Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, 1551 4th Street, 411G, San Francisco, CA, 94158, USA.
Neurotherapeutics. 2023 Jul;20(4):914-931. doi: 10.1007/s13311-023-01405-0. Epub 2023 Jul 25.
The amyloid cascade hypothesis is a useful framework for therapeutic development in Alzheimer's disease (AD). Amyloid b (Aβ) has been the main target of experimental therapies, based on evidence of the neurotoxic effects of Aβ, and of the potential adverse effects of brain Aβ burden detected in humans in vivo by positron emission tomography (PET). Progress on passive anti-amyloid immunotherapy research includes identification of antibodies that facilitate microglial activation, catalytical disaggregation, and increased flow of Aβ from cerebrospinal fluid (CSF) to plasma, thus decreasing the neurotoxic effects of Aβ. Recently completed phase 2 and 3 trials of 3rd generation anti-amyloid immunotherapies are supportive of their clinical efficacy in reducing brain Aβ burden and preventing cognitive decline. Data from recent trials implicate these agents as the first effective disease-modifying therapies against AD and has led to the US Food and Drug Administration (FDA) recent approval of aducanumab and lecanemab, under an accelerated approval pathway. The clinical effects of these agents are modest, however, and associated with amyloid-related imaging abnormalities (ARIA). Testing the effects of anti-Aβ immunotherapies in pre-symptomatic populations and identification of more potent and safer agents is the scope of ongoing and future research. Innovations in clinical trial design will be the key for the efficient and equitable development of novel anti-Aβ immunotherapies. The progress in the field of AD therapeutics will bring new clinical, logistical, and ethical challenges, which pose to revolutionize the practice of neurology, dementia care, and preventive cognitive healthcare.
淀粉样蛋白级联假说（amyloid cascade hypothesis）是阿尔茨海默病（AD）治疗开发的一个有用框架。淀粉样蛋白β（Aβ）一直是实验性治疗的主要靶点，这基于 Aβ 的神经毒性作用的证据，以及正电子发射断层扫描（PET）在体内检测到的人类大脑 Aβ 负担的潜在不利影响。被动抗淀粉样蛋白免疫疗法研究的进展包括鉴定出能够促进小胶质细胞激活、催化解聚以及增加 Aβ 从脑脊液（CSF）到血浆的流动的抗体，从而降低 Aβ 的神经毒性作用。最近完成的第三代抗淀粉样蛋白免疫疗法的 2 期和 3 期临床试验支持其在降低大脑 Aβ 负担和预防认知能力下降方面的临床疗效。最近的试验数据表明，这些药物是针对 AD 的首批有效疾病修饰疗法，并导致美国食品和药物管理局（FDA）最近根据加速批准途径批准了 aducanumab 和 lecanemab。然而，这些药物的临床效果是温和的，并且与淀粉样蛋白相关的成像异常（amyloid-related imaging abnormalities，ARIA）有关。在有症状前人群中测试抗 Aβ 免疫疗法的效果，并确定更有效和更安全的药物，是正在进行和未来研究的范围。临床试验设计的创新将是新型抗 Aβ 免疫疗法高效和公平开发的关键。AD 治疗领域的进展将带来新的临床、后勤和伦理挑战，这将彻底改变神经病学、痴呆症护理和预防性认知保健的实践。
