Vitamin D receptor and megalin gene polymorphisms and their associations with longitudinal cognitive change in US adults

Background: Vitamin D receptor (VDR) and the megalin gene polymorphism's link with longitudinal cognitive change remains unclear. Objective: The associations of single nucleotide polymorphisms (SNPs) for VDR [rs11568820 (CdX-2:T/C), rs1544410 (BsmI:G/A), rs7975232 (ApaI:A/C), rs731236 (TaqI:G/A)], and Megalin (rs3755166:G/A; rs2075252:C/T; rs4668123:C/T) genes with longitudinal cognitive performance changes were examined. Design: Data from 702 non-Hispanic white participants in the Baltimore Longitudinal Study of Aging were used. Longitudinal annual rates of cognitive change (LARCCs) between age 50 y and the individual mean follow-up age were predicted with linear mixed models by using all cognitive score time points (prediction I) or time points before dementia onset (prediction II). Latent class, haplotype, and ordinary least squares (OLS) regression analyses were conducted. Results: Among key findings, in OLS models with SNP latent classes as predictors for LARCCs, Megalin ₂ [rs3755166(-)/rs2075252(TT)/rs4668123(T-)] compared with Megalin ₁ [rs3755166(-)/rs2075252 (CC)/rs4668123(-)] was associated with greater decline among men for verbal memory (prediction II). Significant sex differences were also found for SNP haplotype (SNPHAP). In women, VDR ₁ [BsmI (G-)/ApaI(C-)/TaqI(A-); baT] was linked to a greater decline in category fluency (prediction I: β = -0.031, P = 0.012). The Megalin ₁ SNPHAP (GCC) was related to greater decline among women for verbal memory, immediate recall [California Verbal Learning Test (CVLT), List A; prediction II: β = -0.043, P = 0.006) but to slower decline among men for delayed recall (CVLT-DR: β > 0, P <0.0125; both predictions). In women, the Megalin ₂ SNPHAP (ACC) was associated with slower decline in category fluency (prediction II: β = +0.026, P = 0.005). Another finding was that Megalin SNP rs3755166:G/A was associated with greater decline in global cognition in both sexes combined and in verbal memory in men. Conclusion: Sex-specific VDR and Megalin gene variations can modify age-related cognitive decline among US adults.