Active Vaccination Strategies for Alzheimer's Disease: An Expanded Review

Alzheimer's disease (AD) is pathologically defined by extracellular β-amyloid (Aβ) aggregates and intracellular hyperphosphorylated Tau, which collectively drive synaptic failure, neuroinflammation and progressive neuronal degeneration. Since current therapies provide predominantly symptomatic relief without halting disease progression, the development of robust disease-modifying interventions remains a critical unmet medical need. Here, we discuss the most recent advances in active immunisation strategies targeting pathological Aβ and Tau species and their potential to meaningfully modify the AD trajectory. Early vaccines such as AN1792 demonstrated proof-of-concept but were limited by T-cell-mediated adverse events. Second-generation approaches, including CAD106, UB-311, ABvac40 and ACI-24, improved safety and immunogenicity through short peptide fragments and liposomal formulations. Next-generation platforms such as MultiTEP and SupraAntigen, alongside nucleic acid-based vaccines, further optimise immune responses, overcoming immunosenescence and selectively targeting toxic oligomers while sparing physiological proteins. Tau-targeted vaccines, including AADvac1, ACI-35 and AV-1980R, show selective reduction of pathological Tau with promising preclinical and early clinical results. Combined Aβ/Tau vaccination demonstrates synergistic effects in preclinical models, supporting multi-target strategies. Future directions focus on preventive vaccination, alternative delivery routes and biomarker-driven personalisation, collectively supporting a shift towards integrated multi-target immunotherapy capable of modulating AD pathology and potentially altering its long-term clinical course.