Alzheimer’s disease (AD) is the leading cause of dementia, with apolipoprotein E (APOE) being the strongest genetic risk factor. Our project, part of the APOE Consortium, is to define how the APOE2 gene and two other APOE genetic variants—Christchurch (APOE-Ch) and Jacksonville (APOE-Jac)—protect against AD-like outcomes such as amyloid beta accumulation and vascular impairment. Because APOE protein 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, we aim to assess how APOE in the blood or brain contributes to its effects on AD pathways. 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 neutral or beneficial effects on brain functions. Our hypothesis is that enhancing a person’s APOE amount with the protective forms, such as APOE2, APOE-Ch or APOE-Jac, will benefit brain functions and reduce AD pathologies. This will be pursued on two tracks: firstly, we will test whether delivery of APOE2, APOE3, APOE3-Ch or APOE3-Jac into Alzheimer’s animals through peripheral bloodstream can reduce amyloid and other AD-related harmful effects. Secondly, we will examine these effects upon delivery of these APOE forms directly into the brain of Alzheimer’s mice. During the first year of our supported research, we have made significant progress toward our original goals: we found that when delivered to the bloodstream, APOE4 worsens brain amyloid and increases toxicity compared with APOE3, likely by impairing blood vessel function. Next, we found that expressing the APOE-Jac protective variant in the brain reduces brain amyloid beta load and eases the related toxicity. Finally, we found that the APOE-Ch protective variant expressed in human cells has reduced binding to a key cell surface molecule called heparin, suggesting a potential protective mechanism. Our efforts also include building the animal cohorts to carry out the additional in vivo studies as planned, as well as exchanging ideas and collaborating with other APOE consortium projects. Successful completion of our proposed studies should provide mechanistic guidance on how to target the beneficial effects of “good” forms of APOE to treat or cure AD.
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.