Vitamin D Receptor and Megalin Gene Polymorphisms Are Associated with Longitudinal Cognitive Change among African-American Urban Adults

Background: The link between longitudinal cognitive change and polymorphisms in the vitamin D receptor (VDR) and MEGALIN [or LDL receptor-related protein 2 (LRP2)] genes remains unclear, particularly among African-American (AA) adults. Objectives: We aimed to evaluate 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 LRP2 [rs3755166: G/A, rs2075252: C/T, rs2228171: C/T] genes with longitudinal cognitive performance change in various domains of cognition. Methods: Data from 1024 AA urban adult participants in the Healthy Aging in Neighborhoods of Diversity Across the Life Span (Baltimore, Maryland) with complete genetic data were used, of whom 660-797 had complete data on 9 cognitive test scores at baseline and/or the first follow-up examination and complete covariate data (similar to 52% female; mean age: similar to 52 y; mean years of education: 12.6 y). Time between examination visits 1 (2004-2009) and 2 (2009-2013) ranged from < 1 y to similar to 8 y, with a mean +/- SD of 4.64 +/- 6 0.93 y. Latent class and haplotype analyses were conducted by creating gene polymorphism groups that were related to longitudinal annual rate of cognitive change predicted from mixed-effects regression models. Results: Among key findings, the rs3755166: G/A MEGALIN SNP was associated with faster decline on the Mini-Mental State Examination overall (beta = -0.002, P = 0.018) and among women. VDR2 (BsmI/ApaI/TaqI: G-/A-/A-) SNP latent class [SNPLC; compared with VDR1 (ApaI: AA'')] was linked to faster decline on the Verbal Fluency Test, Categorical, in women, among whom the MEGALIN(2) (rs2228171: TT'') SNPLC (compared with MEGALIN(1): rs2228171: CC'') was also associated with a faster decline on the Trailmaking Test, Part B (Trails B), but with a slower decline on the Digit Span Backward (DS-B). Moreover, among men, the VDR1 SNP haplotype (SNPHAP; GCA:baT) was associated with a slower decline on the Trails B, whereas the MEGALIN1 SNPHAP (GCC) was associated with a faster decline on the DS-B, reflected as a faster decline on cognitive domain 2 (visual/working memory''). Conclusion: VDR and MEGALIN gene variations can alter age-related cognitive trajectories differentially between men and women among AA urban adults, specifically in global mental status and domains of verbal fluency, visual/working memory, and executive function.