The genetic association between the apolipoprotein E alleles and the sporadic form of Alzheimer's disease (AD) has been established more than two decades ago; the presence of APOE4 dramatically increases the prevalence of the disease whereas APOE2 has an opposite impact and decreases the age-adjusted risk of AD by about a half. Despite these fundamental genetic findings in the human population, very little is known about the molecular mechanisms conferring ApoE2 neuroprotection, and the relevance of ApoE2-based therapeutic approaches still needs to be investigated. The development of new therapies for neurodegenerative diseases remains particularly challenging due to the presence of the blood brain barrier that impermeably isolates the central nervous system (CNS) from the rest of the organism. As a consequence, liposomal formulas, nanoparticles and viral vectors have aroused a great interest to improve gene delivery to the brain. The present proposal aims at evaluating the safety and therapeutic benefit of two different APOE2-based viral vector approaches (direct intracerebral infusion versus intravenous injection) on the progression of amyloidosis and Abeta neurotoxicity in a mouse model of the disease, after amyloid deposition has started. The proposed study will pave the way towards new gene therapy strategies in the context of Alzheimer's disease.