APOE Proteoforms in Human CNS and Validation of APOE Pharmacodynamic Translational Markers

APOE is the single greatest risk factor for Alzheimer’s disease and causes up to half of all AD. The reasons for this genetic risk factor are uncertain, but there are several key ways APOE could cause AD. This includes different kinds, function, stability or amounts of APOE causing increased risk of amyloidosis and neurodegeneration. However, until recently, it has been challenging to accurately compare the amounts and kinds of different forms of APOE (there are three common forms called APOE2, APOE3 and APOE4). The first part of this study will determine the amounts and structure, including fragments, of each APOE form in the brain, cerebrospinal fluid and blood samples from AD and control participants. We will assess which kinds of APOE exist and whether there are specific forms associated with AD. The second part of this study will use these measurement techniques in mouse models to develop drug-specific biomarkers that then could be used in human clinical trials to determine whether a drug targeting APOE is working.