Alzheimer's disease

Last updated

Alzheimer's disease
Other namesAlzheimer's dementia
Diagram of a normal brain compared to the brain of a person with Alzheimer's
Specialty Neurology
Symptoms Memory loss, problems with language, disorientation, mood swings [1] [2]
Complications Infections, falls and aspiration pneumonia in the terminal stage [3]
Usual onsetOver 65 years old [4]
DurationLong term [2]
CausesPoorly understood [1]
Risk factors Genetics, head injuries, clinical depression, hypertension, [1] psychological stress, [5] lack of physical [6] and mental [5] [7] exercise
Diagnostic method Based on symptoms and cognitive testing after ruling out other possible causes [8]
Differential diagnosis Normal brain aging, [1] Lewy body dementia, [9] Trisomy 21 [10]
Medication Acetylcholinesterase inhibitors, NMDA receptor antagonists [11]
Prognosis Life expectancy 3–9 years [12]
Frequency50 million (2020) [13]
Named after Alois Alzheimer

Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens, [2] and is the cause of 60–70% of cases of dementia. [2] [14] The most common early symptom is difficulty in remembering recent events. [1] As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, self-neglect, and behavioral issues. [2] As a person's condition declines, they often withdraw from family and society. [15] Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the average life expectancy following diagnosis is three to twelve years. [16] [12]


The cause of Alzheimer's disease is poorly understood. [15] There are many environmental and genetic risk factors associated with its development. The strongest genetic risk factor is from an allele of apolipoprotein E. [17] [18] Other risk factors include a history of head injury, clinical depression, and high blood pressure. [1] The progress of the protein misfolding disease is largely associated with amyloid plaques, neurofibrillary tangles, and loss of neuronal connections in the brain. [19] A probable diagnosis is based on the history of the illness and cognitive testing, with medical imaging and blood tests to rule out other possible causes. [8] [20] Initial symptoms are often mistaken for normal brain aging. [15] Examination of brain tissue is needed for a definite diagnosis, but this can only take place after death. [21] [22]

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

As of 2020, there were approximately 50 million people worldwide with Alzheimer's disease. [13] It most often begins in people over 65 years of age, although up to 10% of cases are early-onset impacting those in their 30s to mid-60s. [27] [4] It affects about 6% of people 65 years and older, [15] and women more often than men. [28] The disease is named after German psychiatrist and pathologist Alois Alzheimer, who first described it in 1906. [29] Alzheimer's financial burden on society is large, with an estimated global annual cost of US$1 trillion. [13] It is ranked as the seventh leading cause of death worldwide. [30]

Signs and symptoms

The course of Alzheimer's is generally described in three stages, with a progressive pattern of cognitive and functional impairment. [31] [27] The three stages are described as early or mild, middle or moderate, and late or severe. [31] The disease is known to target the hippocampus which is associated with memory, and this is responsible for the first symptoms of memory impairment. As the disease progresses so does the degree of memory impairment. [19]

First symptoms

Stages of atrophy in Alzheimer's Alzheimer's Disease, Spreads through the Brain (24524716351).jpg
Stages of atrophy in Alzheimer's

The first symptoms are often mistakenly attributed to ageing or stress. [32] 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. [33] These early symptoms can affect the most complex activities of daily living. [34] 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. [33]

Subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or impairments in semantic memory (memory of meanings, and concept relationships) can also be symptomatic of the early stages of Alzheimer's disease. [33] Apathy and depression can be seen at this stage, with apathy remaining as the most persistent symptom throughout the course of the disease. [35] [36] 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 and is frequently seen as a prodromal stage of Alzheimer's disease. [37] Amnesic MCI has a greater than 90% likelihood of being associated with Alzheimer's. [38]

Early stage

In people with Alzheimer's disease, the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small percentage, difficulties with language, executive functions, perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems. [39] 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. [40] [41]

Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, leading to a general impoverishment of oral and written language. [39] [42] In this stage, the person with Alzheimer's is usually capable of communicating basic ideas adequately. [39] [42] [43] 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. [39] 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. [39]

Middle stage

Progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities of daily living. [39] 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. [39] [43] Complex motor sequences become less coordinated as time passes and Alzheimer's disease progresses, so the risk of falling increases. [39] During this phase, memory problems worsen, and the person may fail to recognise close relatives. [39] Long-term memory, which was previously intact, becomes impaired. [39]

Behavioral and neuropsychiatric changes become more prevalent. Common manifestations are wandering, irritability and emotional lability, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving. [39] Sundowning can also appear. [44] Approximately 30% of people with Alzheimer's disease develop illusionary misidentifications and other delusional symptoms. [39] Subjects also lose insight of their disease process and limitations (anosognosia). [39] Urinary incontinence can develop. [39] These symptoms create stress for relatives and caregivers, which can be reduced by moving the person from home care to other long-term care facilities. [39] [45]

Late stage

A normal brain on the left and a late-stage Alzheimer's brain on the right Alzheimers brain.jpg
A normal brain on the left and a late-stage Alzheimer's brain on the right

During the final stage, known as the late-stage or severe stage, there is complete dependence on caregivers. [19] [31] [39] Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. [39] [43] Despite the loss of verbal language abilities, people can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy 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 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 ulcers or pneumonia, not the disease itself. [39] In some cases, there is a paradoxical lucidity immediately before death, where there is an unexpected recovery of mental clarity. [46]


Alzheimer's disease is believed to occur when abnormal amounts of amyloid beta (Aβ), accumulating extracellularly as amyloid plaques and tau proteins, or intracellularly as neurofibrillary tangles, form in the brain, affecting neuronal functioning and connectivity, resulting in a progressive loss of brain function. [47] [48] This altered protein clearance ability is age-related, regulated by brain cholesterol, [49] and associated with other neurodegenerative diseases. [50] [51]

The cause for most Alzheimer's cases is still mostly unknown, [13] except for 1–2% of cases where deterministic genetic differences have been identified. [17] Several competing hypotheses attempt to explain the underlying cause; the most predominant hypothesis is the amyloid beta (Aβ) hypothesis. [13]

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. [13] The loss of cholinergic neurons noted in the limbic system and cerebral cortex, is a key feature in the progression of Alzheimer's. [37] The 1991 amyloid hypothesis postulated that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease. [52] [53] Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (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. [10] A specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for Alzheimer's disease. [14] 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. [54]


Late onset

Late-onset Alzheimer's is about 70% heritable. [55] [56] Genetic models in 2020 predict Alzheimer's disease with 90% accuracy. [57] Most cases of Alzheimer's are not familial, and so they are termed sporadic Alzheimer's disease.[ medical citation needed ] Most cases of sporadic Alzheimer's disease are late onset, developing after the age of 65 years. [58]

The strongest genetic risk factor for sporadic Alzheimer's disease is APOEε4. [18] APOEε4 is one of four alleles of apolipoprotein E (APOE). APOE plays a major role in lipid-binding proteins in lipoprotein particles and the ε4 allele disrupts this function. [59] Between 40 and 80% of people with Alzheimer's disease possess at least one APOEε4 allele. [60] The APOEε4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes. [61] Like many human diseases, environmental effects and genetic modifiers result in incomplete penetrance. For example, Nigerian Yoruba people do not show the relationship between dose of APOEε4 and incidence or age-of-onset for Alzheimer's disease seen in other human populations. [62] [63]

Early onset

Only 1–2% of Alzheimer's cases are inherited due to autosomal dominant effects, as Alzheimer's is highly polygenic. When the disease is caused by autosomal dominant variants, it is known as early onset familial Alzheimer's disease, which is rarer and has a faster rate of progression. [17] Less than 5% of sporadic Alzheimer's disease have an earlier onset, [17] and early-onset Alzheimer's is about 90% heritable. [55] [56] FAD usually implies multiple persons affected in one or more generation.[ medical citation needed ] [64]

Early onset familial Alzheimer's disease can be attributed to mutations in one of three genes: those encoding amyloid-beta precursor protein (APP) and presenilins PSEN1 and PSEN2. [38] Most mutations in the APP and presenilin genes increase the production of a small protein called amyloid beta (Aβ)42, which is the main component of amyloid plaques. [65] Some of the mutations merely alter the ratio between Aβ42 and the other major forms—particularly Aβ40—without increasing Aβ42 levels in the brain. [66] Two other genes associated with autosomal dominant Alzheimer's disease are ABCA7 and SORL1. [67]

Alleles in the TREM2 gene have been associated with a three to five times higher risk of developing Alzheimer's disease. [68]

A Japanese pedigree of familial Alzheimer's disease was found to be associated with a deletion mutation of codon 693 of APP. [69] This mutation and its association with Alzheimer's disease was first reported in 2008, [70] 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. [71]


Amyloid-beta and tau protein

In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells. TANGLES HIGH.jpg
In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells.

The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade. [53] In this model, hyperphosphorylated tau begins to pair with other threads of tau as paired helical filaments. Eventually, they form neurofibrillary tangles inside nerve cell bodies. [72] When this occurs, the microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system. [73]

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 that leads to neuroinflammation. [74] This chronic inflammation is also a feature of other neurodegenerative diseases including Parkinson's disease, and ALS. [75] Spirochete infections have also been linked to dementia. [13] DNA damages accumulate in AD brains; reactive oxygen species may be the major source of this DNA damage. [76]


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. [77]

Metal toxicity, smoking, neuroinflammation and air pollution

The cellular homeostasis 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. [13] [78] Smoking is a significant Alzheimer's disease risk factor. [1] Systemic markers of the innate immune system are risk factors for late-onset Alzheimer's disease. [79] Exposure to air pollution may be a contributing factor to the development of Alzheimer's disease. [13]

Other hypotheses

Retrogenesis is a medical hypothesis that just as the fetus goes through a process of neurodevelopment beginning with neurulation and ending with myelination, the brains of people with Alzheimer's disease go through a reverse neurodegeneration process starting with demyelination and death of axons (white matter) and ending with the death of grey matter. [80] Likewise the hypothesis is, that as infants go through states of cognitive development, people with Alzheimer's disease go through the reverse process of progressive cognitive impairment. [81]

The association with celiac disease 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. [82] [83]

According to one theory, dysfunction of oligodendrocytes and their associated myelin during aging contributes to axon damage, which in turn generates in amyloid production and tau hyper-phosphorylation. [84] [85]

Studies have shown a potential link between infection with certain viruses and developing Alzheimer's disease later in life. [86] Notably, a large scale study conducted on 6,245,282 patients has shown an increased risk of developing Alzheimer's disease following COVID-19 infection in cognitively normal individuals over 65. [87]


Histopathologic images of Alzheimer's disease, in the CA3 area of the hippocampus, showing an amyloid plaque (top right), neurofibrillary tangles (bottom left), and granulovacuolar degeneration bodies (bottom center) Histopathology of Alzheimer's disease.jpg
Histopathologic images of Alzheimer's disease, in the CA3 area of the hippocampus, showing an amyloid plaque (top right), neurofibrillary tangles (bottom left), and granulovacuolar degeneration bodies (bottom center)


Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus. [88] Degeneration is also present in brainstem nuclei particularly the locus coeruleus in the pons. [89] Studies using MRI and PET have documented reductions in the size of specific brain regions in people with Alzheimer's disease as they progressed from mild cognitive impairment to Alzheimer's disease, and in comparison with similar images from healthy older adults. [90] [91]

Both plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those with Alzheimer's disease, [92] especially in the hippocampus. [93] However, Alzheimer's disease may occur without neurofibrillary tangles in the neocortex. [94] Plaques are dense, mostly insoluble deposits of beta-amyloid 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. [95] Lewy bodies are not rare in the brains of people with Alzheimer's disease. [96]


Amyloid 01big1.jpg
Amyloid 02big1.jpg
Amyloid 03big1.jpg
Enzymes act on the APP (amyloid-beta precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the formation of amyloid plaques in Alzheimer's disease.

Alzheimer's disease has been identified as a protein misfolding disease, a proteopathy, caused by the accumulation of abnormally folded amyloid beta protein into amyloid plaques, and tau protein into neurofibrillary tangles in the brain. [97] Plaques are made up of small peptides, 39–43  amino acids in length, called amyloid beta (Aβ). Amyloid beta is a fragment from the larger amyloid-beta precursor protein (APP) a transmembrane protein that penetrates the neuron's membrane. APP is critical to neuron growth, survival, and post-injury repair. [98] [99] In Alzheimer's disease, gamma secretase and beta secretase act together in a proteolytic process which causes APP to be divided into smaller fragments. [100] 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. [92] [101]

Alzheimer's disease is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilises the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In Alzheimer's disease, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system. [102] Pathogenic tau can also cause neuronal death through transposable element dysregulation. [103] Necroptosis has also been reported as a mechanism of cell death in brain cells affected with tau tangles. [104] [105]

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. [106] [107] The amyloid hypothesis traditionally points to the accumulation of beta-amyloid peptides as the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces programmed cell death (apoptosis). [108] 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. [109]

Iron dyshomeostasis is linked to disease progression, an iron-dependent form of regulated cell death called ferroptosis could be involved. Products of lipid peroxidation are also elevated in AD brain compared with controls. [110]

Various inflammatory processes and cytokines 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. [111] 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. [112]

Alterations in the distribution of different neurotrophic factors and in the expression of their receptors such as the brain-derived neurotrophic factor (BDNF) have been described in Alzheimer's disease. [113] [114]


PET scan of the brain of a person with Alzheimer's disease showing a loss of function in the temporal lobe PET Alzheimer.jpg
PET scan of the brain of a person with Alzheimer's disease showing a loss of function in the temporal lobe

Alzheimer's disease (AD) can only be definitively diagnosed with autopsy findings; in the absence of autopsy, clinical diagnoses of AD are "possible" or "probable", based on other findings. [21] [22] [115] Up to 23% of those clinically diagnosed with AD may be misdiagnosed and may have pathology suggestive of another condition with symptoms that mimic those of AD. [22]

AD is usually clinically diagnosed based on the person's medical history, history from relatives, and behavioral observations. The presence of characteristic neurological and neuropsychological features and the absence of alternative conditions supports the diagnosis.[ needs update ] [116] [117] Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single-photon emission computed tomography (SPECT) or positron emission tomography (PET), can be used to help exclude other cerebral pathology or subtypes of dementia. [118] Moreover, it may predict conversion from prodromal stages (mild cognitive impairment) to Alzheimer's disease. [119] FDA-approved radiopharmaceutical diagnostic agents used in PET for Alzheimer's disease are florbetapir (2012), flutemetamol (2013), florbetaben (2014), and flortaucipir (2020). [120] Because many insurance companies in the United States do not cover this procedure, its use in clinical practice is largely limited to clinical trials as of 2018. [121]

Assessment of intellectual functioning including memory testing can further characterise the state of the disease. [1] Medical organizations have created diagnostic criteria to ease and standardise the diagnostic process for practising physicians. Definitive diagnosis can only be confirmed with post-mortem evaluations when brain material is available and can be examined histologically for senile plaques and neurofibrillary tangles. [121] [122]


There are three sets of criteria for the clinical diagnoses of the spectrum of Alzheimer's disease: the 2013 fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5); the National Institute on Aging-Alzheimer's Association (NIA-AA) definition as revised in 2011; and the International Working Group criteria as revised in 2010. [38] [121] 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. [123]

Eight intellectual domains are most commonly impaired in AD—memory, language, perceptual skills, attention, motor skills, orientation, problem solving and executive functional abilities, as listed in the fourth text revision of the DSM (DSM-IV-TR). [124]

The DSM-5 defines criteria for probable or possible Alzheimer's for both major and mild neurocognitive disorder. [125] [126] [115] Major or mild neurocognitive disorder must be present along with at least one cognitive deficit for a diagnosis of either probable or possible AD. [125] [127] 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 [128] or if two or more acquired cognitive deficits, and a functional disability that is not from another disorder, are present. [129] Otherwise, possible Alzheimer's disease can be diagnosed as the diagnosis follows an atypical route. [130] 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. [125] [131]

The NIA-AA criteria are used mainly in research rather than in clinical assessments. [132] They define Alzheimer's disease through three major stages: preclinical, mild cognitive impairment (MCI), and Alzheimer's dementia. [133] [134] Diagnosis in the preclinical stage is complex and focuses on asymptomatic individuals; [134] [135] the latter two stages describe individuals experiencing symptoms. [134] The core clinical criteria for MCI is used along with identification of biomarkers, [136] predominantly those for neuronal injury (mainly tau-related) and amyloid beta deposition. [132] [134] The core clinical criteria itself rests on the presence of cognitive impairment [134] without the presence of comorbidities. [137] [138] The third stage is divided into probable and possible Alzheimer's disease dementia. [138] In probable Alzheimer's disease dementia there is steady impairment of cognition over time and a memory-related or non-memory-related cognitive dysfunction. [138] In possible Alzheimer's disease dementia, another causal disease such as cerebrovascular disease is present. [138]


Cognitive tests such as the mini-mental state examination (MMSE) can help in the diagnosis of Alzheimer's disease. In this test instructions are given to copy drawings like the one shown, remember some words, read, and subtract numbers serially. InterlockingPentagons.svg
Cognitive tests such as the mini–mental state examination (MMSE) can help in the diagnosis of Alzheimer's disease. In this test instructions are given to copy drawings like the one shown, remember some words, read, and subtract numbers serially.

Neuropsychological tests including cognitive tests such as the mini–mental state examination (MMSE), the Montreal Cognitive Assessment (MoCA) and the Mini-Cog are widely used to aid in diagnosis of the cognitive impairments in AD. [139] These tests may not always be accurate, as they lack sensitivity to mild cognitive impairment, and can be biased by language or attention problems; [139] more comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease. [140] [141]

Further neurological examinations are crucial in the differential diagnosis of Alzheimer's disease and other diseases. [32] 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. [142] A caregiver's viewpoint is particularly important, since a person with Alzheimer's disease is commonly unaware of their deficits. [143] Many times, families have difficulties in the detection of initial dementia symptoms and may not communicate accurate information to a physician. [144]

Supplemental testing can rule out other potentially treatable diagnoses and help avoid misdiagnoses. [145] Common supplemental tests include blood tests, thyroid function tests, as well as tests to assess vitamin B12 levels, rule out neurosyphilis and rule out metabolic problems (including tests for kidney function, electrolyte levels and for diabetes). [145] MRI or CT scans might also be used to rule out other potential causes of the symptoms – including tumors or strokes. [139] Delirium and depression can be common among individuals and are important to rule out. [146]

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, [147] or even the cause. [148] [149]

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). [150] 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. [151]


Intellectual activities such as playing chess or regular social interaction have been linked to a reduced risk of Alzheimer's disease in epidemiological studies, although no causal relationship has been found. Honore Daumier 032.jpg
Intellectual activities such as playing chess or regular social interaction have been linked to a reduced risk of Alzheimer's disease in epidemiological studies, although no causal relationship has been found.

There are no disease-modifying treatments available to cure Alzheimer's disease and because of this, AD research has focused on interventions to prevent the onset and progression. [152] There is no evidence that supports any particular measure in preventing Alzheimer's, [1] and studies of measures to prevent the onset or progression have produced inconsistent results. Epidemiological studies have proposed relationships between an individual's likelihood of developing AD and modifiable factors, such as medications, lifestyle, and diet. There are some challenges in determining whether interventions for 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. [153] 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. [153] Further research is needed to determine factors that can help prevent Alzheimer's disease. [153]


Cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and worsened course of AD. [154] [155] The use of statins to lower cholesterol may be of benefit in Alzheimer's. [156] Antihypertensive and antidiabetic medications in individuals without overt cognitive impairment may decrease the risk of dementia by influencing cerebrovascular pathology. [1] [157] 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. [1]

Depression is associated with an increased risk for Alzheimer's disease; management with antidepressants may provide a preventative measure. [5]

Historically, long-term usage of non-steroidal anti-inflammatory drugs (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. [121] 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. [158]


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. [5]

Physical exercise is associated with a decreased rate of dementia, [6] and is effective in reducing symptom severity in those with AD. [159] Memory and cognitive functions can be improved with aerobic exercises including brisk walking three times weekly for forty minutes. [160] It may also induce neuroplasticity of the brain. [161] Participating in mental exercises, such as reading, crossword puzzles, and chess have shown a potential to be preventative. [5] Meeting the WHO recommendations for physical activity is associated with a lower risk of AD. [162]

Higher education and occupational attainment, and participation in leisure activities, contribute to a reduced risk of developing Alzheimer's, [7] or of delaying the onset of symptoms. This is compatible with the cognitive reserve theory, which states that some life experiences result in more efficient neural functioning providing the individual a cognitive reserve that delays the onset of dementia manifestations. [7] Education delays the onset of Alzheimer's disease syndrome without changing the duration of the disease. [163]

Cessation in smoking may reduce risk of developing Alzheimer's' disease, specifically in those who carry APOE ɛ4 allele. [164] [5] The increased oxidative stress caused by smoking results in downstream inflammatory or neurodegenerative processes that may increase risk of developing AD. [165] Avoidance of smoking, counseling and pharmacotherapies to quit smoking are used, and avoidance of environmental tobacco smoke is recommended. [5]

Alzheimer's disease is associated with sleep disorders but the precise relationship is unclear. [166] [167] 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. [166] One theory is that the mechanisms to increase clearance of toxic substances, including , are active during sleep. [166] [168] With decreased sleep, a person is increasing Aβ production and decreasing Aβ clearance, resulting in Aβ accumulation. [169] [166] [167] Receiving adequate sleep (approximately 7–8 hours) every night has become a potential lifestyle intervention to prevent the development of AD. [5]

Stress is a risk factor for the development of Alzheimer's. [5] 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. [170] 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. [171] Meditation, for instance, is a helpful lifestyle change to support cognition and well-being, though further research is needed to assess long-term effects. [161]


There is no cure for Alzheimer's disease; [172] available treatments offer relatively small symptomatic benefits but remain palliative in nature. [13] [173] Treatments can be divided into pharmaceutical, psychosocial, and caregiving.


Three-dimensional molecular model of donepezil, an acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease symptoms Donepezil 1EVE.png
Three-dimensional molecular model of donepezil, an acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease symptoms
Molecular structure of memantine, a medication approved for advanced Alzheimer's disease symptoms Memantine.svg
Molecular structure of memantine, a medication approved for advanced Alzheimer's disease symptoms

Medications used to treat the cognitive symptons of Alzheimer's disease rather than the underlying cause include: four acetylcholinesterase inhibitors (tacrine, rivastigmine, galantamine, and donepezil) and memantine, an NMDA receptor antagonist. The acetylcholinesterase inhibitors are intended for those with mild to severe Alzheimer's, whereas memantine is intended for those with moderate or severe Alzheimer's disease. [121] The benefit from their use is small. [174] [175] [176] [14]

Reduction in the activity of the cholinergic neurons is a well-known feature of Alzheimer's disease. [177] Acetylcholinesterase inhibitors are employed to reduce the rate at which acetylcholine (ACh) is broken down, thereby increasing the concentration of ACh in the brain and combating the loss of ACh caused by the death of cholinergic neurons. [178] There is evidence for the efficacy of these medications in mild to moderate Alzheimer's disease, [179] [174] and some evidence for their use in the advanced stage. [174] The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of Alzheimer's disease. [180] The most common side effects are nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately 10–20% of users, are mild to moderate in severity, and can be managed by slowly adjusting medication doses. [181] Less common secondary effects include muscle cramps, decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid production. [179]

Glutamate is an excitatory neurotransmitter of the nervous system, although excessive amounts in the brain can lead to cell death through a process called excitotoxicity which consists of the overstimulation of glutamate receptors. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological diseases such as Parkinson's disease and multiple sclerosis. [182] Memantine is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA receptors and inhibiting their overstimulation by glutamate. [182] [183] Memantine has been shown to have a small benefit in the treatment of moderate to severe Alzheimer's disease. [184] Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue. [185] [186] The combination of memantine and donepezil [187] has been shown to be "of statistically significant but clinically marginal effectiveness". [188]

An extract of Ginkgo biloba known as EGb 761 has been used for treating Alzheimer's and other neuropsychiatric disorders. [189] Its use is approved throughout Europe. [190] 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. [189] 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. [191]

Atypical antipsychotics are modestly useful in reducing aggression and psychosis in people with Alzheimer's disease, but their advantages are offset by serious adverse effects, such as stroke, movement difficulties or cognitive decline. [192] When used in the long-term, they have been shown to associate with increased mortality. [193] Stopping antipsychotic use in this group of people appears to be safe. [194]


Psychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within behavior-, emotion-, cognition- or stimulation-oriented approaches.[ needs update ] [195]

Behavioral interventions attempt to identify and reduce the antecedents and consequences of problem behaviors. This approach has not shown success in improving overall functioning, [196] but can help to reduce some specific problem behaviors, such as incontinence. [197] There is a lack of high quality data on the effectiveness of these techniques in other behavior problems such as wandering. [198] [199] Music therapy is effective in reducing behavioral and psychological symptoms. [200]

Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration, also called snoezelen, and simulated presence therapy. A Cochrane review has found no evidence that this is effective. [201] 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. [202] 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 behaviors. [203]

The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining, is the reduction of cognitive deficits. Reality orientation consists of the presentation of information about time, place, or person to ease the understanding of the person about its surroundings and his or her place in them. On the other hand, cognitive retraining tries to improve impaired capacities by exercising mental abilities. Both have shown some efficacy improving cognitive capacities. [204]

Stimulation-oriented treatments include art, music and pet therapies, exercise, and any other kind of recreational activities. Stimulation has modest support for improving behavior, mood, and, to a lesser extent, function. Nevertheless, as important as these effects are, the main support for the use of stimulation therapies is the change in the person's routine. [195]


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. [205] [206] 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. [195] [207] [208] If eating becomes problematic, food will need to be prepared in smaller pieces or even puréed. [209] When swallowing difficulties arise, the use of feeding tubes may be required. In such cases, the medical efficacy and ethics of continuing feeding is an important consideration of the caregivers and family members. [210] [211] 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. [195]

During the final stages of the disease, treatment is centred on relieving discomfort until death, often with the help of hospice. [212]


Diet may be a modifiable risk factor for the development of Alzheimer's disease. The Mediterranean diet, and the DASH diet 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. [213] Studies of individual dietary components, minerals and supplements are conflicting as to whether they prevent AD or cognitive decline. [213]


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. [39]

Life expectancy of people with Alzheimer's disease is reduced. [214] The normal life expectancy for 60 to 70 years old is 23 to 15 years; for 90 years old it is 4.5 years. [215] 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. [214]

Fewer than 3% of people live more than fourteen years after diagnosis. [216] Disease features significantly associated with reduced survival are an increased severity of cognitive impairment, decreased functional level, disturbances in the neurological examination, history of falls, malnutrition, dehydration and weight loss. [3] Other coincident diseases such as heart problems, diabetes, or history of alcohol abuse are also related with shortened survival. [217] [218] [219] 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. [220] Men have a less favourable survival prognosis than women.[ needs update ] [216] [221]

Aspiration pneumonia is the most frequent immediate cause of death brought by Alzheimer's disease. [3] While the reasons behind the lower prevalence of cancer in Alzheimer's patients remain unclear, some researchers hypothesize that biological mechanisms shared by both diseases might play a role. However, this requires further investigation. [222]


Two main measures are used in epidemiological studies: incidence and prevalence. Incidence is the number of new cases per unit of person-time at risk (usually number of new cases per thousand person-years); while prevalence is the total number of cases of the disease in the population at any given time.

Deaths per million persons in 2012 due to dementias including Alzheimer's disease
.mw-parser-output .div-col{margin-top:0.3em;column-width:30em}.mw-parser-output .div-col-small{font-size:90%}.mw-parser-output .div-col-rules{column-rule:1px solid #aaa}.mw-parser-output .div-col dl,.mw-parser-output .div-col ol,.mw-parser-output .div-col ul{margin-top:0}.mw-parser-output .div-col li,.mw-parser-output .div-col dd{page-break-inside:avoid;break-inside:avoid-column}
.mw-parser-output .legend{page-break-inside:avoid;break-inside:avoid-column}.mw-parser-output .legend-color{display:inline-block;min-width:1.25em;height:1.25em;line-height:1.25;margin:1px 0;text-align:center;border:1px solid black;background-color:transparent;color:black}.mw-parser-output .legend-text{}
376-1266 Alzheimer's disease and other dementias world map-Deaths per million persons-WHO2012.svg
Deaths per million persons in 2012 due to dementias including Alzheimer's disease

Regarding incidence, cohort 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, [223] [224] 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. [223] [224] 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. [14] 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. [225] However, much Alzheimer's research remains to be done in minority groups, such as the African American, East Asian and Hispanic/Latino populations. [226] [227] 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. [227] [228] [229]

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. [230] Prevalence rates in some less developed regions around the globe are lower. [231] [232] As the incidence and prevalence are steadily increasing, the prevalence itself is projected to triple by 2050.[ clarification needed ] [233] As of 2020, 50 million people globally have AD, with this number expected to increase to 152 million by 2050. [13]


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

The ancient Greek and Roman philosophers and physicians associated old age with increasing dementia. [29] It was not until 1901 that German psychiatrist Alois Alzheimer identified the first case of what became known as Alzheimer's disease, named after him, in a fifty-year-old woman he called Auguste D. He followed her case until she died in 1906 when he first reported publicly on it. [234] During the next five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer's disease. [29] The disease was first described as a distinctive disease by Emil Kraepelin after suppressing some of the clinical (delusions and hallucinations) and pathological features (arteriosclerotic changes) contained in the original report of Auguste D. [235] He included Alzheimer's disease, also named presenile dementia by Kraepelin, as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published on 15 July, 1910. [236]

For most of the 20th century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of dementia. The terminology changed after 1977 when a conference on Alzheimer's disease concluded that the clinical and pathological manifestations of presenile and senile dementia were almost identical, although the authors also added that this did not rule out the possibility that they had different causes. [237] This eventually led to the diagnosis of Alzheimer's disease independent of age. [238] 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. [239]

The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA, now known as the Alzheimer's Association) established the most commonly used NINCDS-ADRDA Alzheimer's Criteria for diagnosis in 1984, [240] extensively updated in 2007. [241] [145] These criteria require that the presence of cognitive impairment, and a suspected dementia syndrome, be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable Alzheimer's disease. A histopathologic confirmation including a microscopic examination of brain tissue is required for a definitive diagnosis. Good statistical reliability and validity have been shown between the diagnostic criteria and definitive histopathological confirmation. [242]

Society and culture

Social costs

Dementia, and specifically Alzheimer's disease, may be among the most costly diseases for societies worldwide. [243] As populations age, these costs will probably increase and become an important social problem and economic burden. [244] Costs associated with AD include direct and indirect medical costs, which vary between countries depending on social care for a person with AD. [243] [245] [246] Direct costs include doctor visits, hospital care, medical treatments, nursing home care, specialized equipment, and household expenses. [243] [244] Indirect costs include the cost of informal care and the loss in productivity of informal caregivers. [244]

In the United States as of 2019, 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. [243] 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. [245]

Costs for those with more severe dementia or behavioral disturbances are higher and are related to the additional caregiving time to provide physical care. [246]

Caregiving burden

Individuals with Alzheimer's will require assistance in their lifetime, and care will most likely come in the form of a full-time caregiver which is often a role that is taken on by the spouse or a close relative. Caregiving tends to include physical and emotional burdens as well as time and financial strain at times on the person administering the aid. [247] [248] Alzheimer's disease is known for placing a great burden on caregivers which includes social, psychological, physical, or economic aspects. [23] [249] [250] Home care is usually preferred by both those people with Alzheimer's disease as well as their families. [251] This option also delays or eliminates the need for more professional and costly levels of care. [251] [252] Nevertheless, two-thirds of nursing home residents have dementias. [195]

Dementia caregivers are subject to high rates of physical and mental disorders. [253] 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. [254] [255] 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. [256] [248]

Cognitive behavioral therapy and the teaching of coping strategies either individually or in group have demonstrated their efficacy in improving caregivers' psychological health. [23] [257]


Alzheimer's disease has been portrayed in films such as: Iris (2001), based on John Bayley's memoir of his wife Iris Murdoch; [258] The Notebook (2004), based on Nicholas Sparks's 1996 novel of the same name; [259] A Moment to Remember (2004); Thanmathra (2005); [260] Memories of Tomorrow (Ashita no Kioku) (2006), based on Hiroshi Ogiwara's novel of the same name; [261] Away from Her (2006), based on Alice Munro's short story The Bear Came over the Mountain ; [262] Still Alice (2014), about a Columbia University professor who has early onset Alzheimer's disease, based on Lisa Genova's 2007 novel of the same name and featuring Julianne Moore in the title role. Documentaries on Alzheimer's disease include Malcolm and Barbara: A Love Story (1999) and Malcolm and Barbara: Love's Farewell (2007), both featuring Malcolm Pointon. [263] [264] [265]

Alzheimer's disease has also been portrayed in music by English musician the Caretaker in releases such as Persistent Repetition of Phrases (2008), An Empty Bliss Beyond This World (2011), and Everywhere at the End of Time (20162019). [266] [267] [268] Paintings depicting the disorder include the late works by American artist William Utermohlen, who drew self-portraits from 1995 to 2000 as an experiment of showing his disease through art. [269] [270]

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. [271]

Emerging hypotheses

Alzheimer's disease is associated with neuroinflammation and loss of function of microglia, the resident immune cells of the central nervous system. [272] Microglia become progressively dysfunctional following exposure to amyloid plaques, and exposure to pro-inflammatory cytokines (e.g., TNFα, IL-1β, IL-12) has been hypothesized to sustain this dysfunction. Aberrant synaptic pruning via microglial phagocytosis may also contribute to AD pathology. [273] The complement system, which is involved in some forms of typical microglial pruning during development, [274] is implicated in animal models of AD by way of dysregulation of the activation (e.g. C1q; C3b) and terminal (e.g. MAC) pathways in synapses with proximity to amyloid plaques. [275]

Detection, prevention and treatment

Antibodies may have the ability to alter the disease course by targeting amyloid beta with immunotherapy medications such as donanemab, aducanumab, and lecanemab. [276] [277] [278] Aducanumab was approved by the US Food and Drug Administration (FDA) in 2021 using the accelerated approval process, although the approval generated controversy and more evidence is needed to address administration, safety, and effectiveness. [279] [280] [281] [282] It has less effectiveness in people who already had severe Alzheimer's symptoms. [283] Lecanemab was also approved via the FDA accelerated approval process, [284] [285] [286] and was converted to traditional approval in July 2023 after further testing, along with the addition of a black box warning about amyloid-related imaging abnormalities. [287] [288] Anti-amyloid drugs also cause brain shrinkage. [289]

Specific medications that may reduce the risk or progression of Alzheimer's disease have been studied. [290] The research trials investigating medications generally impact plaques, inflammation, APOE, neurotransmitter receptors, neurogenesis, growth factors or hormones. [290] [291] [292]

Machine learning algorithms with electronic health records are being studied as a way to predict AD earlier. [293]

As of 2024, precision medicine approaches to cure Alzheimer's disease are being actively researched. [294] [295] [296] [297] [298]

Related Research Articles

<span class="mw-page-title-main">Dementia</span> Long-term brain disorders causing impaired memory, thinking and behavior

Dementia is a syndrome associated with many neurodegenerative diseases, which is characterized by a general decline in cognitive abilities that impacts a person's ability to perform everyday activities. This typically involves problems with memory, thinking, behavior, and motor control. Aside from memory impairment and a disruption in thought patterns, the most common symptoms include emotional problems, difficulties with language, and decreased motivation. The symptoms may be described as occurring in a continuum over several stages. Dementia ultimately has a significant effect on the individual, caregivers, and on social relationships in general. A diagnosis of dementia requires the observation of a change from a person's usual mental functioning and a greater cognitive decline than what is caused by normal aging.

<span class="mw-page-title-main">Dementia with Lewy bodies</span> Type of progressive dementia

Dementia with Lewy bodies (DLB) is a type of dementia characterized by changes in sleep, behavior, cognition, movement, and regulation of automatic bodily functions. Memory loss is not always an early symptom. The disease worsens over time and is usually diagnosed when cognitive impairment interferes with normal daily functioning. Together with Parkinson's disease dementia, DLB is one of the two Lewy body dementias. It is a common form of dementia, but the prevalence is not known accurately and many diagnoses are missed. The disease was first described by Kenji Kosaka in 1976.

<span class="mw-page-title-main">Vascular dementia</span> Dementia resulting from stroke

Vascular dementia is dementia caused by a series of strokes. Restricted blood flow due to strokes reduces oxygen and glucose delivery to the brain, causing cell injury and neurological deficits in the affected region. Subtypes of vascular dementia include subcortical vascular dementia, multi-infarct dementia, stroke-related dementia, and mixed dementia.

<span class="mw-page-title-main">Frontotemporal dementia</span> Types of dementia involving the frontal or temporal lobes

Frontotemporal dementia (FTD), frontotemporal degeneration disease, or frontotemporal neurocognitive disorder encompasses several types of dementia involving the progressive degeneration of the brain's frontal and temporal lobes. FTDs broadly present as behavioral or language disorders with gradual onsets.

<span class="mw-page-title-main">Donepezil</span> Medication used for dementia

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 change the progression of the disease. Treatment should be stopped if no benefit is seen. It is taken by mouth or via a transdermal patch.

Cognitive disorders (CDs), also known as neurocognitive disorders (NCDs), are a category of mental health disorders that primarily affect cognitive abilities including learning, memory, perception, and problem-solving. Neurocognitive disorders include delirium, mild neurocognitive disorders, and major neurocognitive disorder. They are defined by deficits in cognitive ability that are acquired, typically represent decline, and may have an underlying brain pathology. The DSM-5 defines six key domains of cognitive function: executive function, learning and memory, perceptual-motor function, language, complex attention, and social cognition.

<span class="mw-page-title-main">Cerebral amyloid angiopathy</span> Disease of blood vessels of the brain

Cerebral amyloid angiopathy (CAA) is a form of angiopathy in which amyloid beta peptide deposits in the walls of small to medium blood vessels of the central nervous system and meninges. The term congophilic is sometimes used because the presence of the abnormal aggregations of amyloid can be demonstrated by microscopic examination of brain tissue after staining with Congo red. The amyloid material is only found in the brain and as such the disease is not related to other forms of amyloidosis.

<span class="mw-page-title-main">Primary progressive aphasia</span> Medical condition

Primary progressive aphasia (PPA) is a type of neurological syndrome in which language capabilities slowly and progressively become impaired. As with other types of aphasia, the symptoms that accompany PPA depend on what parts of the left hemisphere are significantly damaged. However, unlike most other aphasias, PPA results from continuous deterioration in brain tissue, which leads to early symptoms being far less detrimental than later symptoms.

Pittsburgh compound B (PiB) is a radioactive analog of thioflavin T, which can be used in positron emission tomography scans to image beta-amyloid plaques in neuronal tissue. Due to this property, Pittsburgh compound B may be used in investigational studies of Alzheimer's disease.

<span class="mw-page-title-main">Tauopathy</span> Medical condition

Tauopathies are neurodegenerative diseases involving the aggregation of abnormal tau protein. Tangles are formed by hyperphosphorylation of the microtubule protein known as tau, causing the protein to dissociate from microtubules and form insoluble aggregate. Various neuropathologic phenotypes are identified based on the specific engagement of anatomical regions, cell types, and the presence of unique isoforms of tau within pathological deposits. The designation 'primary tauopathy' is assigned to disorders where the predominant feature is the deposition of tau protein. Alternatively, diseases exhibiting tau pathologies attributed to different and varied underlying causes are termed 'secondary tauopathies. Some neuropathologic phenotypes involving tau protein is Alzheimer's disease, Pick disease, Progressive supranuclear palsy and corticobasal degeneration.

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 markers and imaging methods. There are two models that can be used when exploring the concept of "reserve": brain reserve and cognitive reserve. These terms, albeit often used interchangeably in the literature, provide a useful way of discussing the models. Using a computer analogy, brain reserve can be seen as hardware and cognitive reserve as software. All these factors are currently believed to contribute to global reserve. Cognitive reserve is commonly used to refer to both brain and cognitive reserves in the literature.

The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain. Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation.

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 of daily living. MCI may occur as a transitional stage between normal aging and dementia, especially Alzheimer's disease. It includes both memory and non-memory impairments. The cause of the disorder remains unclear, as well as both its prevention and treatment, with some 50 percent of people diagnosed with it going on to develop Alzheimer's disease within five years. The diagnosis can also serve as an early indicator for other types of dementia, although MCI may remain stable or even remit.

The prevention of dementia involves reducing the number of risk factors for the development of dementia, and is a global health priority needing a global response. Initiatives include the establishment of the International Research Network on Dementia Prevention (IRNDP) which aims to link researchers in this field globally, and the establishment of the Global Dementia Observatory a web-based data knowledge and exchange platform, which will collate and disseminate key dementia data from members states. Although there is no cure for dementia, it is well established that modifiable risk factors influence both the likelihood of developing dementia and the age at which it is developed. Dementia can be prevented by reducing the risk factors for vascular disease such as diabetes, high blood pressure, obesity, smoking, physical inactivity and depression. A study concluded that more than a third of dementia cases are theoretically preventable. Among older adults both an unfavorable lifestyle and high genetic risk are independently associated with higher dementia risk. A favorable lifestyle is associated with a lower dementia risk, regardless of genetic risk. In 2020, a study identified 12 modifiable lifestyle factors, and the early treatment of acquired hearing loss was estimated as the most significant of these factors, potentially preventing up to 9% of dementia cases.

<span class="mw-page-title-main">Posterior cortical atrophy</span> Medical condition

Posterior cortical atrophy (PCA), also called Benson's syndrome, is a rare form of dementia which is considered a visual variant or an atypical variant of Alzheimer's disease (AD). The disease causes atrophy of the posterior part of the cerebral cortex, resulting in the progressive disruption of complex visual processing. PCA was first described by D. Frank Benson in 1988.

Solanezumab is a monoclonal antibody being investigated by Eli Lilly as a neuroprotector for patients with Alzheimer's disease. The drug originally attracted extensive media coverage proclaiming it a breakthrough, but it has failed to show promise in Phase III trials.

<span class="mw-page-title-main">Type 3 diabetes</span> Medical condition

Type 3 diabetes is a proposed pathological linkage between Alzheimer's disease and certain features of type 1 and type 2 diabetes. Specifically, the term refers to a set of common biochemical and metabolic features seen in the brain in Alzheimer's disease, and in other tissues in diabetes; it may thus be considered a "brain-specific type of diabetes." It was recognized at least as early as 2005 that some features of brain function in Alzheimer's disease mimic those that underlie diabetes. However, the concept of type 3 diabetes is controversial, and as of 2021 it was not an officially recognized diagnosis.

Alzheimer's Disease Neuroimaging Initiative (ADNI) is a multisite study that aims to improve clinical trials for the prevention and treatment of Alzheimer's disease (AD). This cooperative study combines expertise and funding from the private and public sector to study subjects with AD, as well as those who may develop AD and controls with no signs of cognitive impairment. Researchers at 63 sites in the US and Canada track the progression of AD in the human brain with neuroimaging, biochemical, and genetic biological markers. This knowledge helps to find better clinical trials for the prevention and treatment of AD. ADNI has made a global impact, firstly by developing a set of standardized protocols to allow the comparison of results from multiple centers, and secondly by its data-sharing policy which makes available all at the data without embargo to qualified researchers worldwide. To date, over 1000 scientific publications have used ADNI data. A number of other initiatives related to AD and other diseases have been designed and implemented using ADNI as a model. ADNI has been running since 2004 and is currently funded until 2021.

Florbetaben, a fluorine-18 (18F)-labeled stilbene derivative, trade name NeuraCeq, is a diagnostic radiotracer developed for routine clinical application to visualize β-amyloid plaques in the brain. It is indicated for Positron Emission Tomography (PET) imaging of β-amyloid neuritic plaque density in the brains of adult patients with cognitive impairment who are being evaluated for Alzheimer's disease (AD) and other causes of cognitive impairment. β-amyloid is a key neuropathological hallmark of AD, so markers of β-amyloid plaque accumulation in the brain are useful in distinguishing AD from other causes of dementia. The tracer successfully completed a global multicenter phase 0–III development program and obtained approval in Europe, US and South Korea in 2014.

Alzheimer's disease (AD) in African Americans is becoming a rising topic of interest in AD care, support, and scientific research, as African Americans are disproportionately affected by AD. Recent research on AD has shown that there are clear disparities in the disease among racial groups, with higher prevalence and incidence in African Americans than the overall average. Pathologies for Alzheimer’s also seem to manifest differently in African Americans, including with neuroinflammation markers, cognitive decline, and biomarkers. Although there are genetic risk factors for Alzheimer’s, these account for few cases in all racial groups.


  1. 1 2 3 4 5 6 7 8 9 10 11 Knopman DS, Amieva H, Petersen RC, Chételat G, Holtzman DM, Hyman BT, et al. (May 2021). "Alzheimer disease". Nature Reviews Disease Primers. 7 (1): 33. doi:10.1038/s41572-021-00269-y. PMC   8574196 . PMID   33986301.
  2. 1 2 3 4 5 6 "Dementia Fact sheet". World Health Organization. 15 March 2023. Retrieved 10 July 2023.
  3. 1 2 3 "Ask the Doctors - What is the cause of death in Alzheimer's disease?". Retrieved 18 March 2024.
  4. 1 2 Mendez MF (November 2012). "Early-onset Alzheimer's disease: nonamnestic subtypes and type 2 AD". Archives of Medical Research. 43 (8): 677–685. doi:10.1016/j.arcmed.2012.11.009. PMC   3532551 . PMID   23178565.
  5. 1 2 3 4 5 6 7 8 9 Yu JT, Xu W, Tan CC, Andrieu S, Suckling J, Evangelou E, et al. (November 2020). "Evidence-based prevention of Alzheimer's disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials". Journal of Neurology, Neurosurgery, and Psychiatry. 91 (11): 1201–1209. doi:10.1136/jnnp-2019-321913. PMC   7569385 . PMID   32690803.
  6. 1 2 Cheng ST (September 2016). "Cognitive Reserve and the Prevention of Dementia: the Role of Physical and Cognitive Activities". Current Psychiatry Reports (Review). 18 (9): 85. doi:10.1007/s11920-016-0721-2. PMC   4969323 . PMID   27481112.
  7. 1 2 3 Viña J, Sanz-Ros J (October 2018). "Alzheimer's disease: Only prevention makes sense". European Journal of Clinical Investigation (Review). 48 (10): e13005. doi: 10.1111/eci.13005 . PMID   30028503. S2CID   51703879.
  8. 1 2 "Dementia diagnosis and assessment" (PDF). National Institute for Health and Care Excellence (NICE). Archived from the original (PDF) on 5 December 2014. Retrieved 30 November 2014.
  9. Gomperts SN (April 2016). "Lewy Body Dementias: Dementia With Lewy Bodies and Parkinson Disease Dementia". Continuum (Review). 22 (2 Dementia): 435–463. doi:10.1212/CON.0000000000000309. PMC   5390937 . PMID   27042903.
  10. 1 2 Lott IT, Head E (March 2019). "Dementia in Down syndrome: unique insights for Alzheimer disease research". Nat Rev Neurol. 15 (3): 135–147. doi:10.1038/s41582-018-0132-6. PMC   8061428 . PMID   30733618.
  11. "How Alzheimer's drugs help manage symptoms". Mayo Clinic. 30 August 2023. Retrieved 19 March 2024.
  12. 1 2 "Life Span After Alzheimer's Diagnosis: What Factors Matter Most - Health Encyclopedia - University of Rochester Medical Center". Retrieved 19 March 2024.
  13. 1 2 3 4 5 6 7 8 9 10 11 Breijyeh Z, Karaman R (December 2020). "Comprehensive Review on Alzheimer's Disease: Causes and Treatment". Molecules (Review). 25 (24): 5789. doi: 10.3390/molecules25245789 . PMC   7764106 . PMID   33302541.
  14. 1 2 3 4 Simon RP, Greenberg DA, Aminoff MJ (2018). Clinical neurology (Tenth ed.). [New York]: McGraw Hill. p. 111. ISBN   978-1-259-86173-4. OCLC   1012400314.
  15. 1 2 3 4 Burns A, Iliffe S (February 2009). "Alzheimer's disease". BMJ. 338: b158. doi:10.1136/bmj.b158. PMID   19196745. S2CID   8570146.
  16. "Alzheimer's stages: How the disease progresses". Mayo Clinic. Retrieved 19 March 2024.
  17. 1 2 3 4 Long JM, Holtzman DM (October 2019). "Alzheimer Disease: An Update on Pathobiology and Treatment Strategies". Cell. 179 (2): 312–339. doi:10.1016/j.cell.2019.09.001. PMC   6778042 . PMID   31564456.
  18. 1 2 "Study reveals how APOE4 gene may increase risk for dementia". National Institute on Aging. 16 March 2021. Archived from the original on 17 March 2021. Retrieved 17 March 2021.
  19. 1 2 3 4 "Alzheimer's Disease Fact Sheet". National Institute on Aging. Archived from the original on 23 March 2022. Retrieved 23 March 2022.
  20. Dementia: assessment, management and support for people living with dementia and their carers (Report). National Institute for Health and Care Excellence (NICE). 20 June 2018. NG97. Retrieved 8 July 2023.
  21. 1 2 Khan S, Barve KH, Kumar MS (2020). "Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer's Disease". Curr Neuropharmacol. 18 (11): 1106–1125. doi:10.2174/1570159X18666200528142429. PMC   7709159 . PMID   32484110.
  22. 1 2 3 Gauthreaux K, Bonnett TA, Besser LM, Brenowitz WD, Teylan M, Mock C, et al. (May 2020). "Concordance of Clinical Alzheimer Diagnosis and Neuropathological Features at Autopsy". Journal of Neuropathology and Experimental Neurology. 79 (5): 465–473. doi:10.1093/jnen/nlaa014. PMC   7160616 . PMID   32186726.
  23. 1 2 3 4 Thompson CA, Spilsbury K, Hall J, Birks Y, Barnes C, Adamson J (July 2007). "Systematic review of information and support interventions for caregivers of people with dementia". BMC Geriatrics. 7: 18. doi: 10.1186/1471-2318-7-18 . PMC   1951962 . PMID   17662119.
  24. Forbes D, Forbes SC, Blake CM, Thiessen EJ, Forbes S (April 2015). "Exercise programs for people with dementia". The Cochrane Database of Systematic Reviews (Submitted manuscript). 132 (4): CD006489. doi:10.1002/14651858.CD006489.pub4. PMC   9426996 . PMID   25874613.
  25. "Low-dose antipsychotics in people with dementia". National Institute for Health and Care Excellence (NICE). Archived from the original on 5 December 2014. Retrieved 29 November 2014.
  26. "Information for Healthcare Professionals: Conventional Antipsychotics". US Food and Drug Administration. 16 June 2008. Archived from the original on 29 November 2014. Retrieved 29 November 2014.
  27. 1 2 "Alzheimer's Disease Fact Sheet". National Institute on Aging. Archived from the original on 24 January 2021. Retrieved 25 January 2021.
  28. Zhu D, Montagne A, Zhao Z (June 2021). "Alzheimer's pathogenic mechanisms and underlying sex difference". Cell Mol Life Sci. 78 (11): 4907–4920. doi:10.1007/s00018-021-03830-w. PMC   8720296 . PMID   33844047.
  29. 1 2 3 Berchtold NC, Cotman CW (1998). "Evolution in the conceptualization of dementia and Alzheimer's disease: Greco-Roman period to the 1960s". Neurobiology of Aging. 19 (3): 173–189. doi:10.1016/S0197-4580(98)00052-9. PMID   9661992. S2CID   24808582.
  30. "The top 10 causes of death". Retrieved 19 March 2024.
  31. 1 2 3 "Alzheimer's disease – Symptoms". National Health Service (NHS). 10 May 2018. Archived from the original on 30 January 2021. Retrieved 25 January 2021.
  32. 1 2 Waldemar G, Dubois B, Emre M, Georges J, McKeith IG, Rossor M, et al. (January 2007). "Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline". European Journal of Neurology. 14 (1): e1-26. doi: 10.1111/j.1468-1331.2006.01605.x . PMID   17222085. S2CID   2725064.
  33. 1 2 3 Bäckman L, Jones S, Berger AK, Laukka EJ, Small BJ (September 2004). "Multiple cognitive deficits during the transition to Alzheimer's disease". Journal of Internal Medicine. 256 (3): 195–204. doi: 10.1111/j.1365-2796.2004.01386.x . PMID   15324363. S2CID   37005854.
  34. Nygård L (2003). "Instrumental activities of daily living: a stepping-stone towards Alzheimer's disease diagnosis in subjects with mild cognitive impairment?". Acta Neurologica Scandinavica. Supplementum. 179 (s179): 42–46. doi:10.1034/j.1600-0404.107.s179.8.x. PMID   12603250. S2CID   25313065.
  35. Deardorff WJ, Grossberg GT (2019). "Behavioral and psychological symptoms in Alzheimer's dementia and vascular dementia". Psychopharmacology of Neurologic Disease. Handbook of Clinical Neurology. Vol. 165. Elsevier. pp. 5–32. doi:10.1016/B978-0-444-64012-3.00002-2. ISBN   978-0444640123. PMID   31727229. S2CID   208037448.
  36. Murray ED, Buttner N, Price BH (2012). "Depression and Psychosis in Neurological Practice". In Bradley WG, Daroff RB, Fenichel GM, Jankovic J (eds.). Bradley's neurology in clinical practice (6th ed.). Philadelphia, PA: Elsevier/Saunders. ISBN   978-1-4377-0434-1.
  37. 1 2 Petersen RC, Lopez O, Armstrong MJ, Getchius TS, Ganguli M, Gloss D, et al. (January 2018). "Practice guideline update summary: Mild cognitive impairment: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology". Neurology. 90 (3): 126–135. doi:10.1212/WNL.0000000000004826. PMC   5772157 . PMID   29282327.
  38. 1 2 3 Atri A (March 2019). "The Alzheimer's Disease Clinical Spectrum: Diagnosis and Management". The Medical Clinics of North America (Review). 103 (2): 263–293. doi: 10.1016/j.mcna.2018.10.009 . PMID   30704681. S2CID   73432842.
  39. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Förstl H, Kurz A (1999). "Clinical features of Alzheimer's disease". European Archives of Psychiatry and Clinical Neuroscience. 249 (6): 288–290. doi:10.1007/s004060050101. PMID   10653284. S2CID   26142779.
  40. Carlesimo GA, Oscar-Berman M (June 1992). "Memory deficits in Alzheimer's patients: a comprehensive review". Neuropsychology Review. 3 (2): 119–169. doi:10.1007/BF01108841. PMID   1300219. S2CID   19548915.
  41. Jelicic M, Bonebakker AE, Bonke B (1995). "Implicit memory performance of patients with Alzheimer's disease: a brief review". International Psychogeriatrics. 7 (3): 385–392. doi:10.1017/S1041610295002134. PMID   8821346. S2CID   9419442.
  42. 1 2 Taler V, Phillips NA (July 2008). "Language performance in Alzheimer's disease and mild cognitive impairment: a comparative review". Journal of Clinical and Experimental Neuropsychology. 30 (5): 501–556. doi:10.1080/13803390701550128. PMID   18569251. S2CID   37153159.
  43. 1 2 3 Frank EM (September 1994). "Effect of Alzheimer's disease on communication function". Journal of the South Carolina Medical Association. 90 (9): 417–423. PMID   7967534.
  44. Volicer L, Harper DG, Manning BC, Goldstein R, Satlin A (May 2001). "Sundowning and circadian rhythms in Alzheimer's disease". The American Journal of Psychiatry. 158 (5): 704–711. doi:10.1176/appi.ajp.158.5.704. PMID   11329390. S2CID   10492607.
  45. Gold DP, Reis MF, Markiewicz D, Andres D (January 1995). "When home caregiving ends: a longitudinal study of outcomes for caregivers of relatives with dementia". Journal of the American Geriatrics Society. 43 (1): 10–16. doi:10.1111/j.1532-5415.1995.tb06235.x. PMID   7806732. S2CID   29847950.
  46. Mashour GA, Frank L, Batthyany A, Kolanowski AM, Nahm M, Schulman-Green D, et al. (August 2019). "Paradoxical lucidity: A potential paradigm shift for the neurobiology and treatment of severe dementias". Alzheimer's & Dementia. 15 (8): 1107–1114. doi:10.1016/j.jalz.2019.04.002. hdl: 2027.42/153062 . PMID   31229433. S2CID   195063786.
  47. "Alzheimer's disease – Causes". National Health Service (NHS). 24 April 2023. Archived from the original on 29 September 2020. Retrieved 10 July 2023.
  48. Tackenberg C, Kulic L, Nitsch RM (2020). "Familial Alzheimer's disease mutations at position 22 of the amyloid β-peptide sequence differentially affect synaptic loss, tau phosphorylation and neuronal cell death in an ex vivo system". PLOS ONE. 15 (9): e0239584. Bibcode:2020PLoSO..1539584T. doi: 10.1371/journal.pone.0239584 . PMC   7510992 . PMID   32966331.
  49. Wang H, Kulas JA, Wang C, Holtzman DM, Ferris HA, Hansen SB (August 2021). "Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol". Proceedings of the National Academy of Sciences of the United States of America. 118 (33): e2102191118. Bibcode:2021PNAS..11802191W. doi: 10.1073/pnas.2102191118 . ISSN   0027-8424. PMC   8379952 . PMID   34385305. S2CID   236998499.
  50. Vilchez D, Saez I, Dillin A (December 2014). "The role of protein clearance mechanisms in organismal ageing and age-related diseases". Nature Communications. 5: 5659. Bibcode:2014NatCo...5.5659V. doi: 10.1038/ncomms6659 . PMID   25482515.
  51. Jacobson M, McCarthy N (2002). Apoptosis. Oxford, OX: Oxford University Press. p. 290. ISBN   0199638497.
  52. Hardy J, Allsop D (October 1991). "Amyloid deposition as the central event in the aetiology of Alzheimer's disease". Trends in Pharmacological Sciences. 12 (10): 383–388. doi:10.1016/0165-6147(91)90609-V. PMID   1763432.
  53. 1 2 Mudher A, Lovestone S (January 2002). "Alzheimer's disease-do tauists and baptists finally shake hands?". Trends in Neurosciences. 25 (1): 22–26. doi:10.1016/S0166-2236(00)02031-2. PMID   11801334. S2CID   37380445.
  54. Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, et al. (November 1995). "Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein". The New England Journal of Medicine. 333 (19): 1242–1247. doi: 10.1056/NEJM199511093331902 . PMID   7566000.
  55. 1 2 Andrews SJ, Renton AE, Fulton-Howard B, Podlesny-Drabiniok A, Marcora E, Goate AM (April 2023). "The complex genetic architecture of Alzheimer's disease: novel insights and future directions". eBioMedicine. 90: 104511. doi:10.1016/j.ebiom.2023.104511. PMC   10024184 . PMID   36907103.
  56. 1 2 Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, et al. (April 2021). "Alzheimer's disease". Lancet. 397 (10284): 1577–1590. doi:10.1016/S0140-6736(20)32205-4. PMC   8354300 . PMID   33667416.
  57. Sims R, Hill M, Williams J (March 2020). "The multiplex model of the genetics of Alzheimer's disease" (PDF). Nat Neurosci. 23 (3): 311–322. doi:10.1038/s41593-020-0599-5. PMID   32112059. S2CID   256839971.
  58. Piaceri I, Nacmias B, Sorbi S (January 2013). "Genetics of familial and sporadic Alzheimer's disease". Front Biosci (Elite Ed). 5 (1): 167–177. doi: 10.2741/e605 . PMID   23276979.
  59. Perea JR, Bolós M, Avila J (October 2020). "Microglia in Alzheimer's Disease in the Context of Tau Pathology". Biomolecules. 10 (10): 1439. doi: 10.3390/biom10101439 . PMC   7602223 . PMID   33066368.
  60. Mahley RW, Weisgraber KH, Huang Y (April 2006). "Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease". Proceedings of the National Academy of Sciences of the United States of America. 103 (15): 5644–5651. Bibcode:2006PNAS..103.5644M. doi: 10.1073/pnas.0600549103 . PMC   1414631 . PMID   16567625.
  61. Blennow K, de Leon MJ, Zetterberg H (July 2006). "Alzheimer's disease". Lancet. 368 (9533): 387–403. doi:10.1016/S0140-6736(06)69113-7. PMID   16876668. S2CID   47544338.
  62. Hall K, Murrell J, Ogunniyi A, Deeg M, Baiyewu O, Gao S, et al. (January 2006). "Cholesterol, APOE genotype, and Alzheimer disease: an epidemiologic study of Nigerian Yoruba". Neurology. 66 (2): 223–227. doi:10.1212/01.wnl.0000194507.39504.17. PMC   2860622 . PMID   16434658.
  63. Gureje O, Ogunniyi A, Baiyewu O, Price B, Unverzagt FW, Evans RM, et al. (January 2006). "APOE epsilon4 is not associated with Alzheimer's disease in elderly Nigerians". Annals of Neurology. 59 (1): 182–185. doi:10.1002/ana.20694. PMC   2855121 . PMID   16278853.
  64. Piaceri I (2013). "Genetics of familial and sporadic Alzheimer s disease". Frontiers in Bioscience. E5 (1): 167–177. doi: 10.2741/E605 . ISSN   1945-0494. PMID   23276979.
  65. Selkoe DJ (June 1999). "Translating cell biology into therapeutic advances in Alzheimer's disease". Nature. 399 (6738 Suppl): A23–A31. doi: 10.1038/19866 . PMID   10392577. S2CID   42287088.
  66. Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, et al. (November 1996). "Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo". Neuron. 17 (5): 1005–1013. doi: 10.1016/S0896-6273(00)80230-5 . PMID   8938131. S2CID   18315650.
  67. Kim JH (December 2018). "Genetics of Alzheimer's Disease". Dementia and Neurocognitive Disorders. 17 (4): 131–136. doi:10.12779/dnd.2018.17.4.131. PMC   6425887 . PMID   30906402.
  68. Carmona S, Zahs K, Wu E, Dakin K, Bras J, Guerreiro R (August 2018). "The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders". Lancet Neurol. 17 (8): 721–730. doi:10.1016/S1474-4422(18)30232-1. PMID   30033062. S2CID   51706988. Archived from the original on 27 March 2022. Retrieved 21 February 2022.
  69. Tomiyama T (July 2010). "[Involvement of beta-amyloid in the etiology of Alzheimer's disease]". Brain and Nerve = Shinkei Kenkyu No Shinpo. 62 (7): 691–699. PMID   20675873.
  70. Tomiyama T, Nagata T, Shimada H, Teraoka R, Fukushima A, Kanemitsu H, et al. (March 2008). "A new amyloid beta variant favoring oligomerization in Alzheimer's-type dementia". Annals of Neurology. 63 (3): 377–387. doi:10.1002/ana.21321. PMID   18300294. S2CID   42311988.
  71. Tomiyama T, Shimada H (February 2020). "APP Osaka Mutation in Familial Alzheimer's Disease-Its Discovery, Phenotypes, and Mechanism of Recessive Inheritance". International Journal of Molecular Sciences. 21 (4): 1413. doi: 10.3390/ijms21041413 . PMC   7073033 . PMID   32093100.
  72. Goedert M, Spillantini MG, Crowther RA (July 1991). "Tau proteins and neurofibrillary degeneration". Brain Pathology. 1 (4): 279–286. doi: 10.1111/j.1750-3639.1991.tb00671.x . PMID   1669718. S2CID   33331924.
  73. Iqbal K, Alonso A, Chen S, Chohan MO, El-Akkad E, Gong CX, et al. (January 2005). "Tau pathology in Alzheimer disease and other tauopathies". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1739 (2–3): 198–210. doi: 10.1016/j.bbadis.2004.09.008 . PMID   15615638.
  74. Sinyor B, Mineo J, Ochner C (June 2020). "Alzheimer's Disease, Inflammation, and the Role of Antioxidants". Journal of Alzheimer's Disease Reports. 4 (1): 175–183. doi:10.3233/ADR-200171. PMC   7369138 . PMID   32715278.
  75. Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT (2018). "Inflammation as a central mechanism in Alzheimer's disease". Alzheimer's & Dementia. 4: 575–590. doi:10.1016/j.trci.2018.06.014. PMC   6214864 . PMID   30406177.
  76. Lin X, Kapoor A, Gu Y, Chow MJ, Peng J, Zhao K, et al. (February 2020). "Contributions of DNA Damage to Alzheimer's Disease". Int J Mol Sci. 21 (5): 1666. doi: 10.3390/ijms21051666 . PMC   7084447 . PMID   32121304.
  77. Irwin MR, Vitiello MV (March 2019). "Implications of sleep disturbance and inflammation for Alzheimer's disease dementia". The Lancet. Neurology. 18 (3): 296–306. doi:10.1016/S1474-4422(18)30450-2. PMID   30661858. S2CID   58546748.
  78. Huat TJ, Camats-Perna J, Newcombe EA, Valmas N, Kitazawa M, Medeiros R (April 2019). "Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation". J Mol Biol. 431 (9): 1843–1868. doi:10.1016/j.jmb.2019.01.018. PMC   6475603 . PMID   30664867.
  79. Eikelenboom P, van Exel E, Hoozemans JJ, Veerhuis R, Rozemuller AJ, van Gool WA (2010). "Neuroinflammation – an early event in both the history and pathogenesis of Alzheimer's disease". Neuro-Degenerative Diseases. 7 (1–3): 38–41. doi:10.1159/000283480. PMID   20160456. S2CID   40048333.
  80. Alves GS, Oertel Knöchel V, Knöchel C, Carvalho AF, Pantel J, Engelhardt E, et al. (2015). "Integrating retrogenesis theory to Alzheimer's disease pathology: insight from DTI-TBSS investigation of the white matter microstructural integrity". BioMed Research International. 2015: 291658. doi: 10.1155/2015/291658 . PMC   4320890 . PMID   25685779.
  81. Reisberg B, Franssen EH, Hasan SM, Monteiro I, Boksay I, Souren LE, et al. (1999). "Retrogenesis: clinical, physiologic, and pathologic mechanisms in brain aging, Alzheimer's and other dementing processes". European Archives of Psychiatry and Clinical Neuroscience. 249 (3): 28–36. doi:10.1007/pl00014170. PMID   10654097. S2CID   23410069.
  82. Zis P, Hadjivassiliou M (February 2019). "Treatment of Neurological Manifestations of Gluten Sensitivity and Coeliac Disease". Current Treatment Options in Neurology. 21 (3): 10. doi: 10.1007/s11940-019-0552-7 . PMID   30806821. S2CID   73466457.
  83. Makhlouf S, Messelmani M, Zaouali J, Mrissa R (March 2018). "Cognitive impairment in celiac disease and non-celiac gluten sensitivity: review of literature on the main cognitive impairments, the imaging and the effect of gluten free diet". Acta Neurologica Belgica (Review). 118 (1): 21–27. doi:10.1007/s13760-017-0870-z. PMID   29247390. S2CID   3943047.
  84. Bartzokis G (August 2011). "Alzheimer's disease as homeostatic responses to age-related myelin breakdown". Neurobiology of Aging. 32 (8): 1341–1371. doi:10.1016/j.neurobiolaging.2009.08.007. PMC   3128664 . PMID   19775776.
  85. Cai Z, Xiao M (2016). "Oligodendrocytes and Alzheimer's disease". The International Journal of Neuroscience. 126 (2): 97–104. doi:10.3109/00207454.2015.1025778. PMID   26000818. S2CID   21448714.
  86. Zhou L, Miranda-Saksena M, Saksena NK (31 May 2013). "Viruses and neurodegeneration". Virology Journal. 10 (1): 172. doi: 10.1186/1743-422X-10-172 . ISSN   1743-422X. PMC   3679988 . PMID   23724961.
  87. Gonzalez-Fernandez E, Huang J (1 September 2023). "Cognitive Aspects of COVID-19". Current Neurology and Neuroscience Reports. 23 (9): 531–538. doi:10.1007/s11910-023-01286-y. ISSN   1534-6293. PMID   37490194. S2CID   260132167.
  88. Wenk GL (2003). "Neuropathologic changes in Alzheimer's disease". The Journal of Clinical Psychiatry. 64 (Suppl 9): 7–10. PMID   12934968.
  89. Braak H, Del Tredici K (December 2012). "Where, when, and in what form does sporadic Alzheimer's disease begin?". Current Opinion in Neurology. 25 (6): 708–714. doi:10.1097/WCO.0b013e32835a3432. PMID   23160422.
  90. Desikan RS, Cabral HJ, Hess CP, Dillon WP, Glastonbury CM, Weiner MW, et al. (August 2009). "Automated MRI measures identify individuals with mild cognitive impairment and Alzheimer's disease". Brain. 132 (Pt 8): 2048–2057. doi:10.1093/brain/awp123. PMC   2714061 . PMID   19460794.
  91. Moan R (July 2009). "MRI Software Accurately IDs Preclinical Alzheimer's Disease". Diagnostic Imaging. Archived from the original on 21 February 2022. Retrieved 21 February 2022.
  92. 1 2 Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J (June 2004). "The importance of neuritic plaques and tangles to the development and evolution of AD". Neurology. 62 (11): 1984–1989. doi:10.1212/01.WNL.0000129697.01779.0A. PMID   15184601. S2CID   25017332.
  93. DeTure MA, Dickson DW (August 2019). "The neuropathological diagnosis of Alzheimer's disease". Molecular Neurodegeneration. 14 (1): 32. doi: 10.1186/s13024-019-0333-5 . PMC   6679484 . PMID   31375134.
  94. Tiraboschi P, Sabbagh MN, Hansen LA, Salmon DP, Merdes A, Gamst A, et al. (April 2004). "Alzheimer disease without neocortical neurofibrillary tangles: "a second look"". Neurology. 62 (7): 1141–1147. doi:10.1212/01.wnl.0000118212.41542.e7. PMID   15079014. S2CID   22832110.
  95. Bouras C, Hof PR, Giannakopoulos P, Michel JP, Morrison JH (1994). "Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of elderly patients: a quantitative evaluation of a one-year autopsy population from a geriatric hospital". Cerebral Cortex. 4 (2): 138–150. doi:10.1093/cercor/4.2.138. PMID   8038565.
  96. Kotzbauer PT, Trojanowsk JQ, Lee VM (October 2001). "Lewy body pathology in Alzheimer's disease". Journal of Molecular Neuroscience. 17 (2): 225–232. doi:10.1385/JMN:17:2:225. PMID   11816795. S2CID   44407971.
  97. Hashimoto M, Rockenstein E, Crews L, Masliah E (2003). "Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases". Neuromolecular Medicine. 4 (1–2): 21–36. doi:10.1385/NMM:4:1-2:21. PMID   14528050. S2CID   20760249.
  98. Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J (July 2006). "Synapse formation and function is modulated by the amyloid precursor protein". The Journal of Neuroscience. 26 (27): 7212–7221. doi:10.1523/JNEUROSCI.1450-06.2006. PMC   6673945 . PMID   16822978.
  99. Turner PR, O'Connor K, Tate WP, Abraham WC (May 2003). "Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory". Progress in Neurobiology. 70 (1): 1–32. doi:10.1016/S0301-0082(03)00089-3. PMID   12927332. S2CID   25376584.
  100. Hooper NM (April 2005). "Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein". Biochemical Society Transactions. 33 (Pt 2): 335–338. doi:10.1042/BST0330335. PMID   15787600. S2CID   14269634.
  101. Ohnishi S, Takano K (March 2004). "Amyloid fibrils from the viewpoint of protein folding". Cellular and Molecular Life Sciences. 61 (5): 511–524. doi:10.1007/s00018-003-3264-8. PMID   15004691. S2CID   25739126.
  102. Hernández F, Avila J (September 2007). "Tauopathies". Cellular and Molecular Life Sciences. 64 (17): 2219–2233. doi:10.1007/s00018-007-7220-x. PMID   17604998. S2CID   261121643.
  103. Sun W, Samimi H, Gamez M, Zare H, Frost B (August 2018). "Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies". Nature Neuroscience. 21 (8): 1038–1048. doi:10.1038/s41593-018-0194-1. PMC   6095477 . PMID   30038280.
  104. Balusu S, Horré K, Thrupp N, Craessaerts K, Snellinx A, Serneels L, T'Syen D, Chrysidou I, Arranz AM, Sierksma A, Simrén J, Karikari TK, Zetterberg H, Chen WT, Thal DR, Salta E, Fiers M, De Strooper B. MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease. Science. 2023 Sep 15;381(6663):1176-1182. doi : 10.1126/science.abp9556 PMID   37708272
  105. "Scientists discover how brain cells die in Alzheimer's". BBC News. 15 September 2023. Retrieved 27 September 2023.
  106. Van Broeck B, Van Broeckhoven C, Kumar-Singh S (2007). "Current insights into molecular mechanisms of Alzheimer disease and their implications for therapeutic approaches". Neuro-Degenerative Diseases. 4 (5): 349–365. doi:10.1159/000105156. PMID   17622778. S2CID   7949658.
  107. Huang Y, Mucke L (March 2012). "Alzheimer mechanisms and therapeutic strategies". Cell. 148 (6): 1204–1222. doi:10.1016/j.cell.2012.02.040. PMC   3319071 . PMID   22424230.
  108. Yankner BA, Duffy LK, Kirschner DA (October 1990). "Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides". Science. 250 (4978): 279–282. Bibcode:1990Sci...250..279Y. doi:10.1126/science.2218531. PMID   2218531.
  109. Chen X, Yan SD (December 2006). "Mitochondrial Abeta: a potential cause of metabolic dysfunction in Alzheimer's disease". IUBMB Life. 58 (12): 686–694. doi:10.1080/15216540601047767. PMID   17424907. S2CID   85423830.
  110. Ryan SK, Ugalde CL, Rolland AS, Skidmore J, Devos D, Hammond TR (2023). "Therapeutic inhibition of ferroptosis in neurodegenerative disease". Trends in Pharmacological Sciences. 44 (10): 674–688. doi: 10.1016/ . PMID   37657967.
  111. Greig NH, Mattson MP, Perry T, Chan SL, Giordano T, Sambamurti K, et al. (December 2004). "New therapeutic strategies and drug candidates for neurodegenerative diseases: p53 and TNF-alpha inhibitors, and GLP-1 receptor agonists". Annals of the New York Academy of Sciences. 1035: 290–315. doi:10.1196/annals.1332.018. PMID   15681814. S2CID   84659695. Archived from the original on 3 June 2020. Retrieved 19 July 2019.
  112. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. (April 2015). "Neuroinflammation in Alzheimer's disease". The Lancet. Neurology. 14 (4): 388–405. doi:10.1016/S1474-4422(15)70016-5. PMC   5909703 . PMID   25792098.
  113. Tapia-Arancibia L, Aliaga E, Silhol M, Arancibia S (November 2008). "New insights into brain BDNF function in normal aging and Alzheimer disease". Brain Research Reviews. 59 (1): 201–220. doi:10.1016/j.brainresrev.2008.07.007. hdl: 10533/142174 . PMID   18708092. S2CID   6589846.
  114. Schindowski K, Belarbi K, Buée L (February 2008). "Neurotrophic factors in Alzheimer's disease: role of axonal transport". Genes, Brain and Behavior. 7 (Suppl 1): 43–56. doi:10.1111/j.1601-183X.2007.00378.x. PMC   2228393 . PMID   18184369.
  115. 1 2 Sachdev PS, Blacker D, Blazer DG, Ganguli M, Jeste DV, Paulsen JS, et al. (November 2014). "Classifying neurocognitive disorders: the DSM-5 approach". Nature Reviews. Neurology. 10 (11): 634–642. doi:10.1038/nrneurol.2014.181. PMID   25266297. S2CID   20635070. Archived from the original on 20 March 2022. Retrieved 27 November 2021.
  116. Mendez MF (2006). "The accurate diagnosis of early-onset dementia". International Journal of Psychiatry in Medicine. 36 (4): 401–412. doi:10.2190/Q6J4-R143-P630-KW41. PMID   17407994. S2CID   43715976. Archived from the original on 3 June 2020. Retrieved 25 May 2020.
  117. Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J (November 2006). "Therapeutic approaches to Alzheimer's disease". Brain. 129 (Pt 11): 2840–2855. doi: 10.1093/brain/awl280 . PMID   17018549.
  118. Dementia: Quick Reference Guide (PDF). London: (UK) National Institute for Health and Clinical Excellence. 2006. ISBN   978-1-84629-312-2. Archived from the original (PDF) on 27 February 2008. Retrieved 22 February 2008.
  119. Schroeter ML, Stein T, Maslowski N, Neumann J (October 2009). "Neural correlates of Alzheimer's disease and mild cognitive impairment: a systematic and quantitative meta-analysis involving 1351 patients". NeuroImage. 47 (4): 1196–1206. doi:10.1016/j.neuroimage.2009.05.037. PMC   2730171 . PMID   19463961.
  120. Jie CV, Treyer V, Schibli R, Mu L (January 2021). "Tauvid: The First FDA-Approved PET Tracer for Imaging Tau Pathology in Alzheimer's Disease". Pharmaceuticals. 14 (2): 110. doi: 10.3390/ph14020110 . PMC   7911942 . PMID   33573211.
  121. 1 2 3 4 5 Weller J, Budson A (2018). "Current understanding of Alzheimer's disease diagnosis and treatment". F1000Research (Review). 7: 1161. doi: 10.12688/f1000research.14506.1 . PMC   6073093 . PMID   30135715.
  122. Silva MV, Loures CM, Alves LC, de Souza LC, Borges KB, Carvalho MD (May 2019). "Alzheimer's disease: risk factors and potentially protective measures". Journal of Biomedical Science. 26 (1): 33. doi: 10.1186/s12929-019-0524-y . PMC   6507104 . PMID   31072403.
  123. Hane FT, Robinson M, Lee BY, Bai O, Leonenko Z, Albert MS (2017). "Recent Progress in Alzheimer's Disease Research, Part 3: Diagnosis and Treatment". Journal of Alzheimer's Disease (Review). 57 (3): 645–665. doi:10.3233/JAD-160907. PMC   5389048 . PMID   28269772.
  124. Diagnostic and statistical manual of mental disorders: DSM-IV-TR (4th Text Revision ed.). Washington, DC: American Psychiatric Association. 2000. ISBN   978-0-89042-025-6.
  125. 1 2 3 Diagnostic and statistical manual of mental disorders: DSM-5. Washington, D.C: American Psychiatric Association. 2013. p. 611. ISBN   978-0890425558.
  126. Sachs-Ericsson N, Blazer DG (January 2015). "The new DSM-5 diagnosis of mild neurocognitive disorder and its relation to research in mild cognitive impairment". Aging & Mental Health. 19 (1): 2–12. doi:10.1080/13607863.2014.920303. PMID   24914889. S2CID   46244321.
  127. Stokin GB, Krell-Roesch J, Petersen RC, Geda YE (2015). "Mild Neurocognitive Disorder: An Old Wine in a New Bottle". Harvard Review of Psychiatry (Review). 23 (5): 368–376. doi:10.1097/HRP.0000000000000084. PMC   4894762 . PMID   26332219.
  128. Sperry L, Carlson J, Sauerheber J, Sperry J, eds. (2014). Psychopathology and Psychotherapy: DSM-5 Diagnosis, Case Conceptualization, and Treatment (3 ed.). New York: Routledge. pp. 342–343. doi:10.4324/9780203772287. ISBN   978-0-203-77228-7. Archived from the original on 16 November 2021. Retrieved 16 November 2021.
  129. Fink HA, Hemmy LS, Linskens EJ, Silverman PC, MacDonald R, McCarten JR, et al. (2020). Diagnosis and Treatment of Clinical Alzheimer's-Type Dementia: A Systematic Review. AHRQ Comparative Effectiveness Reviews. Rockville (MD): Agency for Healthcare Research and Quality (US). PMID   32369312. Archived from the original on 7 July 2023. Retrieved 16 November 2021.
  130. Stokin GB, Krell-Roesch J, Petersen RC, Geda YE (September 2015). "Mild Neurocognitive Disorder: An Old Wine in a New Bottle". Harvard Review of Psychiatry. 23 (5). Wolters Kluwer Health: 368–376. doi:10.1097/HRP.0000000000000084. PMC   4894762 . PMID   26332219.
  131. Bradfield NI, Ames D (April 2020). "Mild cognitive impairment: narrative review of taxonomies and systematic review of their prediction of incident Alzheimer's disease dementia". BJPsych Bulletin (Review). 44 (2): 67–74. doi:10.1192/bjb.2019.77. PMC   7283119 . PMID   31724527.
  132. 1 2 Vega JN, Newhouse PA (October 2014). "Mild cognitive impairment: diagnosis, longitudinal course, and emerging treatments". Current Psychiatry Reports. 16 (10). SpringerLink: 490. doi:10.1007/s11920-014-0490-8. PMC   4169219 . PMID   25160795.
  133. Parnetti L, Chipi E, Salvadori N, D'Andrea K, Eusebi P (January 2019). "Prevalence and risk of progression of preclinical Alzheimer's disease stages: a systematic review and meta-analysis". Alzheimer's Research & Therapy. 11 (1). Springer Nature: 7. doi: 10.1186/s13195-018-0459-7 . PMC   6334406 . PMID   30646955.
  134. 1 2 3 4 5 Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. (April 2018). "NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease". Alzheimer's & Dementia. 14 (4). Wiley Online Library: 535–562. doi:10.1016/j.jalz.2018.02.018. PMC   5958625 . PMID   29653606.
  135. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. (May 2011). "Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease". Alzheimer's & Dementia. 7 (3). Wiley Online Library: 280–292. doi:10.1016/j.jalz.2011.03.003. PMC   3220946 . PMID   21514248.
  136. Cheng YW, Chen TF, Chiu MJ (16 February 2017). "From mild cognitive impairment to subjective cognitive decline: conceptual and methodological evolution". Neuropsychiatric Disease and Treatment. 13. Dove Medical Press Limited: 491–498. doi: 10.2147/NDT.S123428 . PMC   5317337 . PMID   28243102.
  137. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. (May 2011). "The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease". Alzheimer's & Dementia. 7 (3). Wiley Online Library: 270–279. doi:10.1016/j.jalz.2011.03.008. PMC   3312027 . PMID   21514249.
  138. 1 2 3 4 Chertkow H, Feldman HH, Jacova C, Massoud F (July 2013). "Definitions of dementia and predementia states in Alzheimer's disease and vascular cognitive impairment: consensus from the Canadian conference on diagnosis of dementia". Alzheimer's Research & Therapy. 5 (Suppl 1). BMC: S2. doi: 10.1186/alzrt198 . PMC   3981054 . PMID   24565215.
  139. 1 2 3 Papadakis MA, McPhee SJ, Rabow MW (2021). Current medical diagnosis & treatment (Sixtieth ed.). New York: McGraw Hill. p. 1760. ISBN   978-1-260-46986-8. OCLC   1195972209.
  140. Tombaugh TN, McIntyre NJ (September 1992). "The mini-mental state examination: a comprehensive review". Journal of the American Geriatrics Society. 40 (9): 922–935. doi:10.1111/j.1532-5415.1992.tb01992.x. PMID   1512391. S2CID   25169596.
  141. Pasquier F (January 1999). "Early diagnosis of dementia: neuropsychology". Journal of Neurology. 246 (1): 6–15. doi:10.1007/s004150050299. PMID   9987708. S2CID   2108587.
  142. Harvey PD, Moriarty PJ, Kleinman L, Coyne K, Sadowsky CH, Chen M, et al. (2005). "The validation of a caregiver assessment of dementia: the Dementia Severity Scale". Alzheimer Disease and Associated Disorders. 19 (4): 186–194. doi:10.1097/01.wad.0000189034.43203.60. PMID   16327345. S2CID   20238911.
  143. Antoine C, Antoine P, Guermonprez P, Frigard B (2004). "[Awareness of deficits and anosognosia in Alzheimer's disease]". L'Encéphale (in French). 30 (6): 570–577. doi:10.1016/S0013-7006(04)95472-3. PMID   15738860.
  144. Cruz VT, Pais J, Teixeira A, Nunes B (2004). "[The initial symptoms of Alzheimer disease: caregiver perception]". Acta Médica Portuguesa (in Portuguese). 17 (6): 435–444. PMID   16197855.
  145. 1 2 3 Stern SD (2020). Symptom to diagnosis: an evidence-based guide. Adam S. Cifu, Diane Altkorn (4th ed.). [New York]. pp. 209–210. ISBN   978-1260121117. OCLC   1121597721.{{cite book}}: CS1 maint: location missing publisher (link)
  146. Jha A, Mukhopadhaya K (2021). Alzheimer's disease: diagnosis and treatment guide. Cham, Switzerland: Springer. p. 32. ISBN   978-3-030-56739-2. OCLC   1202472277.
  147. Sun X, Steffens DC, Au R, Folstein M, Summergrad P, Yee J, et al. (May 2008). "Amyloid-associated depression: a prodromal depression of Alzheimer disease?". Archives of General Psychiatry. 65 (5): 542–550. doi:10.1001/archpsyc.65.5.542. PMC   3042807 . PMID   18458206.
  148. Geldmacher DS, Whitehouse PJ (May 1997). "Differential diagnosis of Alzheimer's disease". Neurology. 48 (5 Suppl 6): S2–S9. doi:10.1212/WNL.48.5_Suppl_6.2S. PMID   9153154. S2CID   30018544.
  149. Potter GG, Steffens DC (May 2007). "Contribution of depression to cognitive impairment and dementia in older adults". The Neurologist. 13 (3): 105–117. doi:10.1097/01.nrl.0000252947.15389.a9. PMID   17495754. S2CID   24569198.
  150. Zhang S, Smailagic N, Hyde C, Noel-Storr AH, Takwoingi Y, McShane R, et al. (July 2014). "(11)C-PIB-PET for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI)". The Cochrane Database of Systematic Reviews. 2014 (7): CD010386. doi:10.1002/14651858.CD010386.pub2. PMC   6464750 . PMID   25052054.
  151. Smailagic N, Vacante M, Hyde C, Martin S, Ukoumunne O, Sachpekidis C (January 2015). "18F-FDG PET for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI)". The Cochrane Database of Systematic Reviews. 1 (1): CD010632. doi:10.1002/14651858.CD010632.pub2. PMC   7081123 . PMID   25629415.
  152. Viña J, Sanz-Ros J (October 2018). "Alzheimer's disease: Only prevention makes sense". European Journal of Clinical Investigation. 48 (10): e13005. doi: 10.1111/eci.13005 . PMID   30028503. S2CID   51703879.
  153. 1 2 3 Hsu D, Marshall GA (2017). "Primary and secondary prevention trials in Alzheimer disease: looking back, moving forward". Curr Alzheimer Res. 14 (4): 426–440. doi:10.2174/1567205013666160930112125. PMC   5329133 . PMID   27697063.
  154. Patterson C, Feightner JW, Garcia A, Hsiung GY, MacKnight C, Sadovnick AD (February 2008). "Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease". CMAJ. 178 (5): 548–556. doi:10.1503/cmaj.070796. PMC   2244657 . PMID   18299540.
  155. Rosendorff C, Beeri MS, Silverman JM (2007). "Cardiovascular risk factors for Alzheimer's disease". The American Journal of Geriatric Cardiology. 16 (3): 143–149. doi:10.1111/j.1076-7460.2007.06696.x. PMID   17483665.
  156. Chu CS, Tseng PT, Stubbs B, Chen TY, Tang CH, Li DJ, et al. (April 2018). "Use of statins and the risk of dementia and mild cognitive impairment: A systematic review and meta-analysis". Scientific Reports. 8 (1): 5804. Bibcode:2018NatSR...8.5804C. doi:10.1038/s41598-018-24248-8. PMC   5895617 . PMID   29643479.
  157. Ungvari Z, Toth P, Tarantini S, Prodan CI, Sorond F, Merkely B, et al. (October 2021). "Hypertension-induced cognitive impairment: from pathophysiology to public health". Nature Reviews Nephrology. 17 (10): 639–654. doi:10.1038/s41581-021-00430-6. PMC   8202227 . PMID   34127835.
  158. Lethaby A, Hogervorst E, Richards M, Yesufu A, Yaffe K (January 2008). "Hormone replacement therapy for cognitive function in postmenopausal women". Cochrane Database Syst Rev. 2008 (1): CD003122. doi:10.1002/14651858.CD003122.pub2. PMC   6599876 . PMID   18254016.
  159. Farina N, Rusted J, Tabet N (January 2014). "The effect of exercise interventions on cognitive outcome in Alzheimer's disease: a systematic review". International Psychogeriatrics (Review). 26 (1): 9–18. doi:10.1017/S1041610213001385. PMID   23962667. S2CID   24936334.
  160. Barnard ND, Bush AI, Ceccarelli A, Cooper J, de Jager CA, Erickson KI, et al. (September 2014). "Dietary and lifestyle guidelines for the prevention of Alzheimer's disease". Neurobiology of Aging. 35 (Suppl 2): S74–S78. doi: 10.1016/j.neurobiolaging.2014.03.033 . hdl: 11343/52774 . PMID   24913896. S2CID   8265377.
  161. 1 2 Bhatti GK, Reddy AP, Reddy PH, Bhatti JS (2019). "Lifestyle Modifications and Nutritional Interventions in Aging-Associated Cognitive Decline and Alzheimer's Disease". Frontiers in Aging Neuroscience (Review). 11: 369. doi: 10.3389/fnagi.2019.00369 . PMC   6966236 . PMID   31998117.
  162. López-Ortiz S, Lista S, Valenzuela PL, Pinto-Fraga J, Carmona R, Caraci F, et al. (November 2022). "Effects of physical activity and exercise interventions on Alzheimer's disease: an umbrella review of existing meta-analyses". Journal of Neurology. 270 (2): 711–725. doi:10.1007/s00415-022-11454-8. PMID   36342524. S2CID   253382289.
  163. Imtiaz B, Tolppanen AM, Kivipelto M, Soininen H (April 2014). "Future directions in Alzheimer's disease from risk factors to prevention". Biochemical Pharmacology (Review). 88 (4): 661–670. doi:10.1016/j.bcp.2014.01.003. PMID   24418410.
  164. Imtiaz B, Tolppanen AM, Kivipelto M, Soininen H (April 2014). "Future directions in Alzheimer's disease from risk factors to prevention". Biochem Pharmacol. 88 (4): 661–70. doi:10.1016/j.bcp.2014.01.003. PMID   24418410.
  165. Kivipelto M, Mangialasche F, Ngandu T (November 2018). "Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease". Nat Rev Neurol. 14 (11): 653–666. doi:10.1038/s41582-018-0070-3. PMID   30291317. S2CID   52925352.
  166. 1 2 3 4 Borges CR, Poyares D, Piovezan R, Nitrini R, Brucki S (November 2019). "Alzheimer's disease and sleep disturbances: a review". Arq Neuropsiquiatr. 77 (11): 815–824. doi: 10.1590/0004-282X20190149 . PMID   31826138. S2CID   209327994.
  167. 1 2 Uddin MS, Tewari D, Mamun AA, Kabir MT, Niaz K, Wahed MI, et al. (July 2020). "Circadian and sleep dysfunction in Alzheimer's disease". Ageing Research Reviews. 60: 101046. doi:10.1016/j.arr.2020.101046. PMID   32171783. S2CID   212729131.
  168. Rasmussen MK, Mestre H, Nedergaard M (November 2018). "The glymphatic pathway in neurological disorders". Lancet Neurol. 17 (11): 1016–1024. doi:10.1016/S1474-4422(18)30318-1. PMC   6261373 . PMID   30353860.
  169. Irwin MR, Vitiello MV (March 2019). "Implications of sleep disturbance and inflammation for Alzheimer's disease dementia". Lancet Neurol. 18 (3): 296–306. doi:10.1016/S1474-4422(18)30450-2. PMID   30661858. S2CID   58546748.
  170. Hampel H, Vergallo A, Aguilar LF, Benda N, Broich K, Cuello AC, et al. (April 2018). "Precision pharmacology for Alzheimer's disease". Pharmacological Research. 130: 331–365. doi:10.1016/j.phrs.2018.02.014. PMC   8505114 . PMID   29458203.
  171. Chen Y, Zhang J, Zhang T, Cao L, You Y, Zhang C, et al. (March 2020). "Meditation treatment of Alzheimer disease and mild cognitive impairment: A protocol for systematic review". Medicine. 99 (10): e19313. doi:10.1097/MD.0000000000019313. PMC   7478420 . PMID   32150066.
  172. Winkelman MJ, Szabo A, Frecska E (1 November 2023). "The potential of psychedelics for the treatment of Alzheimer's disease and related dementias". European Neuropsychopharmacology. 76: 3–16. doi: 10.1016/j.euroneuro.2023.07.003 . ISSN   0924-977X. PMID   37451163.
  173. Drislane F, Hovauimian A, Tarulli A, Boegle AK, McIiduff C, Caplan LR (2019). Blueprints neurology (Fifth ed.). Philadelphia: Wolters Kluwer. p. 146. ISBN   978-1-4963-8739-4. OCLC   1048659425.
  174. 1 2 3 Birks JS, Harvey RJ (June 2018). "Donepezil for dementia due to Alzheimer's disease". The Cochrane Database of Systematic Reviews. 2018 (6): CD001190. doi:10.1002/14651858.CD001190.pub3. PMC   6513124 . PMID   29923184.
  175. Fink HA, Linskens EJ, MacDonald R, Silverman PC, McCarten JR, Talley KM, et al. (May 2020). "Benefits and Harms of Prescription Drugs and Supplements for Treatment of Clinical Alzheimer-Type Dementia". Annals of Internal Medicine. 172 (10): 656–668. doi:10.7326/M19-3887. PMID   32340037. S2CID   216595473.
  176. Berkowitz A (2017). Clinical neurology and neuroanatomy: a localization-based approach. New York: McGraw Hill. p. 236. ISBN   978-1-259-83440-0. OCLC   948547621.
  177. Geula C, Mesulam MM (1995). "Cholinesterases and the pathology of Alzheimer disease". Alzheimer Disease and Associated Disorders. 9 (Suppl 2): 23–28. doi:10.1097/00002093-199501002-00005. PMID   8534419.
  178. Stahl SM (November 2000). "The new cholinesterase inhibitors for Alzheimer's disease, Part 2: illustrating their mechanisms of action". The Journal of Clinical Psychiatry. 61 (11): 813–814. doi: 10.4088/JCP.v61n1101 . PMID   11105732.
  179. 1 2 Birks J (January 2006). Birks J (ed.). "Cholinesterase inhibitors for Alzheimer's disease". The Cochrane Database of Systematic Reviews. 2016 (1): CD005593. doi:10.1002/14651858.CD005593. PMC   9006343 . PMID   16437532.
  180. Raschetti R, Albanese E, Vanacore N, Maggini M (November 2007). "Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials". PLOS Medicine. 4 (11): e338. doi: 10.1371/journal.pmed.0040338 . PMC   2082649 . PMID   18044984.
  181. Alldredge BK, Corelli RL, Ernst ME, Guglielmo BJ, Jacobson PA, Kradjan WA, et al. (2013). Applied therapeutics : the clinical use of drugs (10th ed.). Baltimore: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 2385. ISBN   978-1-60913-713-7.
  182. 1 2 Lipton SA (February 2006). "Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond". Nature Reviews. Drug Discovery. 5 (2): 160–170. doi:10.1038/nrd1958. PMID   16424917. S2CID   21379258.
  183. "Memantine". US National Library of Medicine (Medline). 4 January 2004. Archived from the original on 22 February 2010. Retrieved 3 February 2010.
  184. McShane R, Westby MJ, Roberts E, Minakaran N, Schneider L, Farrimond LE, et al. (March 2019). "Memantine for dementia". The Cochrane Database of Systematic Reviews. 3 (3): CD003154. doi:10.1002/14651858.CD003154.pub6. PMC   6425228 . PMID   30891742.
  185. "Namenda- memantine hydrochloride tablet Namenda- memantine hydrochloride kit". DailyMed. 15 November 2018. Archived from the original on 27 January 2022. Retrieved 20 February 2022.
  186. "Namenda XR- memantine hydrochloride capsule, extended release Namenda XR- memantine hydrochloride kit". DailyMed. 15 November 2019. Archived from the original on 21 February 2022. Retrieved 20 February 2022.
  187. "Namzaric- memantine hydrochloride and donepezil hydrochloride capsule Namzaric- memantine hydrochloride and donepezil hydrochloride kit". DailyMed. 22 January 2019. Archived from the original on 20 January 2022. Retrieved 20 February 2022.
  188. Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, et al. (March 2008). "Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline". Annals of Internal Medicine. 148 (5): 379–397. doi:10.7326/0003-4819-148-5-200803040-00009. PMID   18316756. S2CID   22235353.
  189. 1 2 Kandiah N, Ong PA, Yuda T, Ng LL, Mamun K, Merchant RA, et al. (February 2019). "Treatment of dementia and mild cognitive impairment with or without cerebrovascular disease: Expert consensus on the use of Ginkgo biloba extract, EGb 761". CNS Neuroscience & Therapeutics. 25 (2): 288–298. doi:10.1111/cns.13095. PMC   6488894 . PMID   30648358.
  190. McKeage K, Lyseng-Williamson KA (2018). "Ginkgo biloba extract EGb 761 in the symptomatic treatment of mild-to-moderate dementia: a profile of its use". Drugs & Therapy Perspectives. 34 (8): 358–366. doi:10.1007/s40267-018-0537-8. PMC   6267544 . PMID   30546253.
  191. Yang G, Wang Y, Sun J, Zhang K, Liu J (22 October 2015). "Ginkgo Biloba for Mild Cognitive Impairment and Alzheimer's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials". Current Topics in Medicinal Chemistry. 16 (5): 520–528. doi:10.2174/1568026615666150813143520. PMID   26268332.
  192. Ballard C, Waite J (January 2006). Ballard CG (ed.). "The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease". The Cochrane Database of Systematic Reviews (1): CD003476. doi:10.1002/14651858.CD003476.pub2. PMID   16437455.
  193. Ballard C, Hanney ML, Theodoulou M, Douglas S, McShane R, Kossakowski K, et al. (February 2009). "The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomis