Altered Gut Microbiota Mediates the Association between APOE Genotype and Amyloid-β Accumulation in Middle-Aged
Importance:
The apolipoprotein E ( APOE ) ε4 allele is the strongest genetic risk factor for Alzheimer's disease (AD), 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:
To evaluate whether specific microbial taxa mediate APOE-related effects on brain Aβ burden in an established population-based study of middle-aged adults.
Design Setting And Participants:
This cross-sectional study analyzed data from the Framingham Heart Study cohort. Data were collected at the third examination visit (n = 227, %Female = 58, mean age = 56.5 ± 8.3), between 2016 and 2019.
Exposures:
Gut bacterial DNA was sequenced using 16S rRNA, and amplicon sequence variants (ASVs) were agglomerated at various taxonomic levels (14 phyla, 70 families, and ∼140 genera). APOE genotypes were derived from blood DNA using PCR and restriction isotyping. Predicted microbial functional potential was based on KEGG Orthologs.
Main Outcomes And Measures:
Overall and regional measures of cerebral amyloid-β deposition were assessed using carbon-11 Pittsburgh (PiB) Compound-B PET scans. The global PiB deposition served as the primary outcome for " overall " amyloid burden. Regional amyloid deposition values were analyzed as secondary outcomes.
Results:
A higher Aβ burden was significantly associated with the depletion of protective genera (e.g., Faecalibacterium β [95%CI],-0.35 [-0.40,-0.30]; Ruminococcus -0.25 [-0.27,-0.23]; Butyricicoccus -0.27 [-0.32,-0.22]) and the enrichment of pro-inflammatory taxa (e.g., Alistipes 0.07 [0.06, 0.08], Bacteroides 0.10 [0.07, 0.13]) and Barnesiella (0.18 [0.16, 0.20]). 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 And Relevance:
Gut microbiome composition partially mediates the relationship between APOE ε4 and cerebral amyloid burden. These findings support a gut-brain axis mechanism in AD and suggest that microbiome-targeted interventions may mitigate APOE -related risk.
