We aim to identify and prioritize repurposable drugs that normalize endothelial signaling as potential new treatments for Alzheimer disease (AD).

Brain endothelial dysfunction is an early and predominant feature in AD which contributes to the onset and progression of amyloid and tau pathologies. Endothelial pathways are among the most differentially expressed in AD brains. The brain endothelium plays important roles in glycocalyx integrity, blood-brain barrier stability, immune function and synaptic signaling.

We performed a literature-driven curation of endothelial pathways implicated in AD and mapped druggable nodes specifically along the VE-cadherin (CDH5) junctional axis and VEGFR signaling. For VEGFR, we prepared AutoDock Vina/GNINA docking pipelines targeting the ATP site and calibrated parameters using reference tyrosine-kinase inhibitors that reproduce the canonical hinge-binding pose; protein–ligand contacts were examined with PLIP. For CDH5, we evaluated pathway-level modulators that stabilize CDH5 and summarized repurposing candidates. Candidate drugs were compiled from clinical trials and pharmacology databases.

: Curation of endothelial pathways in AD highlighted two actionable axes: VE-cadherin (CDH5) junctional stability and VEGFR signaling. For CDH5, candidate mechanisms include Tie2 activation (e.g., VE-PTP inhibition) to strengthen Ang/Tie2 signaling at endothelial contacts; S1PR1 agonism to drive Rac1/cortactin–mediated cortical actin assembly and support junctional retention; RhoA/ROCK pathway inhibition to reduce contractility-induced junction opening; and metalloproteinase suppression to curb ADAM/MMP-driven CDH5 shedding. Across these levers, the common readout is enhanced barrier integrity and reduced paracellular permeability, nominating them as repurposing avenues to stabilize the brain endothelium. For VEGFR, we identified agents that blunt VEGF-driven endothelial permeability and aberrant angiogenic signaling. These include approved VEGFR tyrosine-kinase inhibitors and VEGF/VEGFR-directed biologics as pharmacologic handles to attenuate downstream MAPK/ERK and PI3K/AKT signaling linked to increased vascular permeability.