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Emerging evidence suggests that the gut microbiome may modulate neurodegeneration; however, its role as a mediator in the APOE\u2013A\u03b2 relationship remains unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Evaluate whether specific microbial taxa mediate APOE-related effects on brain A\u03b2 burden in a population-based study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study involved 227 participants from the Framingham Heart Study with stool 16S rRNA sequencing and carbon-11 Pittsburgh Compound-B imaging for A\u03b2 collected at the third examination (2016\u20132019). Associations between gut microbiota and global\/regional A\u03b2 deposition were assessed using multivariable models. We stratified participants by APOE \u03b54 status and conducted mediation analysis to evaluate whether specific taxa mediated APOE-related effects on A\u03b2. Microbial functional potential was inferred to examine enrichment of metabolic pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Higher A\u03b2 burden was significantly associated with the depletion of protective genera (e.g.,\n                      <jats:italic>Faecalibacterium, Ruminococcus, Butyricicoccus<\/jats:italic>\n                      ) and the enrichment of pro-inflammatory taxa (e.g.,\n                      <jats:italic>Alistipes<\/jats:italic>\n                      ,\n                      <jats:italic>Bacteroides<\/jats:italic>\n                      ) and\n                      <jats:italic>Barnesiella<\/jats:italic>\n                      . These associations were more pronounced in\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54 carriers, who exhibited a broader spectrum of microbial dysbiosis. Mediation analysis showed that\n                      <jats:italic>Ruminococcus<\/jats:italic>\n                      ,\n                      <jats:italic>Butyricicoccus<\/jats:italic>\n                      ,\n                      <jats:italic>Clostridium<\/jats:italic>\n                      , and\n                      <jats:italic>Christensenellaceae<\/jats:italic>\n                      collectively mediated\u2009~\u20090.3\u20130.4% of the effect of\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54 on global A\u03b2 burden. Functional profiling revealed a reduced abundance of microbial genes involved in key metabolic pathways among individuals with higher A\u03b2 levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Gut microbiome composition mediates the deleterious effect of\n                      <jats:italic>APOE<\/jats:italic>\n                      \u03b54 on cerebral amyloid deposition, suggesting that microbiome-targeted interventions may mitigate\n                      <jats:italic>APOE<\/jats:italic>\n                      -related risk.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00415-025-13412-6","type":"journal-article","created":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T08:16:21Z","timestamp":1759392981000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Altered gut microbiota mediates the association between APOE genotype and amyloid-\u03b2 accumulation in middle-aged adults"],"prefix":"10.1007","volume":"272","author":[{"given":"Yannick N.","family":"Wadop","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Bernal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wepnyu Y.","family":"Njamnshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia L.","family":"Satizabal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa","family":"Beiser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agustin","family":"Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred K.","family":"Njamnshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramachandran S.","family":"Vasan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudha","family":"Seshadri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayandra Jung","family":"Himali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8161-1553","authenticated-orcid":false,"given":"Bernard","family":"Fongang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,2]]},"reference":[{"key":"13412_CR1","doi-asserted-by":"crossref","first-page":"659","DOI":"10.3389\/fnins.2019.00659","volume":"13","author":"X-Q Chen","year":"2019","unstructured":"Chen X-Q, Mobley WC (2019) Alzheimer disease pathogenesis: insights from molecular and cellular biology studies of oligomeric A\u03b2 and tau species. 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