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.

doi:10.1101/2025.10.27.684881

bioRxiv · 10.1101/2025.10.27.684881

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.

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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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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. A proteomic signature of vascular dysfunction linked to tauopathy and degeneration in the aging brain. https://doi.org/10.1101/2025.10.27.684881

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