Investigating Causal Relations Between Circulating Metabolites and Alzheimer’s Disease: A Mendelian Randomization Study

Background: Metabolomics is a promising approach that can be used to understand pathophysiological pathways of Alzheimer’s disease (AD). However, the causal relationships between metabolism and AD are poorly understood. Objective: We aimed to investigate the causal association between circulating metabolites and risk of AD through two-sample Mendelian randomization (MR) approach. Methods: Genetic associations with 123 circulating metabolic traits were utilized as exposures. Summary statistics data from International Genomics of Alzheimer’s Project was used in primary analysis, including 21,982 AD cases and 41,944 controls. Validation was performed using family history of AD data from UK Biobank (27,696 cases of maternal AD, 14,338 cases of paternal AD, and 272,244 controls). We utilized inverse-variance weighted method as primary method. Results: We found significantly increased risks of developing AD per standard deviation increase in the levels of circulating ApoB (odd ratio[OR] = 3.18; 95% confidence interval[CI]: 1.52–6.66, p = 0.0022), glycoprotein acetyls (OR = 1.21; 95% CI: 1.05–1.39, p = 0.0093), total cholesterol (OR = 2.73; 95% CI: 1.41–5.30, p = 0.0030), and low-density lipoprotein (LDL) cholesterol (OR = 2.34; 95% CI: 1.53–3.57, p = 0.0001). Whereas glutamine (OR = 0.81; 95% CI: 0.71–0.92, p = 0.0011) were significantly associated with lower risk of AD. We also detected causal effects of several different composition of LDL fractions on increased AD risk, which has been verified in validation. However, we found no association between circulating high-density lipoprotein cholesterol and AD. Conclusion: Our findings suggest causal effects of circulating glycoprotein acetyls, ApoB, LDL cholesterol, and serum total cholesterol on higher risk of AD, whereas glutamine showed the protective effect.