The Role of Clusterin, Complement Receptor 1, and Phosphatidylinositol Binding Clathrin Assembly Protein in Alzheimer Disease Risk and Cerebrospinal Fluid Biomarker Levels

Context: Two recent and simultaneously published genome-wide association studies independently implicated clusterin (CLU), complement receptor 1 (CR1), and phosphatidylinositol binding clathrin assembly protein (PICALM) as putative novel Alzheimer disease (AD) risk loci. Despite their strong statistical support, all 3 signals emerged from heterogeneous case-control populations and lack replication in different settings. Objective: To determine whether genetic variants in CLU, CR1, and PICALM confer risk for AD in independent data sets (n=4254) and to test the impact of these markers on cerebrospinal fluid (CSF)-A beta 42 and total-tau protein levels (n=425). Design: Genetic association study using family-based and case-control designs. Setting: Ambulatory or hospitalized care. Participants: Family samples originate from mostly multiplex pedigrees recruited at different centers in the United States (1245 families, 2654 individuals with AD, and 1175 unaffected relatives). Unrelated case-control subjects originate from 1 clinical center in Germany(214 individuals with AD and 211 controls). All subjects were of European descent. Main Outcome Measures: The association between 5 genetic variants in CLU, CR1, and PICALM and risk for AD, and the correlation between these 5 genetic variants and CSF-A beta 42 and tau levels. Results: All 3 investigated loci showed significant associations between risk for AD(1-tailed P values ranging from <.001 to .02) and consistent effect sizes and direction. For each locus, the overall evidence of association was substantially strengthened on meta-analysis of all available data (2-tailed P values ranging from 1.1 x 10(-16) to 4.1 x 10(-7)). Of all markers tested, only rs541458 in PICALM was shown to have an effect on CSF protein levels, suggesting that the AD risk allele is associated with decreased CSF A beta 42 levels (2-tailed P=.002). Conclusions: This study provides compelling independent evidence that genetic variants in CLU, CR1, and PICALM are genetically associated with risk for AD. Furthermore, the CSF biomarker analyses provide a first insight into the potentially predominant pathogenetic mechanism(s) underlying the association between AD risk and PICALM.