Alzheimer's disease affects 5 million Americans and is increasing in prevalence and economic impact. Existing drugs do little to limit the disease process and no preventive therapies are known. It is known that inheritance of variant APOE4 conveys high risk for development of early-onset Alzheimer's, and that inheritance of APOE2 is protective. Based on our data that gene transfer of the APOE2 coding sequence to the CNS of murine models of Alzheimer's suppresses amyloid burden in the CNS and that we can get widespread expression of APOE2 in a safe manner in the much larger brain of a nonhuman primate, we propose a program with rapid translation to the clinic of adeno-associated virus (AAV)-mediated CNS transfer of the human APOE2 coding sequence to prevent the development and/or progression of Alzheimer's disease. Our proposed program has been formulated with input received from the Food and Drug Administration following a pre-Investigational New Drug Application meeting that we had with them and the project progress meeting with the team at ADDF (April 21, 2017). This proposal has three primary objectives; (1) investigational new drug submission to the FDA and other regulatory bodies and gaining approvals needed to initiate a phase I clinical study; (2) production, purification, and characterization of AAVrh.10hAPOE2 for a phase 1 clinical study with the required lot release testing and stability studies; and (3) to carry out a Phase I clinical trial with n=15 subjects that are APOE4 homozygotes who have mild cognitive decline or early dementia, testing the safety and preliminary efficacy of intracisternal delivery of AAVrh.10hAPOE2 to the CNS. The proposal will be carried out at Weill Cornell Medical College (WCMC) under the co-principal investigator leadership of Ronald Crystal, Chair, Department of Genetic Medicine and Gregory Petsko, Director, Appel Alzheimer's Disease Institute.