(@apadivision40.bsky.social)

Reversible hypervascularization drives cognitive decline and blood-brain barrier damage during aging 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 Alzheimer’s 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. ![Figure][1]</img> Highlights ### Competing Interest Statement A.E. is a co-founder of Deep Piction. The other authors declare no competing interests. Fondation Leducq, 22CVD01 ERA-NET Neuron, MatriSVDs ERC Consolidator Grant, GA 865323 Nomis Heart Atlas Project Grant CRC 1744, ID 548585053 Munich Cluster for Systems Neurology, ID 390857198 [1]: pending:yes https://www.biorxiv.org/content/10.64898/2026.05.04.720441v1