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

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 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. Graphical abstract Highlights VesselPro : 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 . Hypervascular pathology : Linked the hypervascular profile in the cortex and hippocampus to spatial memory impairment, pervasive BBB leakage , and angiogenic inflammatory signaling . Clinical endotype : Cross-species analysis via the UK Biobank confirms this hypervascular signature aligns with vascular dementia risk rather than Alzheimer’s disease. Pharmacological stabilization : Demonstrated that Tie2 signaling activation (AKB-9778) improves the vessel organization, BBB integrity, and memory performance.