A step toward treating Alzheimer's: Discovery of the mechanism that damages the brain

Researchers at Mount Sinai in New York have identified a biological mechanism by which the APOE4 gene variant, a major risk factor for Alzheimer's, causes scarring of blood vessels in the brain and accumulation of harmful proteins. In laboratory experiments and mouse models, the researchers were able to inhibit the process by blocking the TGF-β pathway. The findings may open new treatment avenues but have not yet been tested in humans.

Researchers at the Icahn School of Medicine at Mount Sinai in New York have identified a biological mechanism that may explain how the APOE4 gene variant, the most significant genetic risk factor for common Alzheimer's disease, damages blood vessels in the brain. The findings, reported in two studies, show that APOE4 can cause cells supporting small blood vessels in the brain to transform into cells that promote scar tissue formation. This process leads to scarring around blood vessels and increased accumulation of amyloid, a protein whose buildup is linked to Alzheimer's. The researchers identified a biological pathway called TGF-β involved in the scarring process, and when they blocked its activity in experimental models and in aged mice carrying APOE4, they succeeded in reducing scarring and amyloid accumulation. In another study, using three-dimensional human brain tissue from stem cells, it was found that APOE4 may lead to cholesterol accumulation in support cells in the brain, thereby impairing their ability to break down harmful proteins. However, the studies are preclinical, and no effective treatment has yet been tested in Alzheimer's patients. Identifying these processes may open new research directions, but further studies are needed to examine the safety and efficacy of intervention in humans.