Utilizing an innovative multi-omics approach integrating bulk RNA sequencing data from human BMECs with proteomic analyses of cerebrospinal fluid (CSF) from AD patients and cerebrovascular endothelial extracellular vesicles (CEEVs), we identified Endoglin (ENG), a transmembrane protein, as a critical endothelial cell-specific regulator of astrocyte reactivity. This evidence concerns the gene ENG and Alzheimer disease.