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Alzheimer disease causes progressive cognitive deterioration and is characterized by β-amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical gray matter.
Alzheimer disease 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 β-amyloid. β-Amyloid may lead to neuronal death and formation of neurofibrillary tangles and senile plaques, which consist of degenerated axonal or dendritic processes, astrocytes, and glial cells around an amyloid core.
Other genetic determinants include the apolipoprotein (apo) E alleles (ε). Apo E proteins influence β-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 β-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.
Typically, extracellular β-amyloid deposits, intracellular neurofibrillary tangles (paired helical filaments), and senile plaques develop, and neurons are lost. Cerebrocortical atrophy is common, and use of cerebral glucose is reduced, as is perfusion in the parietal lobe, temporal cortices, and prefrontal cortex.
Other common abnormalities include increased brain and CSF concentrations of the tau protein (a component of neurofibrillary tangles and β-amyloid) and reduced levels of choline acetyltransferase and various neurotransmitters (eg, somatostatin).
Symptoms and signs of Alzheimer disease are similar to those of other dementias, with early, intermediate, and late stages (see Dementia : Symptoms and Signs). Loss of short-term memory is often the first sign. Cognitive deficits tend to involve multiple functions. The disease progresses gradually but may plateau for periods of time. Behavior disorders (eg, wandering, agitation, yelling, persecutory ideation) are common (see Behavioral and Psychologic Symptoms of Dementia).
Generally, diagnosis is similar to that of other dementias (see 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 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 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:
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— 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 ( 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
General treatment is the same as that of all dementias (see Dementia : Treatment).
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 Drugs for Alzheimer Disease).
Memantine, an N -methyl-d-aspartate receptor antagonist, appears to slow the progression of 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 Brand Names
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