Gene delivery and gene therapy for Alzheimer’s disease

Adeno-associated virus (AAV) is the most widely used vector for gene therapy clinical trials focused on neurodegeneration. Not only can it safely and efficiently confer long-term expression in a variety of cell types, but innovations including hybrid serotypes, rationally designed capsids, split vectors, specific promoter/enhancer additions, and convection-enhanced delivery have greatly progressed the field of AAV research for neurodegenerative disease. Indeed, these developments, which enable increased specificity, efficiency, and spread of gene transfer as well as ease of administration to the CNS, have pushed AAV forward into clinical trials for Alzheimer’s disease. Preclinical testing of AAV gene transfer efficacy in animal models of disease has thus intensifi ed. In this chapter, we provide detailed methods for construction of AAV expression vectors, their application in preclinical studies using established animal models of Alzheimer’s disease, and evaluation methods to assess Alzheimer’s disease-like behavior and brain pathology.