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.