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Alzheimer disease causes progressive cognitive deterioration and is characterized by beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical gray matter.
Alzheimer disease, a neurocognitive disorder, is the most common cause of dementia; it accounts for 60 to 80% of dementias in the elderly. In the US, an estimated 13% of people ≥ 65 and 45% of people ≥ 85 have Alzheimer disease. 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 the elderly increases.
Most cases are sporadic, with late onset (≥ 65 yr) 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 yr) 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 presenile 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 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 and formation of neurofibrillary tangles.
Other genetic determinants include the apolipoprotein (apo) E alleles (ε). Apo E proteins influence beta-amyloid deposition, cytoskeletal integrity, and efficiency of neuronal repair. Risk of Alzheimer disease is substantially increased in people with 2 ε4 alleles and may be decreased in those who have the ε2 allele. For people with 2 ε4 alleles, risk of developing Alzheimer disease by age 75 is about 10 to 30 times that for people without the allele.
Variants in SORL1 may also be involved; they are more common among people with late-onset Alzheimer disease. These variants may cause the gene to malfunction, possibly resulting in increased production of beta-amyloid.
The relationship of other factors (eg, low hormone levels, metal exposure) and Alzheimer disease is under study, but no definite causal links have been established.
The 2 pathologic hallmarks of Alzheimer disease are
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.
Prion mechanisms have been identified in Alzheimer disease. In prion diseases, 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.
Patients have symptoms and signs of dementia.
The most common first manifestation is
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)
The disease progresses gradually but may plateau for periods of time.
Behavior disorders (eg, wandering, agitation, yelling, persecutory ideation) are common.
Generally, diagnosis of Alzheimer disease is similar to that of other dementias (see page Dementia : Diagnosis).
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 and Lewy body dementia.
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 most recent National Institute on Aging–Alzheimer's Association diagnostic guidelines also include biomarkers for the pathophysiologic process of Alzheimer disease:
Other biomarkers indicate downstream neuronal degeneration of injury:
Elevated levels of tau protein in CSF
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 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 ε4 allele.
Distinguishing Alzheimer disease from other dementias is difficult. Assessment tools (eg, Hachinski Ischemic Score—see Table: Modified Hachinski Ischemic Score) can help distinguish vascular dementia from Alzheimer disease. Fluctuations in cognition, parkinsonian symptoms, well-formed visual hallucinations, and relative preservation of short-term memory suggest Lewy body dementia rather than Alzheimer disease (see Table: Differences Between Alzheimer Disease and Lewy Body Dementia).
Patients with Alzheimer disease are often better-groomed and neater than patients with other dementias.
Modified Hachinski Ischemic Score
Differences Between Alzheimer Disease and Lewy Body Dementia
Safety and supportive measures are the same as that of 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.
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 drug because it has once/day dosing and is well-tolerated. The recommended dose is 5 mg once/day for 4 to 6 wk, then increased to 10 mg once/day. Donepezil 23 mg once/day dose may be more effective than the traditional 10 mg/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 GI (eg, nausea, diarrhea). Rarely, dizziness and cardiac arrhythmias occur. Adverse effects can be minimized by increasing the dose gradually (see Table: Drugs for Alzheimer Disease).
Memantine, an N -methyl-d-aspartate receptor antagonist, appears to improve cognition and functional capacity of patients with moderate to severe Alzheimer disease. The dose is 5 mg po once/day, which is increased to 10 mg po bid over about 4 wk. For patients with renal insufficiency, the dose should be reduced or the drug should be avoided. Memantine can be used with a cholinesterase inhibitor.
Efficacy of high-dose vitamin E (1000 IU po once/day or bid), selegiline, NSAIDs, Ginkgo biloba extracts, and statins is unclear. Estrogen therapy does not appear useful in prevention or treatment and may be harmful.
Drugs for Alzheimer Disease
Preliminary, observational evidence suggests that risk of Alzheimer disease may be decreased by the following:
However, there is no convincing evidence that people who do not drink alcohol should start drinking to prevent Alzheimer disease.
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, Lewy body dementia) 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.
Drug NameSelect Trade
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