Although extensive observational evidence has established a connection between Alzheimer’s disease (AD) and the gut microbiota (GM), the direction of causality in this association remains unclear. To elucidate whether AD and GM are causally associated, we employed a two-sample Mendelian randomization (TSMR) analysis via publicly available summary data acquired through genome-wide association studies (GWAS).

We leveraged a single-nucleotide polymorphism (SNP) set that did not fulfill genome-wide significance as instrumental variables in two distinct MR analyses. Subsequently, we conducted gene set enrichment analysis to explore variation within gene sets associated with the identified SNPs and their corresponding signaling pathways. Finally, single-cell analysis was employed to determine immune cell infiltration and gene expression patterns in AD.

The findings of our study revealed causal effects of GM components on AD risk. Specifically, the Desulfovibrionaceae and Desulfovibrionales families may be potentially linked to an elevated AD risk, while Ruminococcus was related to a reduced risk. Furthermore, SNP-related genetic variants within PROCR, EDEM2, and TRPC4AP genes may hold significant implications for AD development.

Our results suggest that specific components of the GM exert either beneficial or detrimental causal effects on the risk of developing AD.