[Association between 473 gut microbiota and Alzheimer's disease: a Mendelian randomization mediation analysis of 233...

To investigate the causal associations between gut microbiota (GM) and Alzheimer's disease (AD) and the mediating role of circulating metabolites using Mendelian randomization (MR) analysis.

A two-sample MR analysis was conducted based on genome-wide association study (GWAS) summary data. Valid instrumental variables for 473 GM taxa and 233 circulating metabolites were selected, and the inverse-variance weighted (IVW) method was used as the primary analytical approach, with MR-Egger regression and weighted median method as the complementary analyses. Multiple sensitivity analyses were conducted to assess the robustness of the results, and reverse MR analyses were used to verify the direction of causality. Mediation MR analyses were performed to determine the mediating effects of the circulating metabolites.

A positive causal association was identified between the abundance of Negativibacillus massiliensis and the risk of AD (OR=1.204, 95% CI: 1.020-1.421,P=0.028), and the results were stable and reliable as confirmed by sensitivity analyses (P>0.05). Reverse MR analysis revealed no significant causal effect of AD on the abundance of Negativibacillus massiliensis (P=0.678). Mediation MR analysis showed that the indirect effect mediated by free cholesterol to total lipid ratio in very small very-low-density lipoprotein (v-VLDL FC/TL) accounted for 6.63% of the total effect of Negativibacillus massiliensis on AD.

From a genetic causal inference perspective, Negativibacillus massiliensis is likely associated with an increased risk of AD, and v-VLDL FC/TL may partially mediate this association, suggesting their potential as targets for AD prevention and treatment.