Altered gut microbiota mediates the association between APOE genotype and amyloid-β accumulation in middle-aged adults

BACKGROUND: The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer's disease, yet the mechanisms linking APOE to amyloid-β (Aβ) pathology remain incompletely understood. Emerging evidence suggests that the gut microbiome may modulate neurodegeneration; however, its role as a mediator in the APOE-Aβ relationship remains unclear. OBJECTIVE: Evaluate whether specific microbial taxa mediate APOE-related effects on brain Aβ burden in a population-based study. METHODS: This study involved 227 participants from the Framingham Heart Study with stool 16S rRNA sequencing and carbon-11 Pittsburgh Compound-B imaging for Aβ collected at the third examination (2016-2019). Associations between gut microbiota and global/regional Aβ deposition were assessed using multivariable models. We stratified participants by APOE ε4 status and conducted mediation analysis to evaluate whether specific taxa mediated APOE-related effects on Aβ. Microbial functional potential was inferred to examine enrichment of metabolic pathways. RESULTS: Higher Aβ burden was significantly associated with the depletion of protective genera (e.g., Faecalibacterium, Ruminococcus, Butyricicoccus) and the enrichment of pro-inflammatory taxa (e.g., Alistipes, Bacteroides) and Barnesiella. These associations were more pronounced in APOE ε4 carriers, who exhibited a broader spectrum of microbial dysbiosis. Mediation analysis showed that Ruminococcus, Butyricicoccus, Clostridium, and Christensenellaceae collectively mediated ~ 0.3-0.4% of the effect of APOE ε4 on global Aβ burden. Functional profiling revealed a reduced abundance of microbial genes involved in key metabolic pathways among individuals with higher Aβ levels. CONCLUSION: Gut microbiome composition mediates the deleterious effect of APOE ε4 on cerebral amyloid deposition, suggesting that microbiome-targeted interventions may mitigate APOE-related risk.