Defining and Targeting Mechanisms of APOE4 Cerebrovascular Dysfunction and Amyloid Accumulation in Alzheimer’s Disease

Dr. Blanchard is investigating how APOE4, the strongest genetic risk factor for late-onset Alzheimer’s disease, damages the brain’s blood vessels and promotes the buildup of amyloid beta around them. Although APOE4 has long been associated with Alzheimer’s disease and vascular dysfunction, the biological mechanisms linking them remain poorly understood. Dr. Blanchard’s previous research revealed that APOE4 increases signaling by a molecule called TGFβ. This heightened signaling causes pericytes, cells that normally support and protect the brain’s smallest blood vessels, to adopt a harmful new identity resembling scar-forming cells. These altered cells produce excess material around the blood vessels, trapping amyloid beta and potentially contributing to vascular damage and neurodegeneration. This project will determine when and how this disease process can be therapeutically interrupted. First, Dr. Blanchard and his team will identify the signals through which APOE4 activates TGFβ. Targeting an earlier step in this pathway could avoid the risks of blocking TGFβ itself, which performs many essential functions throughout the body. Second, the team will determine how the altered vascular cells trap amyloid beta. They will then develop peptides and antibodies designed to disrupt these interactions and reduce amyloid accumulation around the brain’s blood vessels. Together, these studies could reveal new therapeutic strategies for protecting the brain’s vasculature and slowing Alzheimer’s disease in people who carry APOE4.