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Alzheimer disease (AD) is the most common cause of dementia in the elderly. While roughly 5% of AD occurs in people younger than 60 years of age, less than half of these cases are caused by autosomal dominant mutations in the β-amyloid protein precursor (APP) and presenilin (PSEN1 and PSEN2) genes. For late-onset AD, a growing number of common public polymorphisms (CPP) appear to confer increased risk for AD but are neither necessary nor sufficient to cause AD. The most well-established, late-onset AD genetic risk factor is apolipoprotein E (APOE). In addition, we recently described CPPs in α2-macroglobulin (α2M) that confer increased risk for AD. While early-onset AD gene mutations increase the production of β-amyloid peptide, the principal component of senile plaques in the AD brain, CPPs in APOE and α2M influence the accumulation of β-amyloid peptide by modulating clearance/degradation and the rate of aggregation of the peptide into amyloid plaques. We have recently completed (with Center of Inherited Disease Research at National Institutes of Health, Bethesda, Md) a high resolution (9 cM) genome screen of more than 400 families to localize additional genetic risk factors for AD. Candidate genes localized in regions of chromosomal hits are being assessed primarily by family-based association techniques. The results of these ongoing analyses were discussed.
Tanzi R. Unraveling the Genetics of Alzheimer Disease. Arch Neurol. 2000;57(8):1236. doi:
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