AAV-mediated gene therapy for Alzheimer’s disease: neuroprotective mechanisms and translational challenges

Abstract

Alzheimer’s disease remains a major neurodegenerative disorder for which effective disease-modifying treatments are limited. Adeno-associated virus-mediated gene therapy provides a strategy for sustained modulation of disease-related pathways in the central nervous system. Recent studies have explored this approach for regulating amyloid-β (Aβ) metabolism, tau pathology, neuroinflammation, genetic risk factors and neurotrophic support. This review summarizes the biological basis for adeno-associated virus delivery in the central nervous system and discusses major therapeutic strategies for Alzheimer’s disease, including approaches targeting Aβ production and clearance, tau expression and degradation, immune microenvironment remodeling, apolipoprotein E modulation and synaptic protection. We further examine key translational barriers, including blood-brain barrier restriction, cross-species differences, immune responses, dose-related toxicity, manufacturing constraints and limited clinical evidence. Finally, we propose that future development should move beyond delivery efficiency alone toward biologically informed vector design, target selection, disease-stage matching and biomarker-guided clinical evaluation.