This study investigates the transcriptomic mechanisms responsible for impaired angiogenesis and blood-brain barrier (BBB) function in Alzheimer's disease (AD). Single-nucleus RNA sequencing of vascular cells from AD and non-diseased control brains reveals that endothelial cells (EC) are enriched for genes associated with AD susceptibility. Increased β-amyloid (Aβ) levels are linked to BBB impairment and dysfunctional angiogenic responses, characterized by reduced VEGFA signaling in EC. This is accompanied by vascular inflammatory activation, EC senescence, and apoptosis. The analysis of genomic signatures of vascular cell risk genes suggests that EC pathology plays a crucial role in AD and that reducing vascular inflammatory activation and restoring effective angiogenesis could mitigate vascular dysfunction contributing to early AD progression. The study provides a comprehensive transcriptomic characterization of how increased Aβ levels impair perfusion, reduce vascular clearance, disrupt adaptive angiogenesis, and lead to BBB integrity loss.This study investigates the transcriptomic mechanisms responsible for impaired angiogenesis and blood-brain barrier (BBB) function in Alzheimer's disease (AD). Single-nucleus RNA sequencing of vascular cells from AD and non-diseased control brains reveals that endothelial cells (EC) are enriched for genes associated with AD susceptibility. Increased β-amyloid (Aβ) levels are linked to BBB impairment and dysfunctional angiogenic responses, characterized by reduced VEGFA signaling in EC. This is accompanied by vascular inflammatory activation, EC senescence, and apoptosis. The analysis of genomic signatures of vascular cell risk genes suggests that EC pathology plays a crucial role in AD and that reducing vascular inflammatory activation and restoring effective angiogenesis could mitigate vascular dysfunction contributing to early AD progression. The study provides a comprehensive transcriptomic characterization of how increased Aβ levels impair perfusion, reduce vascular clearance, disrupt adaptive angiogenesis, and lead to BBB integrity loss.