The Effects of Peripheral APOE2 on Alzheimer’s Disease Pathology and Pathways

This project aims to evaluate how peripheral APOE2, which is protective against Alzheimer’s disease risk, impacts brain neuropathology and pathways to inform therapeutic strategies.

Despite encouraging news on anti-amyloid drugs, researchers are still far from developing safe and effective therapies to prevent or cure Alzheimer’s disease. The APOE gene is a strong risk factor, with APOE4 increasing and APOE2 reducing risk. This project will study the protective effect of APOE2 using new model systems and advanced technologies. These studies will address how APOE2 in the blood affects brain cognition and Alzheimer’s disease pathology.

Outcomes from these studies should provide new knowledge on how different forms of APOE affect Alzheimer’s disease and how APOE expressed in the periphery affects brain function and neuropathology. More importantly, the study outcomes will guide us to design APOE-targeted therapies to delay the onset or slow the progression of Alzheimer’s disease.

The APOE gene is the strongest genetic risk factor for Alzheimer’s disease. Despite progress on learning how APOE4 increases risk, we have limited knowledge on why APOE2 is protective compared to the common form APOE3. As such, studying the effects of APOE2 on Alzheimer’s neuropathology and neurobehaviors is highly innovative. Another unique aspect of our study is to understand the effects of peripheral APOE on brain cognition and pathology through brain vasculature as APOE-targeted therapies will likely affects both circulating and brain APOE.

Upon completion of our study, we will gain new knowledge on how different forms of APOE have different effects on Alzheimer’s disease and how APOE expressed in the periphery populating circulating blood affects brain function and neuropathology. More importantly, the study outcomes will guide us to design APOE-targeted therapies to delay the onset or slow the progression of Alzheimer’s disease. Our eventual goal is to prevent or cure Alzheimer’s disease by targeting multiple targets and pathways including amyloids and APOE.