Presented by Rudy Tanzi. AD is now widely considered to be a multifactorial disease with only a few dominant genetic mutations that can be considered as directly causing the disease, i.e., APP and the presenilins. The majority of genetic loci are likely to play broader, but less specific roles, in the disease and are commonly grouped together as "risk factors."
Dr. Tanzi reviewed the evidence from his group for a genetic association between AD and the gene encoding for α2-macroglobulin (A2M), a broad-spectrum protease inhibitor that is present in brain and plasma. The approach involved a family-based "sibship" analysis (exluding individuals younger than age 50 since they are more likely to represent familial forms associated with APP or the presenilins). The evidence strongly supports (p.00009) an increased incidence of a specific deletion affecting the α2M gene in affected siblings with no effect on age of onset. He noted that other groups had failed to find a similar linkage using "case-control" studies and suggested that this is probably due to the fact that identification of genes having subtle effects on disease risk are likely to be masked by population admixture. Family-based studies avoid this problem by effectively controlling for genetic background. He suggested that future studies will need to take this into consideration in order to unravel the complex nature of diseases for which many genes may contribute risk.—Keith Crutcher
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