APOE4 Linked to Potentially Reversible Mechanisms of Brain Blood Vessel Damage in Alzheimer’s

Two studies from researchers at the Icahn School of Medicine at Mount Sinai have uncovered the mechanisms by which the APOE4 gene, a known genetic risk factor for Alzheimer's disease, damages the brain's blood vessels and leads to the buildup of abnormal proteins. The findings, published in Cell and Cell Stem Cell, offer new insights and potential therapeutic strategies for protecting the brain's circulation in individuals with high genetic risk for Alzheimer's.

In the Cell study, scientists developed a single-cell transcriptomic atlas of the human brain's vasculature by combining existing datasets. This allowed them to identify that APOE4 causes pericytes, cells that stabilize small blood vessels and help maintain the blood-brain barrier, to transform into scar-forming myofibroblast-like cells.

This transformation promotes vascular fibrosis and increases amyloid accumulation around the vessels, which may compromise blood flow and promote neurodegeneration. Researchers observed that blocking TGF-β signaling, a pathway involved in cellular communication and tissue remodeling, could restore pericyte coverage and reduce both fibrosis and vascular amyloid, demonstrating the potential for reversing APOE4-associated cerebrovascular degeneration.

In the Cell Stem Cell study, researchers used miBrains, 3D human brain tissues developed in the Mount Sinai lab, to investigate how APOE4 promotes abnormal protein build-up in diseases like Alzheimer's and Parkinson's. APOE4 causes cholesterol to accumulate in astrocytes, impairing their lysosomal waste-disposal system and reducing their ability to break down alpha-synuclein, the protein associated with Lewy body dementia and Parkinson's disease.

This leads to protein aggregation and spread to neurons, resulting in harmful protein deposits. The study highlights cholesterol metabolism in astrocytes and lysosomal function as promising therapeutic targets for Alzheimer's and Parkinson's disease. Mount Sinai Assistant Professor Louise Mesentier-Louro, PhD, led the study and emphasized the potential of miBrains for reproducible, scalable disease modeling and efficient drug development.