Alzheimer's disease affects 5 million Americans and is rapidly increasing in prevalence and economic impact. Existing drugs do little to limit the disease process and no preventive therapies are known. Based on the knowledge that inheritance of variant apoE4 conveys high risk for development of early-onset Alzheimer's, that inheritance of apoE2 is protective, and that gene transfer of the apoE2 coding sequence to the CNS of murine models of Alzheimer's suppresses amyloid burden, 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 in individuals carrying the apoE4 gene. Our proposed program has two stages: (1) clinical development through submission to and approval by the FDA of an IND to carry out the clinical study; and (2) the clinical study. As requested by Howard Fillit and Robert Belfer in a meeting with Ronald Crystal and Greg Petsko, the present proposal is only for the first stage: to get to an approved IND to carry out the clinical study. Based on prior funding from the ADDF, we have sufficient funds to complete the murine model efficacy studies and the nonhuman primate vector delivery studies. Thus, the goal of the proposal is to move to the clinic as rapidly as possible, including AAV vector manufacture, efficacy, toxicology and regulatory submissions to gain FDA approval for an IND to initiate a gene therapy clinical trial of AAV-mediated transfer of the human apoE2 coding sequences to the CNS of individuals at high risk for the development of Alzheimer's disease. The proposal will be carried out under the co-principal investigator leadership of Drs. Crystal and Petsko. Steven Paul, former Director of the Appel Alzheimer's Disease Research institute, will serve as a collaborator.