The majority of putative disease-modifying treatments in development for Alzheimer’s disease are directed against the amyloid-β (Aβ) peptide. Among the anti-Aβ therapeutic approaches, the most extensively developed is immunotherapy—specifically, passive immunization through administration of exogenous monoclonal antibodies (mAbs). Although testing of mAbs has been fraught with failure and confusing results, the experience gained from these trials has provided important clues for better treatments. This review summarizes the experience to date with anti-Aβ mAbs to enter clinical trials for Alzheimer’s disease and examines the evidence for clinical efficacy and the major problems with safety—i.e., amyloid-related imaging abnormalities. As mAbs differ considerably with regard to their epitopes and the conformations of Aβ that they recognize (monomers, oligomers, protofibrils, fibrils), the consequences of targeting different species are also considered. An often-cited explanation for the failure of anti-Aβ mAb trials is that they are set too late in the disease process. New trials are indeed evaluating treatments at prodromal and preclinical stages. We should expect to see additional studies of presymptomatic Alzheimer’s disease to join the ongoing prevention trials, for which mAbs continue to serve as the mainstay.

中文翻译：

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用于阿尔茨海默病的抗淀粉样蛋白 β 单克隆抗体：

阿尔茨海默病开发中的大多数推定的疾病修饰疗法都是针对淀粉样蛋白 β (Aβ) 肽的。在抗 Aβ 治疗方法中，发展最广泛的是免疫疗法——特别是通过施用外源性单克隆抗体 (mAb) 进行被动免疫。尽管 mAb 的测试充满了失败和令人困惑的结果，但从这些试验中获得的经验为更好的治疗提供了重要线索。本综述总结了迄今为止抗 Aβ mAb 进入阿尔茨海默病临床试验的经验，并检查了临床疗效的证据和安全性的主要问题——即淀粉样蛋白相关的成像异常。由于 mAb 在它们的表位和它们识别的 Aβ 构象（单体、低聚物、原纤维、原纤维），还考虑了针对不同物种的后果。抗 Aβ mAb 试验失败的一个经常被引用的解释是，它们在疾病过程中设置得太晚了。新的试验确实在评估前驱和临床前阶段的治疗。我们应该期待看到更多关于症状前阿尔茨海默病的研究加入正在进行的预防试验，其中单克隆抗体继续作为中流砥柱。