APOE4 Drives Endothelial Senescence, IFNγ–JAK/STAT Signaling, Metabolic and Barrier Impairment, Predisposing to Vascular Compromise in Alzheimer’s Disease [03-scrna-vamp]

Utilizing a single-nucleus transcriptome dataset from 1,359 extensively phenotyped human brains, we show that endothelial cells (ECs) from cognitively normal APOE4 carriers exhibit a transcriptomic signature characterized by elevated IFN-γ response and reduced oxidative phosphorylation.

Isogenic iPSC-derived APOE44 versus APOE33 ECs showed similar transcriptomic profiles, independent of neurons or glia. AD-like EC phenotypes, including a transition to upregulated oxidative phosphorylation, were induced by inflammatory cues or iPSC-APOE44 mural cells. Functionally, APOE44 ECs displayed barrier impairment, heightened inflammatory responses with increased secretion of TNFα, IL6, ICAM1, and L1CAM; L1CAM was also elevated in cerebrospinal fluid of cognitively normal APOE4 carriers.