Oral Microbiota and Alzheimer's Disease: A Bidirectional Mendelian Randomization Study Based on East Asian Ethnicity

The "oral-microbiota-brain axis" has been hypothesized to contribute to Alzheimer's disease (AD) pathogenesis, but causal evidence remains limited. We performed a bidirectional Mendelian randomization (MR) study to investigate potential genetic causality between oral microbiota and AD in East Asians.

Two-sample MR integrated genome-wide data from 2984 Chinese participants (saliva/tongue dorsum microbiomes) and 7036 Japanese participants (3962 AD cases/4074 controls). Genetic instruments were selected using pragmatically moderated significance thresholds (forward: p < 5 × 10^-4; reverse: p < 5 × 10^-5), with causality assessed via inverse-variance weighted (IVW) regression and four Supporting methods. Sensitivity analyses validated robustness. We examined 3117 microbial taxa-AD pairs, followed by exploratory Gene Ontology (GO) enrichment analysis.

Forward MR identified 12 candidate causal taxa: five with risk-increasing associations (e.g., Prevotella sp. MGS2526, OR = 1.32 [1.14-1.52], p = 1.4 × 10^-4) and seven with protective associations (e.g., Streptococcus mitis MGS519, OR = 0.81 [0.69-0.94], p = 7.9 × 10^-3). Reverse MR suggested AD may influence the abundance of three microbial species (e.g., Streptococcus sanguinis MGS515, OR = 1.04 [1.01-1.07], p = 3.6 × 10^-3). Exploratory GO analysis highlighted enrichment in pathways related to synaptic transmission and nutrient metabolism.

This study provides genetic evidence consistent with a bidirectional relationship between oral microbiota and AD in East Asians, nominating 15 microbial taxa as candidates for further investigation. The implicated biological pathways offer hypotheses for mechanistic links via the oral-microbiota-brain axis. These findings advance the etiological understanding of AD and highlight priority targets for future experimental and clinical validation.