Immunotherapy for Alzheimer's disease: targeting β-amyloid and beyond

Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly worldwide. However, the complexity of AD pathogenesis leads to discrepancies in the understanding of this disease, and may be the main reason for the failure of AD drug development. Fortunately, many ongoing preclinical and clinical studies will continually open up avenues to unravel disease mechanisms and guide strategies for AD diagnosis and drug development. For example, immunotherapeutic strategies targeting amyloid-β (Aβ) and tau proteins were once deemed almost certainly effective in clinical treatment due to the excellent preclinical results. However, the repeated failures of clinical trials on vaccines and humanized anti-Aβ and anti-tau monoclonal antibodies have resulted in doubts on this strategy. Recently, a new anti-Aβ monoclonal antibody (Aducanumab) has been approved by the US Food and Drug Administration, which brings us back to the realization that immunotherapy strategies targeting Aβ may be still promising. Meanwhile, immunotherapies based on other targets such as tau, microglia and gut-brain axis are also under development. Further research is still needed to clarify the forms and epitopes of targeted proteins to improve the accuracy and effectiveness of immunotherapeutic drugs. In this review, we focus on the immunotherapies based on Aβ, tau and microglia and their mechanisms of action in AD. In addition, we present up-to-date advances and future perspectives on immunotherapeutic strategies for AD.