mRNA vaccine platform demonstrates potent immunotherapeutic targeting of amyloid-β and tau pathologies in Alzheimer's disease

Abstract Current Alzheimer’s disease (AD) immunotherapeutics face efficacy and safety limitations with antibody-based approaches. While active immunization targeting Aβ and Tau pathologies represents a promising therapeutic avenue, existing peptide/protein vaccines fail to sustain adequate antibody titers or durable immune responses. mRNA vaccines offer a promising alternative, combining sustained immunogenicity, flexible antigen design, and favorable safety profiles. We developed an AD mRNA vaccine platform generating Aβ- and Tau-targeting candidates. These engineered vaccines induced robust, persistent antigen-specific antibodies in AD models without harmful T-cell responses or cerebrovascular complications. They mediated broad clearance of pathogenic aggregates across brain regions, resolved chronic neuroinflammation, and halted neurodegeneration-driven cognitive decline. Mechanistically, vaccine-induced antibodies crossed the blood-brain barrier, directly neutralized pathological proteins, enhanced microglial phagocytic activity, and modulated neuroinflammatory pathways, collectively restoring neuronal homeostasis. This mRNA platform overcomes key constraints of current clinical candidates by achieving potent pathological clearance while circumventing treatment-limiting toxicities, positioning mRNA-based active immunization as a transformative therapeutic strategy with near-term translational potential for AD.