Genetics of Alzheimer's Disease: A centennial review

Alzheimer's disease (AD) genetics may be one of the most prolifically published areas in medicine and biology. Nearly 200 reviews on this topic have been published since 199 1, when the first report on an autosomal dominant mutation in the amyloid precursor protein gene (APP) came out. Three early-onset AD genes with causative mutations (APP, presenilin I [PSEN1] and presenilin 2 [PSEN2] and one late-onset AD susceptibility gene, apolipoprotein E (APOE) exist with ample biologic, genetic, and epi demiologic data and, essentially, universal acceptance about their roles in AD. Evidence from family and twin studies suggests a significant genetic component underlying AD that is not explained by the known genetic risk factors. The past 10 years in AD genetics research have led to 10 independent whole-genome linkage and association studies with implications for multiple genomic areas for harboring AD susceptibility genes. To date, about 900 papers have reported associations between variations in more than 350 genes spread over 23 autosomes. One hundred years after the first published article on AD, much is known about the pathophysiology of this disease; however, Much more remains to be discovered about its cause. This article summarizes the evidence for the genetic component in AD and the identification of the early-onset familial AD (EOFAD) genes and APOE, and examines the current state of knowledge about additional AD susceptibility loci and alleles. The future directions for genetic research in AD as a common and complex condition are also discussed.