell's
calcium Calcium is a chemical element with the 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 ...
ion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conv ...
homeostasis In biology, homeostasis (British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and i ...
, induces
programmed cell death Programmed cell death (PCD; sometimes referred to as 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 usually confers ...
(
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes includ ...
). It is also known that Aβ selectively builds up in the mitochondria in the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilisation of glucose by neurons. Various inflammatory processes and
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autoc ...
s may also have a role in the pathology of Alzheimer's disease. Inflammation 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 factors 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.


Diagnosis

Alzheimer's disease 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 the person's medical history, history from relatives, and behavioral observations. The presence of characteristic
neurological Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...
and
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 often focus on how injuries or illnesses of t ...
features and the absence of alternative conditions supports the diagnosis. 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 rev ...
with computed tomography (CT) or magnetic resonance imaging (MRI), and with
single-photon emission computed tomography Single-photon emission computed tomography (SPECT, or less commonly, SPET) is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera (that is, ...
(SPECT) or positron emission tomography (PET), can be used to help exclude other cerebral pathology or subtypes of dementia. Moreover, it may predict conversion from
prodromal In medicine, a prodrome is an early sign or symptom (or set of signs and symptoms) that often indicates the onset of a disease before more diagnostically specific signs and symptoms develop. It is derived from the Greek word ''prodromos'', mean ...
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 i ...
diagnostic agents used in PET for Alzheimer's disease are
florbetapir Florbetapir (18F), sold under the brand name Amyvid, is a PET scanning radiopharmaceutical compound containing the radionuclide fluorine-18 that was approved for use in the United States in 2012, as a diagnostic tool for Alzheimer's disease. * ...
(2012),
flutemetamol Flutemetamol (18F) (trade name Vizamyl, by GE Healthcare) is a PET scanning radiopharmaceutical containing the radionuclide fluorine-18, used as a diagnostic tool for Alzheimer's disease. Adverse effects Adverse effects of flutemetamol include h ...
(2013),
florbetaben Florbetaben, a fluorine-18 (18F)-labeled stilbene derivative (formerly known as BAY-949172), trade name NeuraCeq, is a diagnostic radiotracer developed for routine clinical application to visualize β-amyloid plaques in the brain. It is indica ...
(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 (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 or to evaluate any d ...
evaluations when brain material is available and can be examined
histologically Histology, also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vis ...
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'' (
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 Psychiatric ...
); 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 the ...
-
Alzheimer's Association The Alzheimer's Association was founded by Jerome H. Stone with the help of several family members in Chicago, Illinois, and incorporated on April 10, 1980, as the Alzheimer's Disease and Related Disorders Association, Inc. It is a non-profit A ...
(NIA-AA) definition as revised in 2011; and the International Working Group criteria as revised in 2010. Three broad time periods, which can span decades, define the progression of Alzheimer's disease from the preclinical phase, to mild cognitive impairment (MCI), followed by Alzheimer's disease dementia. Eight intellectual domains are most commonly impaired in AD— memory, language, perceptual skills,
attention Attention is the behavioral and cognitive process of selectively concentrating on a discrete aspect of information, whether considered subjective or objective, while ignoring other perceivable information. William James (1890) wrote that "At ...
, motor skills, orientation,
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 are necessary for the cognitive control of behavior: selecting and succe ...
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 Psychiatric ...
defines criteria for probable or possible Alzheimer's 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 Alzheimer's disease, probable Alzheimer's disease can be diagnosed if the individual has genetic evidence of Alzheimer's or if two or more acquired cognitive deficits, and a functional disability that is not from another disorder, are present. Otherwise, possible Alzheimer's disease can be diagnosed as the diagnosis follows an atypical route. For mild neurocognitive disorder due to Alzheimer's, probable Alzheimer's disease can be diagnosed if there is genetic evidence, whereas possible Alzheimer's disease 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 Alzheimer's disease 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. The core clinical criteria for MCI is used along with identification of 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 Alzheimer's disease dementia. In probable Alzheimer's disease dementia there is steady impairment of cognition over time and a memory-related or non-memory-related cognitive dysfunction. In possible Alzheimer's disease dementia, another causal disease such as cerebrovascular disease is present.


Techniques

Neuropsychological tests 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 de ...
(MMSE), the Montreal Cognitive Assessment (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 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. 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 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 test or a choleste ...
s, thyroid function tests, as well as tests to assess vitamin
B12 Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, in both fatty acid and amino acid metabolism. It ...
levels, rule out neurosyphilis and rule out metabolic problems (including tests for kidney function, electrolyte levels and for diabetes). MRI or CT scans might also be used to rule out other potential causes of the symptoms – including tumors or strokes.
Delirium Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances in ...
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 Alzheimer's disease (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 Alzheimer's disease 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.


Prevention

There are no disease-modifying treatments available to cure Alzheimer's disease and because of this, AD research has focused on interventions to prevent the onset and progression. There is no evidence that supports any particular measure in preventing Alzheimer's, 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 Alzheimer's disease 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 Alzheimer's disease. Further research is needed to determine factors that can help prevent Alzheimer's disease.


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, diabetes, and smoking, are associated with a higher risk of onset and worsened course of AD. The use of statins to lower cholesterol may be of benefit in Alzheimer's. Antihypertensive and antidiabetic medications in individuals without overt cognitive impairment may decrease the risk of dementia by influencing cerebrovascular pathology. More research is needed to examine the relationship with Alzheimer's disease 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 Alzheimer's disease; management with antidepressants may provide a preventative measure. Historically, long-term usage of
non-steroidal anti-inflammatory drugs Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...
(NSAIDs) were thought to be associated with a reduced likelihood of developing Alzheimer's disease as it reduces inflammation; however, NSAIDs do not appear to be useful as a treatment. Additionally, because women have a higher incidence of Alzheimer's disease than men, it was once thought that estrogen deficiency during menopause was a risk factor. However, 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 Alzheimer's. 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 of the brain. Participating in mental exercises, such as reading, crossword puzzles, and chess have shown a potential to be preventative. Meeting the WHO 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 Alzheimer's, 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 delays the onset of Alzheimer's disease syndrome without changing the duration of the disease. Cessation in smoking may reduce risk of developing Alzheimer's' disease, specifically in those who carry 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 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 is examining whether sleep disorders may increase the prevalence of AD. One theory is that the mechanisms to increase clearance of toxic substances, including
Amyloid beta (Aβ or Abeta) 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 precursor protein (APP), which is ...
, 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 Alzheimer's. The mechanism by which stress predisposes someone to development of Alzheimer's is unclear, but it is suggested that lifetime stressors may affect a person's epigenome, leading to an overexpression or under expression of specific genes. Although the relationship of stress and Alzheimer's 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 Alzheimer's disease; available treatments offer relatively small symptomatic benefits but remain palliative in nature. Treatments can be divided into pharmaceutical, psychosocial, and caregiving.


Pharmaceutical

Medications used to treat the cognitive problems of Alzheimer's disease 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 and ...
s (
tacrine Tacrine is a centrally acting acetylcholinesterase inhibitor and indirect cholinergic agonist (parasympathomimetic). It was the first centrally acting cholinesterase inhibitor approved for the treatment of Alzheimer's disease, and was marketed un ...
,
rivastigmine Rivastigmine (sold under the trade name Exelon among others) is a cholinesterase inhibitor used for the treatment of mild to moderate Alzheimer's disease. The drug can be administered orally or via a transdermal patch; the latter form reduces t ...
,
galantamine Galantamine is used for the treatment of cognitive decline in mild to moderate Alzheimer's disease and various other memory impairments. It is an alkaloid that has been isolated from the bulbs and flowers of ''Galanthus nivalis'' (Common snowdro ...
, 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 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 dizziness. Severe side effects may include blood clots ...
, an NMDA receptor antagonist. The acetylcholinesterase inhibitors are intended for those with mild to severe Alzheimer's, 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. F ...
neurons is a well-known feature of Alzheimer's disease. Acetylcholinesterase inhibitors are employed to reduce the rate at which
acetylcholine Acetylcholine (ACh) is an organic chemical 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. Parts ...
(ACh) is broken down, thereby increasing the concentration of ACh in the brain and combating the loss of ACh caused by the death of cholinergic neurons. There is evidence for the efficacy of these medications in mild to moderate Alzheimer's disease, and some evidence for their use in the advanced stage. The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of Alzheimer's disease. The most common
side effects In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequenc ...
are nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately 10–20% of users, are mild to moderate in severity, and can be managed by slowly adjusting medication doses. 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 af ...
s, decreased heart rate (
bradycardia Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, a ...
), 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 regul ...
and weight, and increased
gastric acid Gastric acid, gastric juice, or stomach acid is a digestive fluid formed within the stomach lining. With a pH between 1 and 3, gastric acid plays a key role in digestion of proteins by activating digestive enzymes, which together break down the ...
production. Glutamate is an excitatory neurotransmitter of the nervous system, although excessive amounts in the brain can lead to
cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
death through a process called
excitotoxicity In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate r ...
which consists of the overstimulation of glutamate
receptors Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological diseases such as Parkinson's disease and multiple sclerosis.
Memantine Memantine 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 dizziness. Severe side effects may include blood clots ...
is a noncompetitive NMDA receptor antagonist first used as an anti- influenza agent. It acts on the
glutamatergic system Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
by blocking NMDA receptors and inhibiting their overstimulation by glutamate. Memantine has been shown to have a small benefit in the treatment of moderate to severe Alzheimer's disease. Reported adverse events with memantine are infrequent and mild, including hallucinations,
confusion In medicine, confusion is the quality or state of being bewildered or unclear. The term "acute mental confusion"
, dizziness, headache and fatigue. The combination of memantine and donepezil has been shown to be "of
statistically significant In statistical hypothesis testing, a result has statistical significance when it is very unlikely to have occurred given the null hypothesis (simply by chance alone). More precisely, a study's defined significance level, denoted by \alpha, is the p ...
but clinically marginal effectiveness". An extract of '' Ginkgo biloba'' known as ''EGb 761'' has been used for treating Alzheimer's 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 Alzheimer's disease and vascular dementia. EGb 761 may have a role either on its own or as an add-on if other therapies prove ineffective. A 2016 review concluded that the quality of evidence from clinical trials on ''Ginkgo biloba'' has been insufficient to warrant its use for treating Alzheimer's disease.
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 major tranquilizers and n ...
s are modestly useful in reducing
aggression Aggression is overt or covert, often harmful, social interaction with the intention of inflicting damage or other harm upon another individual; although it can be channeled into creative and practical outlets for some. It may occur either reacti ...
and
psychosis Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior t ...
in people with Alzheimer's disease, but their advantages are offset by serious adverse effects, such as stroke, movement difficulties or cognitive decline. When used in the long-term, they have been shown to associate with increased mortality. Se
lay summary
January 2009.
Stopping antipsychotic use in this group of people appears to be safe.


Psychosocial

Psychosocial 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 shown success in improving overall functioning, but can help to reduce some specific problem behaviors, such as
incontinence Incontinence or Incontinent may refer to: *Fecal incontinence, the involuntary excretion of bowel contents * Urinary incontinence, the involuntary excretion of urine * Lack of moderation or self-control, especially related to sexual desire - see ...
. There is a lack of high quality data on the effectiveness of these techniques in other behavior problems such as wandering. Music therapy is effective in reducing behavioral and psychological symptoms. Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy,
sensory integration Multisensory integration, also known as multimodal integration, is the study of how information from the different sensory modalities (such as sight, sound, touch, smell, self-motion, and taste) may be integrated by the nervous system. A coherent r ...
, 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 "S ...
, 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 Alzheimer's disease. There is partial evidence indicating that SPT may reduce
challenging behavior Challenging behaviour, also known as behaviours which challenge, is defined as "culturally abnormal behaviour(s) of such intensity, frequency or duration that the physical safety of the person or others is placed in serious jeopardy, or behaviou ...
s. The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining, is the reduction of
cognitive deficit Cognitive deficit is an inclusive term to describe any characteristic that acts as a barrier to the cognition process. The term may describe * deficits in overall intelligence (as with intellectual disabilities), * specific and restricted defici ...
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 shown some efficacy improving cognitive capacities. Stimulation-oriented treatments include
art Art is a diverse range of human activity, and resulting product, that involves creative or imaginative talent expressive of technical proficiency, beauty, emotional power, or conceptual ideas. There is no generally agreed definition of wha ...
, music 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 appearances, intelligence, ...
therapies, exercise, and any other kind of
recreational activities Recreation is an activity of leisure, leisure being discretionary time. The "need to do something for recreation" is an essential element of human biology and psychology. Recreational activities are often done for enjoyment, amusement, or pleasur ...
. 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 Alzheimer's has no cure and it gradually renders people incapable of tending to their own needs, caregiving is essentially the treatment and must be carefully managed over the course of the disease. During the early and moderate stages, modifications to the living environment and lifestyle can increase safety and reduce caretaker burden. 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., app ...
d. When
swallowing difficulties Dysphagia is difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, in some contexts it is classified as a condition in its own right. It may be a sensation that suggests difficulty in the passage of solids or liqui ...
arise, the use of feeding tubes may be required. In such cases, the medical efficacy and ethics of continuing feeding is an important consideration of the caregivers and family members. 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.


Diet

Diet may be a modifiable risk factor for the development of Alzheimer's disease. The Mediterranean diet, and the
DASH diet The DASH diet (Dietary Approaches to Stop Hypertension) is a dietary pattern 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 Department of Healt ...
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. Studies of individual dietary components, minerals and supplements are conflicting as to whether they prevent AD or cognitive decline.


Prognosis

The early stages of Alzheimer's disease 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 Life expectancy is a statistical measure of the average time an organism is expected to live, based on the year of its birth, current age, and other demographic factors like sex. The most commonly used measure is life expectancy at birth ...
of people with Alzheimer's disease 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 Alzheimer's disease 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. Disease features significantly associated with reduced survival are an increased severity of cognitive impairment, decreased functional level, history of falls, and disturbances in the neurological examination. Other coincident diseases such as
heart problems Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, hea ...
, diabetes, or history of
alcohol abuse Alcohol abuse encompasses a spectrum of unhealthy alcohol drinking behaviors, ranging from binge drinking to alcohol dependence, in extreme cases resulting in health problems for individuals and large scale social problems such as alcohol-rel ...
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. Pneumonia and dehydration are the most frequent immediate causes of death brought by Alzheimer's disease, while cancer is a less frequent cause of death than in the general population.


Epidemiology

Two main measures are used in
epidemiological Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and determinants of health and disease conditions in a defined population. It is a cornerstone of public health, and shapes policy decisions and evid ...
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 (educational group), a group of students working together through the same academic curriculum * Cohort (floating point), a set of different encodings of the same numerical value * Cohort (military unit) ...
longitudinal studies (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 Alzheimer's disease, 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 Alzheimer's disease 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 Alzheimer's disease 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 Alzheimer's research remains to be done in minority groups, such as the
African American African Americans (also referred to as Black Americans and Afro-Americans) are an ethnic group consisting of Americans with partial or total ancestry from sub-Saharan Africa. The term "African American" generally denotes descendants of enslav ...
and the Hispanic/Latino populations. Studies have shown that these groups are underrepresented in clinical trials and do not have the same risk of developing Alzheimer's when carrying certain genetic risk factors (i.e. APOE4), compared to their caucasian counterparts. The prevalence of Alzheimer's disease in populations is dependent upon factors including incidence and survival. Since the incidence of Alzheimer's disease increases with age, prevalence depends on the mean age of the population for which prevalence is given. In the United States in 2020, Alzheimer's 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. As the incidence and prevalence are steadily increasing, the prevalence itself is projected to triple by 2050. As of 2020, 50 million people globally have AD, with this number expected to increase to 152 million by 2050.


History

The ancient Greek and Roman philosophers and physicians associated old age with increasing dementia. It was not until 1901 that German psychiatrist
Alois Alzheimer Alois Alzheimer ( , , ; 14 June 1864 – 19 December 1915) was a German psychiatrist and neuropathologist and a colleague of Emil Kraepelin. Alzheimer is credited with identifying the first published case of "presenile dementia", which Kraep ...
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 Auguste Deter (; 16 May 1850 – 8 April 1906) was a German woman notable for being the first person to be diagnosed with Alzheimer's disease. Life Auguste was born in Kassel, Hesse-Kassel on May 16, 1850. Born into a working-class family, Aug ...
. 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, 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 psychi ...
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 by Kraepelin, as a subtype of ''senile dementia'' in the eighth edition of his ''Textbook of Psychiatry'', published on 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 the causes and effects of disease or injury. 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 th ...
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 to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology. The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the
Alzheimer's Disease and Related Disorders Association The Alzheimer's Association was founded by Jerome H. Stone with the help of several family members in Chicago, Illinois, and incorporated on April 10, 1980, as the Alzheimer's Disease and Related Disorders Association, Inc. It is a non-profit Ame ...
(ADRDA, now known as the
Alzheimer's Association The Alzheimer's Association was founded by Jerome H. Stone with the help of several family members in Chicago, Illinois, and incorporated on April 10, 1980, as the Alzheimer's Disease and Related Disorders Association, Inc. It is a non-profit A ...
) 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 Cognitive deficit is an inclusive term to describe any characteristic that acts as a barrier to the cognition process. The term may describe * deficits in overall intelligence (as with intellectual disabilities), * specific and restricted defici ...
, and a suspected dementia syndrome, be confirmed by
neuropsychological testing 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 research into brain function and in a clinical setting f ...
for a clinical diagnosis of possible or probable Alzheimer's disease. A histopathologic confirmation including a microscopic examination of
brain tissue The human brain is the central organ of the human nervous system, and with the spinal cord makes up the central nervous system. The brain consists of the cerebrum, the brainstem and the cerebellum. It controls most of the activities of the ...
is required for a definitive diagnosis. Good statistical reliability and validity have been shown 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 A social issue is a problem that affects many people within a society. It is a group of common problems in present-day society and ones that many people strive to solve. It is often the consequence of factors extending beyond an individual's cont ...
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 elderly or disabled people. Nursing homes may also be referred to as skilled nursing facility (SNF) or long-term care facilities. Often, these terms have slightly different meanings to in ...
, specialized equipment, and household expenses. Indirect costs include the cost of informal care and the loss in productivity 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

The role of the main
caregiver A caregiver or carer is a paid or unpaid member of a person's social network who helps them with activities of daily living. Since they have no specific professional training, they are often described as informal caregivers. Caregivers most commo ...
is often taken by the spouse or a close relative. Alzheimer's disease is known for placing a great burden on
caregiver A caregiver or carer is a paid or unpaid member of a person's social network who helps them with activities of daily living. Since they have no specific professional training, they are often described as informal caregivers. Caregivers most commo ...
s which includes social, psychological, physical, or economic aspects. Home care is usually preferred by people with Alzheimer's disease and 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 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 carer 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 ...
. Regarding economic problems, family caregivers often give up time from work to spend 47 hours per week on average with the person with Alzheimer's disease, while the costs of caring for them are high. Direct and indirect costs of caring for somebody with Alzheimer's average between $18,000 and $77,500 per year in the United States, depending on the study.
Cognitive behavioral therapy Cognitive behavioral therapy (CBT) is a psycho-social intervention that aims to reduce symptoms of various mental health conditions, primarily depression and anxiety disorders. CBT focuses on challenging and changing cognitive distortions (su ...
and the teaching of coping strategies 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 Iris most often refers to: *Iris (anatomy), part of the eye *Iris (mythology), a Greek goddess * ''Iris'' (plant), a genus of flowering plants * Iris (color), an ambiguous color term Iris or IRIS may also refer to: Arts and media Fictional ent ...
'' (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 ...
; '' The Notebook'' (2004), based on
Nicholas Sparks Nicholas Charles Sparks (born December 31, 1965) is an American novelist, screenwriter, and philanthropist. He has published twenty-three novels and two non-fiction books, some of which have been ''New York Times'' bestsellers, with over 115 m ...
' 1996 novel of the same name; ''
A Moment to Remember ''A Moment to Remember'' (; lit. "Eraser in My Head") is a 2004 South Korean film based on the 2001 Japanese television drama ''Pure Soul''. It stars Son Ye-jin and Jung Woo-sung and follows the theme of discovery in a relationship and the burdens ...
'' (2004); ''
Thanmathra ''Thanmathra'' ( ml, തന്മാത്ര, en, Molecule) is a 2005 Indian Malayalam-language drama film written and directed by Blessy, based on Padmarajan's short story "Orma". It portrays the effects of Alzheimer's disease on the life of ...
'' (2005); '' Memories of Tomorrow (Ashita no Kioku)'' (2006), based on Hiroshi Ogiwara's novel of the same name; ''
Away from Her ''Away from Her'' is a 2006 Canadian independent drama film written and directed by Sarah Polley and starring Julie Christie and Gordon Pinsent. Olympia Dukakis, Michael Murphy, Wendy Crewson, Alberta Watson, and Kristen Thomson are featured ...
'' (2006), based on
Alice Munro Alice Ann Munro (; ; born 10 July 1931) is a Canadian short story writer who won the Nobel Prize in Literature in 2013. Munro's work has been described as revolutionizing the architecture of short stories, especially in its tendency to move fo ...
's
short story A short story is a piece of prose fiction that typically can be read in one 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 oldest ...
'' The Bear Came over the Mountain''; '' Still Alice'' (2014), about a Columbia University professor who has early onset Alzheimer's disease, based on
Lisa Genova Lisa Genova (born November 22, 1970) is an American neuroscientist and author. She self-published her debut novel ''Still Alice'' (2007), about a Harvard University professor who suffers early onset Alzheimer's disease. The book gained popular ...
's 2007 novel of the same name and featuring Julianne Moore in the title role. Documentaries on Alzheimer's disease include ''Malcolm and Barbara: A Love Story'' (1999) and ''Malcolm and Barbara: Love's Farewell'' (2007), both featuring Malcolm Pointon. Alzheimer's disease has also been portrayed in music by English musician
the Caretaker ''The Caretaker'' is a play in three acts by Harold Pinter. Although it was the sixth of his major works for stage and television, this psychological study of the confluence of power, allegiance, innocence, and corruption among two brothers a ...
in releases such as ''
Persistent Repetition of Phrases ''Persistent Repetition of Phrases'' is the seventh studio album by the Caretaker, an alias of musician Leyland Kirby. Released on 1 April 2008, it was his first record to cover themes of Alzheimer's disease. The album was also the first Caretake ...
'' (2008), ''
An Empty Bliss Beyond This World ''An Empty Bliss Beyond This World'' is the ninth studio album by the Caretaker, an ambient music project of English musician Leyland Kirby, released on 1 June 2011 through History Always Favours the Winners. The record is based on a study rega ...
'' (2011), and ''
Everywhere at the End of Time ''Everywhere at the End of Time'' is the eleventh and final recording by the Caretaker, an alias of English electronic musician Leyland Kirby. Released between 2016 and 2019, its six studio albums use degrading loops of sampled ballroom music ...
'' (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 1995 diagnosis of probable Alzheimer's disease. He had developed progressive Memory ...
, who drew self-portraits from 1995 to 2000 as an experiment of showing his disease through art.


Research directions

Additional research on the lifestyle effect may provide insight into neuroimaging biomarkers and better understanding of the mechanisms causing both Alzheimer's disease and early-onset AD.


Treatment and prevention

There is ongoing research examining the role of specific medications in reducing the prevalence (primary prevention) and/or progression (secondary prevention) of Alzheimer's disease. The research trials investigating medications generally impact
Amyloid beta (Aβ or Abeta) 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 precursor protein (APP), which is ...
plaques, inflammation,
APOE Apolipoprotein E (APOE) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular disease. APOE belongs to a family of fat-binding proteins called apolipoproteins. ...
, neurotransmitter receptors, neurogenesis, epigenetic regulators, growth factors and hormones. These studies have led to a better understanding of the disease, but none identified a prevention strategy. Experimental models are commonly used by researchers in order to understand disease mechanisms as well develop and test novel therapeutics aimed at treating Alzheimer's disease. Antibodies are being developed that may have the ability to alter the disease course by targeting amyloid beta, such as donanemab and
aducanumab Aducanumab, sold under the brand name Aduhelm, is a medication designed to treat Alzheimer's disease (AD). It is a monoclonal antibody that targets aggregated forms (plaque) of amyloid beta (Aβ) found in the brains of people with Alzheimer's ...
. Aducanumab was approved by the FDA in 2021, but its use and effectiveness remain unclear and controversial. Although it received FDA approval,
aducanumab Aducanumab, sold under the brand name Aduhelm, is a medication designed to treat Alzheimer's disease (AD). It is a monoclonal antibody that targets aggregated forms (plaque) of amyloid beta (Aβ) found in the brains of people with Alzheimer's ...
failed to show effectiveness in people who already had Alzheimer's symptoms.


References


Further reading

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External links

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