Vitamin D, Cognition, and Alzheimer's Disease: Observational and Two-Sample Mendelian Randomization Studies

Background: Observational studies have found that vitamin D supplementation is associated with improved cognition. Further, recent Mendelian randomization (MR) studies have shown that higher vitamin D levels, 25(OH)D, may protect against Alzheimer's disease. Thus, it is possible that 25(OH)D may protect against Alzheimer's disease by improving cognition. Objective: We assessed this hypothesis, by examining the relationship between 25(OH)D levels and seven cognitive measurements. Methods: To mitigate bias from confounding, we performed two-sample MR analyses. We used instruments from three publications: Manousaki et al. (2020), Sutherland et al. (2022), and the Emerging Risk Factors Collaboration/EPIC-CVD/Vitamin D Studies Collaboration (2021). Results: Our observational studies suggested a protective association between 25(OH)D levels and cognitive measures. An increase in the natural log of 25(OH)D by 1 SD was associated with a higher PACC score (Beta(PACC score) = 0.06, 95%CI = (0.04-0.08); p = 1.8x10(-10)). However, in the MR analyses, the estimated effect of 25(OH)D on cognitive measures was null. Specifically, per 1 SD increase in genetically estimated natural log of 25(OH)D, the PACC scores remained unchanged in the overall population, (Beta(PACC score) = -0.01, 95% CI (-0.06 to 0.03); p = 0.53), and amongst individuals aged over 60 (Beta(PACC score) = 0.03, 95% CI (-0.028 to 0.08); p = 0.35). Conclusions: In conclusion, our MR study found no clear evidence to support a protective role of increased 25(OH)D concentrations on cognitive performance in European ancestry individuals. However, our study cannot entirely dismiss the potential beneficial effect on PACC for individuals over the age of 60.