{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T08:42:33Z","timestamp":1777020153721,"version":"3.51.4"},"posted":{"date-parts":[[2025,6,8]]},"group-title":"Pathology","reference-count":91,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,8]],"date-time":"2025-06-08T00:00:00Z","timestamp":1749340800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>The gut microbiome modulates metabolic and neurovascular processes implicated in Alzheimer\u2019s disease and related dementias (ADRD), but the underlying mechanisms remain unclear. Here, we identify the bacterial metabolite imidazole propionate (ImP) as a modifier of ADRD pathology. In a cohort of 1,196 cognitively unimpaired adults, higher plasma ImP levels were associated with lower preclinical cognitive scores and biomarkers of ADRD, both cross-sectionally and longitudinally. Fecal metagenomic analysis linked putative ImP producers to ADRD phenotypes. Genome-wide integrative analysis revealed a locus on chromosome 12 associated with both plasma ImP levels and AD risk in humans, supporting a host genetic contribution to ImP regulation and a causal role of this metabolite in AD. In mice, chronic ImP administration exacerbated AD-like pathology. Mechanistically, ImP impaired brain endothelial barrier and promoted tau hyperphosphorylation in primary neurons, an effect blocked by glycogen synthase kinase-3\u03b2 inhibition. Together, our study links ImP to hallmarks of neurodegeneration and suggest that targeting ImP may represent a potential strategy to modify ADRD risk.<\/jats:p>","DOI":"10.1101\/2025.06.08.657719","type":"posted-content","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T03:00:38Z","timestamp":1749438038000},"source":"Crossref","is-referenced-by-count":1,"title":["Gut bacterial metabolite imidazole propionate potentiates Alzheimer\u2019s disease pathology"],"prefix":"10.64898","author":[{"given":"Vaibhav","family":"Vemuganti","sequence":"first","affiliation":[{"name":"Department of Bacteriology, University of Wisconsin-Madison; Madison, WI, USA"},{"name":"Cellular and Molecular Pathology Graduate Training Program, University of Wisconsin-Madison; Madison, WI, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jea Woo","family":"Kang","sequence":"additional","affiliation":[{"name":"Wisconsin Alzheimer\u2019s Disease Research Center, School of Medicine and Public Health, University of Wisconsin-Madison; Madison, WI, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1003-7355","authenticated-orcid":false,"given":"Qijun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Bacteriology, University of Wisconsin-Madison; Madison, WI, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric R.","family":"McGregor","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison; Madison, WI, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James R.","family":"Hilser","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, David Geffen School of Medicine of UCLA, Los Angeles, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruben","family":"Aquino-Martinez","sequence":"additional","affiliation":[{"name":"Department of Bacteriology, University of Wisconsin-Madison; 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M\u00f6lndal, Sweden"},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital; M\u00f6lndal, Sweden."},{"name":"Paris Brain Institute, ICM, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Sorbonne University; Paris, France."},{"name":"Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC; Hefei, P.R. 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