Brain HealthAPOE4 Triggers Brain Blood Vessel Scarring — and TGF-β Inhibition May Reverse It
Researchers at Mount Sinai have discovered a key mechanism explaining why the APOE4 gene — the strongest genetic risk factor for Alzheimer's disease — damages brain blood vessels. Using single-cell analysis of human brain tissue, they found that APOE4 causes pericytes (cells that maintain blood vessel integrity) to transform into scar-forming myofibroblasts. These rogue cells secrete fibronectin, a protein that promotes vascular amyloid buildup and fibrosis. The culprit driving this cellular transformation is overactive TGF-β signaling. Critically, when TGF-β was inhibited, pericyte coverage was restored and vascular fibrosis and amyloid levels dropped to those seen in non-APOE4 carriers. This reveals a concrete, druggable pathway connecting APOE4 to cerebrovascular degeneration and opens a new therapeutic avenue for Alzheimer's prevention.
