Exploring Causal Relationships Between Gut Microbiota and Alzheimer’s Disease: A Bidirectional Mendelian Randomization Study

Abstract

Background: Many observational studies have investigated the link between the gut microbiota and Alzheimer’s disease (AD), but the causality remains uncertain. Objective: This study aimed to evaluate the causal impact of gut microbiota on AD. Methods: A two-sample Mendelian randomization (MR) study was conducted employing summary data. Summary statistics for AD were from the latest genome-wide association study (cases and proxy cases: 85,934; controls: 401,577). Summary data for gut microbiota were acquired from MiBioGen consortium. Causal effect estimations primarily relied on the inverse variance weighting method along with the sensitivity analyses for testing for pleiotropy and heterogeneity. Additionally, reverse MR analyses were performed to examine potential reverse causality. Results: Seven gut microbiota were identified as associated with AD risk. Order Selenomonadales (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.03–1.24, p = 0.01), Family Pasteurellaceae (OR 1.07, 95% CI 1.01–1.13, p = 0.01), and Genus Methanobrevibacter (OR 1.07, 95% CI 1.00–1.13, p = 0.04) were correlated with an elevated likelihood of AD, while Class Mollicutes (OR 0.87, 95% CI 0.79–0.95, p = 0.00), Genus Ruminiclostridium9 (OR 0.87, 95% CI 0.78–0.97, p = 0.01), Genus Clostridiuminnocuumgroup (OR 0.94, 95% CI 0.89–0.99, p = 0.03), and Genus Eggerthella (OR 0.94, 95% CI 0.89–1.00, p = 0.04) exerted beneficial impact in mitigating AD. No statistically significant reverse causality was found between AD and each of these seven specific gut microbiota species. Conclusions: This study unveiled a causal link between certain gut microbiota and AD, offering new insights for advancing clinical treatments.