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A proteomic signature of vascular dysfunction linked to tauopathy and degeneration in the aging brain

Radabaugh, H. L.; Keller, J. N.; Radtke, C. H.; Kunney, C.; Karvelas, N.; Chan, H. W.; Brathaban, N.; Meyer-Franke, A.; Casaletto, K.; Zetterberg, H.; Miller, B. L.; Cruchaga, C.; Kramer, J.; Akassoglou, K.; Ferguson, A. R.; Elahi, F. M.

2025-10-29 neuroscience
10.1101/2025.10.27.684881 bioRxiv
Show abstract

Small vessel disease (SVD) impacts healthy aging of organs across the body, yet its contributions to adverse brain aging remain poorly defined. 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 fibrinogens 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.

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