Departments of Neurology and Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States of America.
Georgetown Day School, Washington DC 20016, United States of America.
J Neurol Sci. 2022 Jul 15;438:120294. doi: 10.1016/j.jns.2022.120294. Epub 2022 May 23.
The search for a clinically effective therapy for patients with Alzheimer's disease (AD) has been long and arduous. In some circles the recent US Food and Drug Administration (FDA) approval of the human monoclonal antibody, Aducanumab, was viewed as a welcome advance. However, the administrative decision, in the face of a negative review by the members of the FDA neurology advisory board raised many questions concerning its appropriateness. In response the FDA has modified the conditions under which the drug should be administered. Currently, the etiology of AD remains unknown. Thus, application of therapies based on the still controversial amyloid hypothesis deserves critical scrutiny. While successful animal studies based on the hypothesis have stimulated many clinical trials in humans, none of these have shown statistically clinical benefit, raising questions regarding the intrinsic validity of the hypothesis itself. However, each successive trial has benefited from the experiences of those which preceded it. Given these caveats, the relevance of an apparent beneficial response in a subset of Aducanumab treated study participants must be weighed carefully. There are competing hypotheses regarding the etiology and pathophysiology responsible for the development of AD, including tau protein aggregation, acetylcholine deficiency, neuroinflammation, among others, all of which remain controversial. Nonetheless, the newly approved agent, Aducanumab did show some subtle benefit in some mild AD patients. Understanding the current hypotheses and controversies may help better evaluate the limitations and challenges in anti-amyloid therapy and in exploration of more efficacious therapies in treating patients with AD in the future.
寻找一种对阿尔茨海默病（AD）患者具有临床疗效的疗法一直以来都非常艰难。在某些圈子里，最近美国食品和药物管理局（FDA）批准人源单克隆抗体 Aducanumab 被视为一个受欢迎的进展。然而，面对 FDA 神经病学顾问委员会成员的负面评价，这一行政决策引发了许多关于其适当性的问题。作为回应，FDA 已经修改了该药的管理条件。目前，AD 的病因仍然未知。因此，基于仍有争议的淀粉样蛋白假说的治疗方法的应用值得仔细审查。虽然基于该假说的成功动物研究激发了许多人类临床试验，但没有一项临床试验显示出统计学上的临床获益，这引发了对该假说本身内在有效性的质疑。然而，每一项后续试验都从之前的试验中吸取了经验。鉴于这些警告，在接受 Aducanumab 治疗的研究参与者亚组中出现的明显获益反应必须仔细权衡。关于导致 AD 发展的病因和病理生理学有许多相互竞争的假说，包括 tau 蛋白聚集、乙酰胆碱缺乏、神经炎症等，所有这些都存在争议。尽管如此，新批准的药物 Aducanumab 确实在一些轻度 AD 患者中显示出了一些微妙的益处。了解当前的假说和争议可能有助于更好地评估抗淀粉样蛋白治疗的局限性和挑战，并为未来治疗 AD 患者探索更有效的治疗方法提供参考。
