Lessons from Anti-Amyloid-β Immunotherapies in Alzheimer Disease: Aiming at a Moving Target

Background: Available drugs for the global Alzheimer disease (AD) epidemic only treat the symptoms without modifying disease progression. Accumulating evidence supports amyloid-β42 (Aβ42)as the key triggering agent in AD, making it the ideal target for disease-modifying therapies. Preclinical studies provided extensive support for passive Aβ42 immunotherapy, leading to human clinical trials with different antibodies. Objective: Examine the status of clinical trials for passive immunotherapy against Aβ42. Methods: We performed a thorough literature review of passive Aβ42 immunotherapy. Results: Ten anti-Aβ42 antibodies targeting lineal or conformational epitopes have been tested in clinical trials. Antibody engineering and appropriate dosing have overcome undesired side effects, leading to increased safety profiles. Unfortunately, few trials have shown cognitive protection, leading to legitimate questions about the utility of Aβ42 as an AD target. There is still hope that solanezumab, aducanumab, and other ongoing trials will identify antibodies, patient subpopulations, and administration protocols, with consistent clinical benefits. Conclusions: Despite the overall disappointing results, there is still hope that Aβ immunotherapy in presymptomatic patients will prevent neuronal loss and provide significant clinical benefits that can be applied to larger populations as preventive therapies. Advances with other targets may soon provide additional therapeutic options for AD with increased efficacy.