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Across multiple cohorts, we demonstrated that plasma GDF15 is associated with greater dementia risk over 15-to 25-year follow-up periods when measured in midlife, with stronger associations observed for vascular dementia compared to Alzheimer\u2019s disease (AD). Two-sample Mendelian randomization supported plasma GDF15\u2019s mechanistic role in AD and related dementias, while cohort studies linked it to cerebral small vessel disease, diffuse neurodegeneration, phosphorylated tau, and a cerebrospinal fluid proteomic signature indicative of neuro-immune activation. Exposure of cultured myeloid cells to recombinant GDF15 altered biological pathways that we subsequently demonstrated are predictive of dementia risk, including interferon\/antiviral responses, pyruvate metabolism, and scavenging of heme. These findings support circulating GDF15\u2019s role as an early biomarker \u2013 particularly for vascular dementia and neuroinflammation \u2013 and identify the mechanisms by which it may drive dementia risk.<\/jats:p>","DOI":"10.1101\/2025.07.18.25331297","type":"posted-content","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T00:15:24Z","timestamp":1753143324000},"source":"Crossref","is-referenced-by-count":2,"title":["Plasma GDF15 affects long-term dementia risk and alters neuro-immune signaling"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9840-5298","authenticated-orcid":false,"given":"Cassandra O.","family":"Blew","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1029-4423","authenticated-orcid":false,"given":"Michael 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