Impact of Genetic Variation in SORCS1 on Memory Retention

Objective: We previously reported that genetic variants in SORCS1 increase the risk of AD, that over-expression of SorCS1 reduces c-secretase activity and A beta levels, and that SorCS1 suppression increases c-secretase processing of APP and A beta levels. We now explored the effect of variation in SORCS1 on memory. Methods: We explored associations between SORCS1-SNPs and memory retention in the NIA-LOAD case control dataset (162 cases, 670 controls) and a cohort of Caribbean Hispanics (549 cases, 544 controls) using single marker and haplotype analyses. Results: Three SNPs in intron 1, were associated with memory retention in the NIA-LOAD dataset or the Caribbean Hispanic dataset (rs10884402(A allele: beta = -0.15, p = 0.008), rs7078098(C allele: beta = 0.18, p = 0.007) and rs950809(C allele: beta = 0.17, p = 0.008)) and all three SNPs were significant in a meta-analysis of both datasets (0.002 <0.03). The corresponding A-T-T haplotype for these SNPs was associated with lower scores in both datasets (p = 0.02, p = 0.0009), and the complementary G-C-C haplotype was associated with higher scores in NIA-LOAD (p = 0.02). These associations were restricted to cases. Conclusions: Variation in intron 1 in SORCS1 is associated with memory changes in AD.