BackgroundSeveral recent studies have confirmed a causal relationship between gut microbiota and Alzheimer's disease (AD), but the potential mediators remain unclear.ObjectiveThis study aimed first to investigate the causal relationship between gut microbiota and AD, and second to explore potential mediators involved in this relationship.MethodsWe used a two-step Mendelian randomization study. Firstly, we mainly used inverse-variance weighted (IVW), weighted median, weighted mode, MR-Egger, and simple mode methods to assess the causal relationship between gut microbiota and AD. Secondly, we conducted mediation analysis to evaluate the roles of inflammatory factors, immune cells, and metabolites in this causal pathway. In addition, we performed sensitivity analysis, Steiger test, and linkage disequilibrium score regression (LDSC).ResultsOur results showed that ten types of gut microbiota were causally associated with AD, of which seven were associated with an increased risk of AD and three with a reduced risk. In addition, the mediation analysis showed that CD45 on Mo MDSC mediated 21.89% of the effect of class Actinobacteria on AD, while the cortisol to taurocholate ratio mediated 18.35% of the effect of genus Lactococcus on AD. Beta-hydroxyisovalerate and glycodeoxycholate levels respectively mediated 10.56% and 16.22% of the effects of class Betaproteobacteria on AD.ConclusionsOur research not only supports modulating gut microbiota as a preventive measure for AD but also emphasizes the mediating roles of inflammatory factors, immune cells, and metabolites. These findings enhance our understanding of the gut-brain axis, providing new perspectives and potential targets for AD prevention.
