Interaction of nutrition and genetics via DNMT3L-mediated DNA methylation determines cognitive decline

Low homocysteine levels and B vitamin treatment are reported to protect against declining cognitive health. Both B vitamins and homocysteine are involved in the production of S-adenosylmethionine, a universal methyl donor essential for the process of DNA methylation. We investigated the effect of a damaging coding variant within the DNA methyltransferase gene DNMT3L (R278G, A/G) by examining B vitamin intake, homocysteine levels, cognitive performance, and brain atrophy in individuals in the VITACOG study of mild cognitive impairment and the TwinsUK cohort. In the VITACOG study, individuals who received a 2-year treatment of B vitamins and carried the G allele showed better "visuospatial associative memory" and slower rates of brain atrophy. In the TwinsUK study, improved "visuospatial associative memory" was evident in individuals who reported regular vitamin intake and were A/A homozygotes. In silico modeling indicated that R278G disrupts protein interaction between DNMT3L and DNMT3A, affecting the DNMT3A-3L-H3 complex required for DNA methylation. These findings show that vitamin intake and genetic variation within DNMT3L interact to influence cognitive decline.