Exploring causal gut-brain axes in Alzheimer's disease using mediation Mendelian randomization analysis

Background Alzheimer's disease (AD) is a progressive neurodegenerative condition with unclear etiology. Recent studies suggest gut microbiota may be involved in AD pathogenesis through imbalances that increase intestinal permeability, affect blood-brain barrier function, and promote neuroinflammation. However, observational studies are susceptible to confounding biases and reverse causality. Objective This study aimed to explore causal relationships between gut microbiota, brain imaging-derived phenotypes (IDPs), and AD using mediation Mendelian randomization analysis to identify specific gut-brain axes involved in AD mechanisms. Methods We conducted a three-phase Mendelian randomization analysis using large-scale genome-wide association study (GWAS) data. Phase 1 analyzed causal effects of 412 gut microbiota on AD. Phase 2 examined causal effects of 920 IDPs on AD. Phase 3 performed mediation analysis to understand the role of IDPs in the gut microbiota-AD pathway. Data sources included Dutch population study (7738 individuals), MiBioGen consortium (18,340 individuals), UK Biobank brain imaging (8428 samples), and AD GWAS dataset (487,511 participants). Inverse variance weighted method was the primary analysis approach. Results We identified 12 gut microbiota metabolic pathways and 32 gut microbiota species causally related to AD, plus 29 IDPs with potential causal relationships to AD. Mediation analysis revealed four distinct gut-brain axes: genus Butyrivibrio-brain stem-AD, genus Lachnospiraceae-brain stem-AD, PEPTIDOGLYCANSYN pathway-L1 External capsule Left-AD, and TCA cycle pathway-L1 External capsule Left-AD. Conclusions This study identified four specific gut microbiota-brain structure axes causally involved in AD mechanisms, providing novel insights for understanding the gut-brain axis role in AD pathogenesis and potential therapeutic targets.