Reversible hypervascularization drives cognitive decline and blood-brain barrier damage during aging

Todorov, M. I.; Todorov-Völgyi, K.; Minde, D.-P.; Kapoor, S.; Ali, M.; Malik, R.; Paetzold, J. C.; McGinnis, J.; Zhang, L.; Nottebrock, A.; Liu, L.; Simons, M.; Singh Bhatia, H.; Georgakis, M. K.; Dichgans, M.; Hellal, F.; Ertürk, A.

doi:10.64898/2026.05.04.720441

bioRxiv · 10.64898/2026.05.04.720441

Reversible hypervascularization drives cognitive decline and blood-brain barrier damage during aging

Todorov, M. I.·Todorov-Völgyi, K.·Minde, D.-P.·Kapoor, S.·Ali, M.·Malik, R.·Paetzold, J. C.·McGinnis, J.·Zhang, L.·Nottebrock, A.·Liu, L.·Simons, M.·Singh Bhatia, H.·Georgakis, M. K.·Dichgans, M.·Hellal, F.·Ertürk, A.

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Abstract

Cerebrovascular dysfunction emerges early in neurodegeneration, yet how vascular structure, blood-brain barrier (BBB) failure, and cognition are linked remains undefined. Using VesselPro, a whole-brain pipeline integrating perfusion-resolved 3D imaging with spatial proteomics, we mapped vascular aging across the mouse lifespan. We identify two discrete trajectories: a hypovascular state and a previously unrecognized hyper-vascular, BBB-compromised state, defined relative to a young-adult vascular baseline. The hyper-vascular trajectory, concentrated in the cortex and hippocampus, was associated with marked spatial memory impairment and pervasive BBB leakage. Spatial proteomics revealed a coordinated program involving angiogenic activation, endothelial stress, cytoskeletal remodeling, and inflammatory signaling. Cross-species comparison with human proteomic biomarkers from the UK Biobank showed strong alignment between the mouse hypervascular signature and vascular dementia risk, but minimal concordance with Alzheimers disease, defining a vascular-specific dementia endotype. Transient Tie2 activation with AKB-9778 attenuated this trajectory, improving vessel organization, BBB integrity, and memory performance. Our findings show that endothelial instability is a key mechanistic driver of this heterogeneous vascular aging state. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/720441v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@39494aorg.highwire.dtl.DTLVardef@faa4acorg.highwire.dtl.DTLVardef@1511dd5org.highwire.dtl.DTLVardef@7db29b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIVesselPro: we developed a pipeline for capturing perfused blood vessels in the brain: unexpected bifurcation in vascular aging: traditional hypovascular state and a novel, hypervascular, BBB-compromised state. C_LIO_LIHypervascular pathology: Linked the hypervascular profile in the cortex and hippocampus to spatial memory impairment, pervasive BBB leakage, and angiogenic inflammatory signaling. C_LIO_LIClinical endotype: Cross-species analysis via the UK Biobank confirms this hypervascular signature aligns with vascular dementia risk rather than Alzheimers disease. C_LIO_LIPharmacological stabilization: Demonstrated that Tie2 signaling activation (AKB-9778) improves the vessel organization, BBB integrity, and memory performance. C_LI

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Todorov, M. I., Todorov-Völgyi, K., Minde, D.-P., Kapoor, S., Ali, M., Malik, R., Paetzold, J. C., McGinnis, J., Zhang, L., Nottebrock, A., Liu, L., Simons, M., Singh Bhatia, H., Georgakis, M. K., Dichgans, M., Hellal, F., Ertürk, A.. 2026-05-06. Reversible hypervascularization drives cognitive decline and blood-brain barrier damage during aging. https://doi.org/10.64898/2026.05.04.720441

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