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Background <p>The apolipoprotein E (<i>APOE</i>) ε4 allele is the strongest genetic risk factor for Alzheimer’s disease, yet the mechanisms linking <i>APOE</i> 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.</p> Objective <p>Evaluate whether specific microbial taxa mediate APOE-related effects on brain Aβ burden in a population-based study.</p> Methods <p>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.</p> Results <p>Higher Aβ burden was significantly associated with the depletion of protective genera (e.g., <i>Faecalibacterium, Ruminococcus, Butyricicoccus</i>) and the enrichment of pro-inflammatory taxa (e.g., <i>Alistipes</i>, <i>Bacteroides</i>) and <i>Barnesiella</i>. These associations were more pronounced in <i>APOE</i> ε4 carriers, who exhibited a broader spectrum of microbial dysbiosis. Mediation analysis showed that <i>Ruminococcus</i>, <i>Butyricicoccus</i>, <i>Clostridium</i>, and <i>Christensenellaceae</i> collectively mediated ~ 0.3–0.4% of the effect of <i>APOE</i> 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.</p> Conclusion <p>Gut microbiome composition mediates the deleterious effect of <i>APOE</i> ε4 on cerebral amyloid deposition, suggesting that microbiome-targeted interventions may mitigate <i>APOE</i>-related risk.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月2日

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  • Yannick N. Wadop,
  • Rebecca Bernal,
  • Wepnyu Y. Njamnshi,
  • Claudia L. Satizabal,
  • Alexa Beiser,
  • Agustin Ruiz,
  • Alfred K. Njamnshi,
  • Ramachandran S. Vasan,
  • Sudha Seshadri,
  • Jayandra Jung Himali,
  • Bernard Fongang

摘要

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.