Immunization targeting diseased proteins in synucleinopathy and tauopathy: insights from clinical trials

Synucleinopathies and tauopathies are neurodegenerative disorders characterized by the pathological accumulation of α-synuclein (α-syn) and tau proteins, respectively. These disorders are traditionally managed with symptomatic treatments without addressing the underlying pathologies. Recent advancements in passive immunotherapies, notably the FDA approval of the amyloid-beta (Aβ)-targeting antibody lecanemab, have sparked new hope in directly targeting pathological proteins. However, unlike the extracellular Aβ pathology, immunotherapies aimed at α-syn and tau, which predominantly form intracellular inclusions, face substantial challenges. To date, the therapeutic efficacy of five α-syn and 14 tau antibodies has been assessed in patients with synucleinopathies and tauopathies. These immunizations have demonstrated promising preclinical outcomes in alleviating pathological and behavioral deficits, but have not yielded significant clinical improvements in symptoms or measurable biomarkers. Therefore, a clear understanding of potential causes for the discrepancies between preclinical successes and clinical outcomes is critical for the successful translation of immunotherapy in the future. In this review, we examine existing passive immunotherapeutic strategies targeting α-syn and tau, specifically in patients with Alzheimer's disease and Parkinson's disease. Lessons learned from initial trial failures are also discussed, including refinement of animal models, inclusion and stratification of participants, improvement of clinical evaluations, and development of biomarkers. Given the overlapping pathologies and clinical manifestations of synucleinopathies and tauopathies, we further explore the potential of combined therapies targeting co-pathologies, offering novel insights for future therapeutic development against these neurodegenerative disorders.