Amyloid-β-targeting immunotherapies for Alzheimer's disease.

Recent advances in clinical passive immunotherapy have provided compelling evidence that eliminating amyloid-β (Aβ) slows cognitive decline in Alzheimer's disease (AD). However, the modest benefits and side effects observed in clinical trials indicate that current immunotherapy therapy is not a panacea, highlighting the need for a deeper understanding of AD mechanisms and the significance of early intervention through optimized immunotherapy or immunoprevention. This review focuses on the centrality of Aβ pathology in AD and summarizes recent clinical progress in passive and active immunotherapies targeting Aβ, discussing their lessons and failures to inform future anti-Aβ biotherapeutics design. Various delivery strategies to optimize Aβ-targeting immunotherapies are outlined, highlighting their benefits and drawbacks in overcoming challenges such as poor stability and limited tissue accessibility of anti-Aβ biotherapeutics. Additionally, the perspectives and challenges of immunotherapy and immunoprevention targeting Aβ are concluded in the end, aiming to guide the development of next-generation anti-Aβ immunotherapeutic agents towards improved efficacy and safety.