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Here we show thromboinflammation, a core feature of SVD, as a driver of adverse brain aging. We identify cerebrospinal fluid fibrinogen as a marker of brain thromboinflammation and screen neurovascular biosignatures mediating its impact on synaptic vulnerability along the full spectrum of brain aging from cognitively typical, amyloid-negative to cognitively impaired, amyloid-positive older adults. We identified 53 proteins mediating fibrinogen\u2019s effects on synaptic markers in 1,655 donors from three independent cohorts. Single-cell transcriptomic mapping revealed mediator enrichment in neurovascular unit cells. Pathway analysis demonstrated dysregulation of angiogenesis, fibrosis, and immune signaling. Vascular and microglial-enriched biosignatures associated with compromised white matter integrity. These findings indicate thromboinflammation as an early, amyloid-independent pathway to neurodegeneration and tauopathy, establishing vascular health as fundamental to preserving brain healthspan.<\/jats:p>","DOI":"10.1101\/2025.10.27.684881","type":"posted-content","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T23:40:17Z","timestamp":1761781217000},"source":"Crossref","is-referenced-by-count":3,"title":["A proteomic signature of vascular dysfunction linked to tauopathy and degeneration in the aging brain"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9820-9862","authenticated-orcid":false,"given":"Hannah L.","family":"Radabaugh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7725-7840","authenticated-orcid":false,"given":"Jonah N.","family":"Keller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caleb H.","family":"Radtke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Kunney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1452-1192","authenticated-orcid":false,"given":"Nikolaos","family":"Karvelas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harrison W.","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nivetha","family":"Brathaban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"Meyer-Franke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitlin","family":"Casaletto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce L.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Cruchaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel","family":"Kramer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katerina","family":"Akassoglou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7102-1608","authenticated-orcid":false,"given":"Adam R.","family":"Ferguson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4663-4992","authenticated-orcid":false,"given":"Fanny M.","family":"Elahi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025110104501016000_2025.10.27.684881v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-2667(21)00249-8"},{"key":"2025110104501016000_2025.10.27.684881v1.2","doi-asserted-by":"crossref","first-page":"2865","DOI":"10.1002\/alz.12901","article-title":"The worldwide costs of dementia in 2019","volume":"19","year":"2023","journal-title":"Alzheimers. 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