{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:48:14Z","timestamp":1782280094573,"version":"3.54.5"},"posted":{"date-parts":[[2025,7,31]]},"group-title":"Neuroscience","reference-count":84,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>\n                    The apolipoprotein E (\n                    <jats:italic>APOE<\/jats:italic>\n                    ) \u03b54 allele is the strongest genetic risk factor for Alzheimer\u2019s disease (AD), yet the mechanisms linking\n                    <jats:italic>APOE<\/jats:italic>\n                    to amyloid-\u03b2 (A\u03b2) pathology remain incompletely understood. 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>To evaluate whether specific microbial taxa mediate APOE-related effects on brain A\u03b2 burden in an established population-based study of middle-aged adults.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Design, Setting, and Participants<\/jats:title>\n                  <jats:p>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 \u00b1 8.3), between 2016 and 2019.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Exposures<\/jats:title>\n                  <jats:p>\n                    Gut bacterial DNA was sequenced using 16S rRNA, and amplicon sequence variants (ASVs) were agglomerated at various taxonomic levels (14 phyla, 70 families, and \u223c140 genera).\n                    <jats:italic>APOE<\/jats:italic>\n                    genotypes were derived from blood DNA using PCR and restriction isotyping. Predicted microbial functional potential was based on KEGG Orthologs.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Main Outcomes and Measures<\/jats:title>\n                  <jats:p>\n                    Overall and regional measures of cerebral amyloid-\u03b2 deposition were assessed using carbon-11 Pittsburgh (PiB) Compound-B PET scans. The global PiB deposition served as the primary outcome for \u201c\n                    <jats:italic>overall<\/jats:italic>\n                    \u201d amyloid burden. Regional amyloid deposition values were analyzed as secondary outcomes.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    A higher A\u03b2 burden was significantly associated with the depletion of protective genera (e.g.,\n                    <jats:italic>Faecalibacterium<\/jats:italic>\n                    \u03b2 [95%CI],-0.35 [-0.40,-0.30];\n                    <jats:italic>Ruminococcus<\/jats:italic>\n                    -0.25 [-0.27,-0.23];\n                    <jats:italic>Butyricicoccus<\/jats:italic>\n                    -0.27 [-0.32,-0.22]) and the enrichment of pro-inflammatory taxa (e.g.,\n                    <jats:italic>Alistipes<\/jats:italic>\n                    0.07 [0.06, 0.08],\n                    <jats:italic>Bacteroides<\/jats:italic>\n                    0.10 [0.07, 0.13]) and\n                    <jats:italic>Barnesiella<\/jats:italic>\n                    (0.18 [0.16, 0.20]). 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 \u223c0.3-0.4% 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 and Relevance<\/jats:title>\n                  <jats:p>\n                    Gut microbiome composition partially mediates the relationship between\n                    <jats:italic>APOE<\/jats:italic>\n                    \u03b54 and cerebral amyloid burden. These findings support a gut-brain axis mechanism in AD and suggest that microbiome-targeted interventions may mitigate\n                    <jats:italic>APOE<\/jats:italic>\n                    -related risk.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.27.667048","type":"posted-content","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T19:05:18Z","timestamp":1753988718000},"source":"Crossref","is-referenced-by-count":1,"title":["Altered Gut Microbiota Mediates the Association between APOE Genotype and Amyloid-\u03b2 Accumulation in Middle-Aged Adults"],"prefix":"10.64898","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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1115-4430","authenticated-orcid":false,"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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0052-1511","authenticated-orcid":false,"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":"54368","reference":[{"key":"2025080203500996000_2025.07.27.667048v1.1","doi-asserted-by":"crossref","unstructured":"Chen, X.-Q. & Mobley, W. 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