Of replications and refutations: the status of Alzheimer's disease genetic research.

Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. To date, mutations in three genes (APP, PSEN1, PSEN2) have been described to cause familial early-onset AD. In addition, a common polymorphism in the gene encoding apolipoprotein E (APOE) has been associated with the more common late-onset form of the disease. However, many studies have shown that genetic factors other than APOE play an important role in late-onset AD. Along these lines, a recent report predicted the existence of at least four additional late-onset AD genes, one of which was estimated to have a much greater contribution to age of onset variation than the APOE epsilon 4-allele. However, most of the nearly three dozen loci that have been proposed as putative AD genes to date have been followed by both replications and refutations, making consensus impossible. In this overview, we discuss the current status of genetic research in AD, including a brief summary of applicable analytic tools, and a summary of recent findings suggesting the existence of novel AD genes on chromosomes 10, 11, and 12.