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Most cases are sporadic, with late onset (e 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 (e). 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 e4 alleles and may be decreased in those who have the e2 allele. For people with 2 e4 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.

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