Fibronectin mediates APOE4-driven blood-brain barrier dysfunction in Alzheimer's disease.

Blood-brain barrier (BBB) dysfunction is an early feature of Alzheimer's disease (AD) and is particularly pronounced in individuals carrying the APOE ε4 allele, but the mechanisms linking APOE ε4 to BBB failure remain unclear. Here we show that astrocyte-derived fibronectin (FN1) is a key mediator of apolipoprotein E4 (APOE4)-driven BBB dysfunction in AD. Using postmortem human brain tissue, human three-dimensional vascular models and in vivo models, we demonstrate that APOE4, amyloid-β42 and inflammatory signals induce astrocytic FN1 upregulation and excessive perivascular deposition. Fibronectin accumulation is sufficient to cause BBB leakage and disrupt VEGF/HB-EGF/IGF-1 signaling through integrin-mediated focal adhesion kinase activity. Reducing fibronectin or restoring growth factor signaling rescues BBB function in vitro and in vivo. Together, evidence from experimental models, human brain tissue and clinical datasets identifies fibronectin as a proximal mediator of APOE4-driven gliovascular dysfunction and highlights FN1 as a potential therapeutic target for vascular and BBB dysfunction in AD.