Circulating metabolites mediate the effects of lipids on Alzheimer's disease: A Mendelian randomization and mediation analysis

Background Although observational studies have reported correlations between lipid, circulating metabolites, and Alzheimer's disease (AD), the causality of these associations remain unresolved. Objective To investigate the effects of lipids and circulating metabolites on AD risk. Methods We applied a two-step Mendelian randomization (MR) framework to evaluate the causal effects of lipids on AD and to assess whether these effects are mediated by circulating metabolites. Causal estimates were primarily derived using the inverse-variance weighted method, with robustness evaluated through a series of complementary sensitivity analyses, including Cochran's Q statistic, MR-Egger intercept testing, Radial MR, MR-PRESSO, and leave-one-out analyses. Additional validation was provided by Steiger directionality testing, linkage disequilibrium score regression, multivariable MR analyses, and independent replication, collectively ensuring the reliability of the causal inferences. Results MR analyses showed that PI(18:1/18:1) and TAG(52:3) were causally associated with a lower risk of AD. Mediation analyses further identified triglyceride levels in low-density lipoproteins (LDL), medium LDL, and small LDL as intermediates, accounting for 17.6%, 22.8%, and 18.1% of the protective effect of PI(18:1/18:1) on AD risk, respectively. By contrast, the free cholesterol to total lipid ratio in medium high-density lipoproteins (HDL) emerged as a deleterious mediator, explaining 13.0% of the protective association between TAG(52:3) and AD. Conclusions This study highlights the importance of PI(18:1/18:1) and TAG(52:3) in AD development, and suggests that triglyceride levels in LDL, medium LDL, and small LDL, as well as the free cholesterol to total lipids ratio in medium HDL, may act as mediators in this pathway.