Genetic variants at the CLU, CR1 and PICALM loci associate with risk for late-onset Alzheimer’s disease (LOAD) in genome-wide association studies (GWAS). In this study, our aim was to determine whether the LOAD risk variants at these three loci influence memory endophenotypes in African-American and Caucasian subjects.
We pursued an association study between single nucleotide polymorphism (SNP) genotypes at the CLU, CR1 and PICALM loci and memory endophenotypes. We assessed African-American subjects (AA: 44 with LOAD, 224 controls) recruited at Mayo Clinic Florida and Caucasians recruited at Mayo Clinic Minnesota (RS: 372 with LOAD, 1,690 controls) and Florida (JS: 60 with LOAD, 529 controls). SNPs at the LOAD risk loci CLU (rs11136000), CR1 (rs6656401, rs3818361) and PICALM (rs3851179) were genotyped and tested for association with Logical Memory immediate recall (LMIR), delayed recall (LMDR) and percent retention (LMPR) and Visual Reproduction (VRIR, VRDR, VRPR) scores from Wechsler Memory Scale-Revised, using multivariable linear regression analysis, adjusting for age-at-exam, sex, education and APOE ε4 dosage.
We identified nominally significant or suggestive associations between the LOAD risky CR1 variants and worse LMIR scores in the African-Americans (p=0.068 - 0.046, β= −2.7 to −1.2). The LOAD protective CLU variant is associated with better logical memory endophenotypes in the Caucasian subjects (p=0.099-0.027, β= 0.31 to 0.93). The CR1 associations persisted when the control subjects from the African-American series were assessed separately. The CLU associations appeared to be driven by one of the Caucasian series (RS) and were also observed when the control subset from RS was analyzed.
These results suggest for the first time that LOAD risk variants at CR1 may influence memory endophenotypes in African-Americans. Additionally, CLU LOAD protective variant may confer enhanced memory in Caucasians. Although these results would not remain significant after stringent corrections for multiple testing, they need to be considered in the context of the LOAD associations, with which they have biological consistency. They also provide estimates for effect sizes on memory endophenotypes that could guide future studies. The detection of memory effects for these variants in clinically normal subjects, implies that these LOAD risk loci might modify memory prior to clinical diagnosis of AD.