Researchers identify potentially reversible mechanisms of APOE4-driven neurodegeneration

Mount Sinai scientists have identified how the APOE4 gene damages brain blood vessels and impairs removal of toxic proteins, mechanisms that appear reversible in experimental settings. The studies used a novel stem cell-derived human brain tissue platform to map how APOE4 disrupts vascular cells called pericytes that normally stabilize blood vessels. These findings open new therapeutic avenues for treating Alzheimer's, Parkinson's, and related neurodegenerative conditions.

Scientists have long observed that blood vessel deterioration occurs in Alzheimer's patients, particularly those carrying the APOE4 variant. However, researchers previously treated this vascular damage as a secondary effect rather than a primary driver of neurodegeneration. The Mount Sinai team's work reframes this understanding by demonstrating that APOE4 actively initiates a cellular conversion process, transforming pericytes—support cells crucial for vessel stability—into scar-tissue-producing cells.

The research employed a novel experimental approach using stem cell-derived human brain tissue, which allowed scientists to observe these cellular changes in a system more closely resembling actual human biology than traditional models. By blocking a specific cellular signaling pathway called TGF-β, researchers successfully reversed the damaging transformation in both laboratory settings and in aged mice, suggesting that therapeutic intervention at this stage may be feasible.