A Megalin Polymorphism Associated With Promoter Activity and Alzheimer's Disease Risk

Elevated cerebral levels of amyloid beta-protein (A beta) occur in Alzheimer's disease (AD), yet only a few patients show evidence of increased A beta production. This observation suggests that many, perhaps most, cases of AD are caused by faulty clearance of A beta. Megalin, which plays an important role in mediating A beta clearance, is an attractive candidate gene for genetic association with AD. To investigate this hypothesis, we analyzed the megalin gene in a population of 2,183 subjects. Genetic analysis indicated that the rs3755166 (G/A) polymorphism located in the megalin promoter associated with risk for All, dependently of apolipoprotein E genotype. The rs3755166 AA genotype frequency was significantly greater in AD patients than in control subjects. Furthermore, the luciferase reporter assay indicated that the rs3755166 A variant has 20% less transcriptional activity than the rs3755166 G variant. This study provides strong evidence that this megalin polymorphism confers a greater risk for AD, and supports a biological role for megalin in the neurodegenerative processes involved in AD. (C) 2010 Wiley-Liss, Inc.