Alzheimer’s disease as the leading cause of dementia has become a growing epidemic in our aging society. While aging promotes AD development, a gene called apolipoprotein E (APOE) is the strongest genetic risk factor for AD. The goal of our study is to address how a specific gene variant called APOE4 drives up the risk, and how we can target this protein for the development of new therapy. Interestingly, APOE is present not just in the brain, but also at a high concentration in the blood produced primarily by the liver to transport cholesterol and other lipids among different organs. In addition to AD, individuals carrying the APOE4 gene also are at a greater risk of developing hypercholesterolemia and atherosclerosis compared with those carrying the APOE3 gene. Using a new set of animal models and blood transfusion studies, we have shown that blood APOE4 impairs brain functions and increases AD pathology by injuring blood vessels, whereas blood APOE2 and APOE3 have beneficial effects on brain functions. In addition, a recent finding identified a mutant form of APOE (named Christchurch) that can protect an individual from neurodegeneration and AD development. Our hypothesis is that changing a person’s APOE form from toxic APOE4 to APOE2 (or protective APOE variants) will benefit brain functions and reduce AD pathologies. This will be pursued on two tracks: firstly, we will test whether delivery of APOE2, APOE3 or protective APOE variants into APOE4 Alzheimer’s animals through peripheral bloodstream can improve inflammatory responses, blood vessel integrity, memory performance and AD-related pathways, including the clearance of amyloid beta, which forms the amyloid plaques thought to be the central driver of AD development. Secondly, we will examine how delivery of APOE2, APOE3 or protective APOE variants directly into the brain of APOE4 Alzheimer’s mice impacts brain functions and AD-related pathways. Our findings not only will inform strategies to target APOE4, but also will explore an opportunity to treat AD in an individualized manner through precision medicine.