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

Article type: Research Article

Authors: Ilboudo, Yann^{a; b} | Yoshiji, Satoshi^{a; b; c; d; e} | Lu, Tianyuan^{a; f; h} | Butler-Laporte, Guillaume^g | Zhou, Sirui^{a; c} | Richards, J. Brent^{a; b; g; h; i; *}

Affiliations: [a] Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada | [b] Department of Medicine, McGill University, Montreal, QC, Canada | [c] Department of Human Genetics, McGill University, Montréal, QC, Canada | [d] Kyoto-McGill International Collaborative Program in Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan | [e] Japan Society for the Promotion of Science, Tokyo, Japan | [f] Department of Statistical Sciences, University of Toronto, Toronto, ON, Canada | [g] Department of Epidemiology and Biostatistics, McGill University, Montreal, QC, Canada | [h] Department of Twin Research, King’s College London, London, UK | [i] 5 Prime Sciences, Montréal, QC, Canada

Correspondence: [*] Correspondence to: J. Brent Richards, Professor of Medicine, McGill University, Senior Lecturer, King’s College London (Honorary), Pavilion H-413, Jewish General Hospital, 3755 Côte-Ste-Catherine Montréal, QC, H3T 1E2, Canada. Tel.: +1 514 340 8222; Fax: +1 514 340 7529; E-mail: [email protected].

Abstract: 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 (BetaPACC score = 0.06, 95% CI = (0.04–0.08); p = 1.8×10-10). 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, (BetaPACC score = –0.01, 95% CI (–0.06 to 0.03); p = 0.53), and amongst individuals aged over 60 (BetaPACC 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.

Keywords: Aging, Alzheimer’s disease, cognitive dysfunction, databases, genetics, mendelian randomization analysis, observational study, vitamin D deficiency

DOI: 10.3233/JAD-221223

Journal: Journal of Alzheimer's Disease, vol. 99, no. 4, pp. 1243-1260, 2024