(See also Overview of Delirium and Dementia Overview of Delirium and Dementia Delirium (sometimes called acute confusional state) and dementia are the most common causes of cognitive impairment, although affective disorders (eg, depression) can also disrupt cognition... read more and Dementia Dementia Dementia is chronic, global, usually irreversible deterioration of cognition. Diagnosis is clinical; laboratory and imaging tests are usually used to identify treatable causes. Treatment is... read more .)
Alzheimer disease, a neurocognitive disorder, is the most common cause of dementia Dementia Dementia is chronic, global, usually irreversible deterioration of cognition. Diagnosis is clinical; laboratory and imaging tests are usually used to identify treatable causes. Treatment is... read more ; it accounts for 60 to 80% of dementias in older people. In the US, an estimated 10% of people ≥ 65 have Alzheimer disease. The percentage of people with Alzheimer disease increases with age (1 General reference Alzheimer disease causes progressive cognitive deterioration and is characterized by beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical gray matter. Diagnosis... read more ):
Age 65 to 74: 3%
Age 75 to 84: 17%
Age ≥ 85: 32%
The disease is twice as common among women as among men, partly because women have a longer life expectancy. Prevalence in industrialized countries is expected to increase as the proportion of older people increases.
General reference
1. Alzheimer's Association: 2022 Alzheimer's Disease Facts and Figures. Alzheimers Dement 18 (4):700–789, 2022. doi: 10.1002/alz.12638
Etiology of Alzheimer Disease
Most cases of Alzheimer disease are sporadic, with late onset (≥ 65 years) and unclear etiology. Risk of developing the disease is best predicted by age. However, about 5 to 15% of cases are familial; half of these cases have an early (presenile) onset (< 65 years) and are typically related to specific genetic mutations.
At least 5 distinct genetic loci, located on chromosomes 1, 12, 14, 19, and 21, influence initiation and progression of Alzheimer disease.
Mutations in genes for the amyloid precursor protein, presenilin I, and presenilin II may lead to autosomal dominant forms of Alzheimer disease, typically with early onset. In affected patients, the processing of amyloid precursor protein is altered, leading to deposition and fibrillar aggregation of beta-amyloid; beta-amyloid is the main component of neuritic (senile) plaques, which consist of degenerated axonal or dendritic processes, astrocytes, and glial cells around an amyloid core. Beta-amyloid may also alter kinase and phosphatase activities in ways that eventually lead to hyperphosphorylation of tau (a protein that stabilizes microtubules) and formation of neurofibrillary tangles.
Other genetic determinants include the apolipoprotein (apo) E (epsilon) alleles. Apo E proteins influence beta-amyloid deposition, cytoskeletal integrity, and efficiency of neuronal repair. Risk of Alzheimer disease is substantially increased in people with two epsilon-4 alleles and may be decreased in those who have the epsilon-2 allele. For people with two epsilon-4 alleles, risk of developing Alzheimer disease by age 75 is about 10 to 30 times that for people without the allele.
Vascular risk factors, such as hypertension, diabetes, dyslipidemia, and smoking, can increase the risk of Alzheimer disease. Growing evidence suggests that aggressive treatment of these risk factors as early as midlife can attenuate the risk of developing cognitive impairment in older age.
The relationship of other factors, such as low hormone levels and metal exposure, to Alzheimer disease has not been established.
Pathophysiology of Alzheimer Disease
The two pathologic hallmarks of Alzheimer disease are
Extracellular beta-amyloid deposits (in neuritic plaques)
Intracellular neurofibrillary tangles (paired helical filaments)
The beta-amyloid deposition and neurofibrillary tangles lead to loss of synapses and neurons, which results in gross atrophy of the affected areas of the brain, typically starting at the mesial temporal lobe.
The mechanism by which beta-amyloid peptide and neurofibrillary tangles cause such damage is incompletely understood. There are several theories.
The amyloid hypothesis posits that progressive accumulation of beta-amyloid in the brain triggers a complex cascade of events ending in neuronal cell death, loss of neuronal synapses, and progressive neurotransmitter deficits; all of these effects contribute to the clinical symptoms of dementia.
A sustained immune response and inflammation have been observed in the brain of patients with Alzheimer disease. Some experts have proposed that inflammation is the third core pathologic feature of Alzheimer disease (1 Pathophysiology references Alzheimer disease causes progressive cognitive deterioration and is characterized by beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical gray matter. Diagnosis... read more ).
Glucose metabolism derangement has been shown to play a potentially important role in the development of Alzheimer's disease (2 Pathophysiology references Alzheimer disease causes progressive cognitive deterioration and is characterized by beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical gray matter. Diagnosis... read more ).
Prion mechanisms have been identified in Alzheimer disease. In prion diseases Overview of Prion Diseases Prion diseases are progressive, fatal, and untreatable degenerative brain disorders. Prominent types of prion diseases include Creutzfeldt-Jakob disease (CJD), the prototypic example (usually... read more , a normal cell-surface brain protein called prion protein becomes misfolded into a pathogenic form termed a prion. The prion then causes other prion proteins to misfold similarly, resulting in a marked increase in the abnormal proteins, which leads to brain damage. In Alzheimer disease, it is thought that the beta-amyloid in cerebral amyloid deposits and tau in neurofibrillary tangles have prion-like, self-replicating properties.
Pathophysiology references
1. Kinney JW, Bemiller SM, Murtishaw AS, et al: Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dement (NY) 4:575–590, 2018. doi: 10.1016/j.trci.2018.06.014
2. González A, Calfío C, Churruca M, Maccioni RB: Alzheimers Res Ther 14 (1):56, 2022. doi: 10.1186/s13195-022-00996-8
Symptoms and Signs of Alzheimer Disease
Patients with Alzheimer disease have symptoms and signs of dementia Symptoms and Signs Dementia is chronic, global, usually irreversible deterioration of cognition. Diagnosis is clinical; laboratory and imaging tests are usually used to identify treatable causes. Treatment is... read more .
The most common first manifestation of Alzheimer disease is
Loss of short-term memory (eg, asking repetitive questions, frequently misplacing objects or forgetting appointments)
Other cognitive deficits tend to involve multiple functions, including the following:
Impaired reasoning, difficulty handling complex tasks, and poor judgment (eg, being unable to manage bank account, making poor financial decisions)
Language dysfunction (eg, difficulty thinking of common words, errors speaking and/or writing)
Visuospatial dysfunction (eg, inability to recognize faces or common objects)
Alzheimer disease progresses gradually but may plateau for periods of time.
Behavior disorders Behavioral and Psychologic Symptoms of Dementia Disruptive actions are common among patients with dementia and are the primary reason for up to 50% of nursing home admissions. Disruptive actions include wandering, restlessness, yelling, throwing... read more (eg, wandering, agitation, yelling, persecutory ideation) are common.
Diagnosis of Alzheimer Disease
Similar to that of other dementias
Formal mental status examination
History and physical examination
Laboratory testing
Neuroimaging
Generally, diagnosis of Alzheimer disease is similar to the diagnosis of other dementias Diagnosis Dementia is chronic, global, usually irreversible deterioration of cognition. Diagnosis is clinical; laboratory and imaging tests are usually used to identify treatable causes. Treatment is... read more . However, despite clinical and specific laboratory and imaging characteristics, definitive diagnosis of Alzheimer disease can only be confirmed by histologic evaluation of brain tissue.
Recommendations about diagnosis of dementia, including Alzheimer's disease, are available from the National Institute for Health and Care Excellence.
Evaluation includes a thorough history and standard neurologic examination. Clinical criteria are 85% accurate in establishing the diagnosis and differentiating Alzheimer disease from other forms of dementia, such as vascular dementia Vascular Cognitive Impairment and Dementia Vascular cognitive impairment and dementia is acute or chronic cognitive deterioration due to diffuse or focal cerebral infarction that is most often related to cerebrovascular disease. (See... read more and dementia with Lewy bodies Dementia with Lewy Bodies and Parkinson Disease Dementia Lewy body dementia includes clinically diagnosed dementia with Lewy bodies and Parkinson disease dementia. Dementia with Lewy bodies is chronic cognitive deterioration characterized by cellular... read more .
Traditional diagnostic criteria for Alzheimer disease include all of the following:
Dementia established clinically and documented by a formal mental status examination
Deficits in ≥ 2 areas of cognition
Gradual onset (ie, over months to years, rather than days or weeks) and progressive worsening of memory and other cognitive functions
No disturbance of consciousness
Onset after age 40, most often after age 65
No systemic or brain disorders (eg, tumor, stroke) that could account for the progressive deficits in memory and cognition
However, deviations from these criteria do not exclude a diagnosis of Alzheimer disease, particularly because patients may have mixed dementia.
The 2011 National Institute on Aging–Alzheimer's Association diagnostic guidelines (1 Diagnosis references Alzheimer disease causes progressive cognitive deterioration and is characterized by beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical gray matter. Diagnosis... read more , 2 Diagnosis references Alzheimer disease causes progressive cognitive deterioration and is characterized by beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical gray matter. Diagnosis... read more ) also include biomarkers for the pathophysiologic process of Alzheimer disease:
A low level of beta-amyloid in cerebrospinal fluid (CSF)
Beta-amyloid deposits in the brain detected by positron emission tomography (PET) imaging using radioactive tracer that binds specifically to beta-amyloid plaques (eg, Pittsburgh compound B [PiB], florbetapir)
Other biomarkers indicate downstream neuronal degeneration or injury:
Elevated levels of tau protein in CSF or tau deposits in the brain detected by PET imaging using radioactive tracer that binds specifically to tau
Decreased cerebral metabolism in the temporoparietal cortex measured using PET with fluorine-18 (18F)–labeled deoxyglucose (fluorodeoxyglucose, or FDG)
Local atrophy in the medial, basal, and lateral temporal lobes and the medial parietal cortex, detected by MRI
These findings increase the probability that dementia is due to Alzheimer disease. However, the guidelines (1 Diagnosis references Alzheimer disease causes progressive cognitive deterioration and is characterized by beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical gray matter. Diagnosis... read more , 2 Diagnosis references Alzheimer disease causes progressive cognitive deterioration and is characterized by beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical gray matter. Diagnosis... read more , 3 Diagnosis references Alzheimer disease causes progressive cognitive deterioration and is characterized by beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical gray matter. Diagnosis... read more ) do not advocate routine use of these biomarkers for diagnosis because standardization and availability are limited at this time. Also, they do not recommend routine testing for the apo epsilon-4 allele.
Laboratory tests (eg, thyroid-stimulating hormone, vitamin B12 levels) and neuroimaging (MRI or CT) are done to check for other, treatable causes of dementia and disorders that can worsen symptoms. If clinical findings suggest another underlying disorder (eg, HIV, syphilis), tests for those disorders are indicated.
Differential diagnosis
Distinguishing Alzheimer disease from other dementias is difficult. The Modified Hachinski Ischemic Score is sometimes used to help distinguish vascular dementia (mainly multi-infarct dementia) Vascular Cognitive Impairment and Dementia Vascular cognitive impairment and dementia is acute or chronic cognitive deterioration due to diffuse or focal cerebral infarction that is most often related to cerebrovascular disease. (See... read more from Alzheimer disease; it has limited clinical usefulness, but it is helpful when neuroimaging is not available (4 Diagnosis references Alzheimer disease causes progressive cognitive deterioration and is characterized by beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical gray matter. Diagnosis... read more ). Key features can help distinguish Alzheimer disease from multi-infarct dementia, a type of vascular cognitive impairment and dementia (see table ). Fluctuations in cognition, parkinsonian symptoms, well-formed visual hallucinations, and relative preservation of short-term memory suggest dementia with Lewy bodies Dementia with Lewy Bodies and Parkinson Disease Dementia Lewy body dementia includes clinically diagnosed dementia with Lewy bodies and Parkinson disease dementia. Dementia with Lewy bodies is chronic cognitive deterioration characterized by cellular... read more rather than Alzheimer disease (see table ).
Patients with Alzheimer disease are often better-groomed and neater than patients with other dementias.
Diagnosis references
1. Jack CR Jr, Albert MS, Knopman DS, et al: Introduction to the revised criteria for the diagnosis of Alzheimer’s disease: National Institute on Aging and Alzheimer's Association workgroups. Alzheimers Dement 7 (3):257–262, 2011. doi: 10.1016/j.jalz.2011.03.004
2. McKhann GM, Knopman DS, Chertkow H, et al: The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 7 (3):263–269, 2011. doi: 10.1016/j.jalz.2011.03.005
3. Chételat G, Arbizu J, Barthel H, et al: Amyloid-PET and 18 F-FDG-PET in the diagnostic investigation of Alzheimer's disease and other dementias. Lancet Neurol 19:951–962, 2020. doi: 10.1016/S1474-4422(20)30314-8
4. Hachinski VC, Iliff LD, Zilhka E, et al: Cerebral blood flow in dementia, Arch Neurol 32 (9):632–637, 1975. doi: 10.1001/archneur.1975.00490510088009
Treatment of Alzheimer Disease
Safety and support measures
Possibly cholinesterase inhibitors and memantine
Safety and supportive measures Treatment Dementia is chronic, global, usually irreversible deterioration of cognition. Diagnosis is clinical; laboratory and imaging tests are usually used to identify treatable causes. Treatment is... read more for Alzheimer disease are the same as those for all dementias. For example, the environment should be bright, cheerful, and familiar, and it should be designed to reinforce orientation (eg, placement of large clocks and calendars in the room). Measures to ensure patient safety (eg, signal monitoring systems for patients who wander) should be implemented.
Providing help for caregivers Caregiver assistance Dementia is chronic, global, usually irreversible deterioration of cognition. Diagnosis is clinical; laboratory and imaging tests are usually used to identify treatable causes. Treatment is... read more , who may experience substantial stress, is also important. Nurses and social workers can teach caregivers how to best meet the patient’s needs. Health care practitioners should watch for early symptoms of caregiver stress and burnout and, when needed, suggest support services.
Medications to treat Alzheimer disease
Cholinesterase inhibitors modestly improve cognitive function and memory in some patients. Four are available. Generally, donepezil, rivastigmine, and galantamine are equally effective, but tacrine is rarely used because of its hepatotoxicity.
Donepezil is a first-line medication because it has once-a-day dosing and is well-tolerated. The recommended dose is 5 mg orally once a day for 4 to 6 weeks, then increased to 10 mg once a day. Donepezil 23 mg once a day may be more effective than the traditional 10 mg once-a-day dose for moderate to severe Alzheimer disease. Treatment should be continued if functional improvement is apparent after several months, but otherwise it should be stopped. The most common adverse effects are gastrointestinal (eg, nausea, diarrhea). Rarely, dizziness and cardiac arrhythmias occur. Adverse effects can be minimized by increasing the dose gradually (see table ).
Memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, appears to improve cognition and functional capacity of patients with moderate to severe Alzheimer disease. The dose is 5 mg orally once a day, which is increased to 10 mg orally twice a day over about 4 weeks. For patients with renal insufficiency, the dose should be reduced or the medication should be avoided. Memantine can be used with a cholinesterase inhibitor.
Aducanumab, a human IgG1 anti-amyloid monoclonal antibody specific for beta-amyloid oligomers implicated in the pathophysiology of Alzheimer disease, is available as a monthly infusion to treat Alzheimer disease. Although some experts consider aducanumab to be the first efficacious disease-modifying treatment for Alzheimer disease, its approval by the US Food and Drug Administration (FDA) was controversial. The medication’s accelerated approval was based mainly on its ability to reduce brain beta-amyloid plaques in patients in clinical trials. But evidence of clinical benefit (slowing progression of the disease) in these trials was inconsistent; thus, additional trials are needed to confirm clinical benefit.
Anti-amyloid monoclonal antibody therapies, including aducanumab, also have adverse effects, including amyloid-related imaging abnormalities (ARIA), which consist of MRI signal changes of cerebral edema (ARIA-E) and/or microhemorrhage and superficial hemosiderosis (ARIA-H). ARIA-E developed in 35.2% of patients receiving a high dose of aducanumab in phase 3 clinical trials; ARIA-E usually occurred early in treatment and caused no symptoms. However, up to 0.9% of patients with ARIA had severe symptoms, including confusion, disorientation, gait disturbance, ataxia, visual disturbance, headache, nausea, and falls (1 Treatment reference Alzheimer disease causes progressive cognitive deterioration and is characterized by beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical gray matter. Diagnosis... read more ).
Other medications are being studied. Efficacy of high-dose vitamin E (1000 IU orally once or twice a day), selegiline, nonsteroidal anti-inflammatory drugs (NSAIDs), Ginkgo biloba extracts, and statins is unclear. Estrogen therapy does not appear useful in prevention or treatment and may be harmful.
Treatment reference
1. Alexander GC, Emerson S, Kesselheim AS: Evaluation of aducanumab for Alzheimer disease: scientific evidence and regulatory review involving efficacy, safety, and futility. JAMA 325(17):1717-1718, 2021. PMID: 33783469. doi: 10.1001/jama.2021.3854
Prognosis for Alzheimer Disease
Although progression rate varies in patients with Alzheimer disease, cognitive decline is inevitable. Average survival from time of diagnosis is 7 years, although this figure is debated. Average survival from the time patients can no longer walk is about 6 months.
End-of-life issues
Because insight and judgment deteriorate in patients with dementia, appointment of a family member, guardian, or lawyer to oversee finances may be necessary. Early in dementia, before the patient is incapacitated, the patient’s wishes about care should be clarified, and financial and legal arrangements (eg, durable power of attorney, durable power of attorney for health care Durable power of attorney for health care Advance directives are legal documents that extend a person's control over health care decisions in the event that the person becomes incapacitated. They are called advance directives because... read more ) should be made. When these documents are signed, the patient’s capacity Capacity (Competence) and Incapacity Historically, “incapacity” was considered primarily a clinical finding, and “incompetency” was considered a legal finding. That distinction, at least in terminology, is no longer firmly recognized... read more should be evaluated, and evaluation results recorded. Decisions about artificial feeding and treatment of acute disorders are best made before the need develops.
In advanced dementia, palliative measures Palliative Care and Hospice Dying patients can have needs that differ from those of other patients. So that their needs can be met, dying patients must first be identified. Before death, patients tend to follow 1 of 3... read more may be more appropriate than highly aggressive interventions or hospital care.
Prevention of Alzheimer Disease
Preliminary, observational evidence suggests that risk of Alzheimer disease may be decreased by the following:
Continuing to do challenging mental activities (eg, learning new skills, doing crossword puzzles) well into old age
Exercising regularly
Controlling hypertension
Lowering cholesterol levels
Consuming a diet rich in omega-3 fatty acids and low in saturated fats
Drinking alcohol in modest amounts
However, there is no convincing evidence that people who do not drink alcohol should start drinking to prevent Alzheimer disease. Once dementia develops, abstaining from alcohol is usually recommended because alcohol can worsen dementia symptoms.
Key Points
Although genetic factors can be involved, most cases of Alzheimer disease are sporadic, with risk predicted best by patient age.
Differentiating Alzheimer disease from other causes of dementia (eg, vascular dementia, dementia with Lewy bodies) can be difficult but is often best done using clinical criteria, which are 85% accurate in establishing the diagnosis.
Treat Alzheimer disease similarly to other dementias.
More Information
The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
Alzheimer's Association: This web site describes biomarkers for earlier diagnosis of Alzheimer disease and other diagnostic tools for the diagnosis of Alzheimer disease (eg, neuroimaging, blood and urine tests), as well as links to resources for support and information about ongoing research.
