Investigating the Genetic Influence of Omega-3 Fatty Acids on Alzheimer's Disease Risk Through Mendelian Randomization

Objectives: This study examines the contradictory findings on the impact of omega-3 fatty acids (n-3 FAs) on Alzheimer's Disease (AD) risk. Utilizing a two-sample Mendelian Randomization (MR) approach, we aim to elucidate the causal relationships between serum levels of n-3 FAs, predicted by genetics, and the risk of AD, using publicly available summary data. Methods: Leveraging genome-wide association study data from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and the International Genomics of Alzheimer's Project, we identified single nucleotide polymorphisms (SNPs) that independently and robustly predict n-3 FA levels, serving as instrumental variables (IVs), and extracted their associations with both the exposures and the outcomes. We applied univariable Mendelian Randomization (UVMR) to quantify the total causal effect of individual n-3 FAs. To address potential horizontal pleiotropic effects arising from shared IVs (i.e., SNPs) among n-3 FAs and n-6 FAs, we applied multivariable Mendelian Randomization (MVMR), to isolate the direct causal effect of each n-3 FA on AD risk. Results: The analysis did not reveal any significant causal effects of genetically predicted n-3 FA levels on the risk of developing AD. The odds ratios (OR) and 95% confidence intervals (CI) for a one standard deviation increase in serum levels of alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) were 0.96 (95% CI: 0.88, 1.06), 1.02 (95%CI: 0.99, 1.06), 1.03 (95% CI: 0.97, 1.09), and 1.00 ( 95% CI: 0.81, 1.26), respectively. These findings remained consistent when adjusting for the presence of n-6 FAs in the MVMR analysis, suggesting no direct genetic influence of n-3 FAs on AD risk within the bounds of this study. Conclusions: Our findings indicate no genetic evidence to suggest a causal relationship between n-3 FA levels and the risk of AD. These results may clarify the context of conflicting evidence from observational studies and randomized controlled trials. Funding Sources: The study was supported by the United States Department of Agriculture (USDA), Agriculture Research Service (ARS) and by NIH grant.