Vaccination Strategies in Neurodegenerative Proteinopathies

Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and prion diseases represent a growing global health crisis. Despite significant research efforts, disease-modifying therapies remain elusive. Immunotherapy, particularly vaccination, offers a promising avenue by leveraging the body's immune system to clear pathological protein aggregates central to these disorders. This review critically analyzes the historical trajectory, current advancements, and future perspectives of vaccine development across AD, PD, and prion diseases. We highlight the evolution from first-generation pan-protein-targeting strategies to precision immunogens focusing on specific pathogenic conformers, the pivotal role of immunomodulation in balancing efficacy and safety, and the emerging landscape of novel vaccine platforms and delivery systems. A central argument advanced herein is the imperative shift from broad-spectrum immune activation to highly targeted, conformation-specific immunotherapies, coupled with early intervention strategies, to unlock the full therapeutic potential of vaccines in preventing and modifying the course of NDs. We propose that integrating lessons from diverse NDs and embracing multi-target, adaptive immunization approaches, alongside advanced biomarker identification, will be critical for achieving clinical success.