阿尔茨海默病中的β-淀粉样蛋白免疫疗法：挑战与机遇。
完整摘要 · 中文译文
被动抗淀粉样蛋白-β免疫疗法已从反复的3期试验失败，转变为在生物标志物定义的早期阿尔茨海默病中实现可重复的、尽管疗效适度的临床减缓。我们回顾了第一代抗体的经验教训，包括靶点结合不足、纳入晚期患者以及结局指标敏感性有限。随后，我们比较了第二代药物（即阿杜卡尼单抗、仑卡奈单抗和多纳尼单抗），重点突出其淀粉样蛋白-β亚型选择性、斑块清除动力学和持久性，并讨论新兴的给药创新。安全性问题以淀粉样蛋白相关影像学异常为主，这可能反映了脑血管淀粉样蛋白的脆弱性，需要及时进行基线磁共振成像（MRI）筛查；开展载脂蛋白E（APOE）知情咨询；以及标准化、前置负荷的MRI监测，并辅以症状触发的评估。我们总结了常染色体显性遗传和散发性临床前人群中的预防试验，并考虑了与靶向tau蛋白疗法联合或序贯治疗方案的前景。最后，我们聚焦于生物标志物指导的实施：血液为基础的预筛查、确认路径、生物学反应监测，以及治疗至清除或停药概念，同时探讨卫生系统准备度、公平性和预算影响等未解决问题。我们强调利用注册登记系统进行学习，以生成真实世界的安全性和有效性证据。
完整摘要 · 英文原文
Passive anti-amyloid-β immunotherapy has shifted from repeated phase 3 failure to reproducible, although modest, clinical slowing in biomarker-defined early Alzheimer's disease. We review lessons from first-generation antibodies, including inadequate target engagement, late-stage enrollment, and limited outcome sensitivity. We then compare second-generation agents (i.e., aducanumab, lecanemab, and donanemab) highlighting amyloid-β species selectivity, plaque clearance kinetics, and durability, and we discuss emerging delivery innovations. Safety is dominated by amyloid-related imaging abnormalities, likely reflecting cerebrovascular amyloid vulnerability, and requires timely baseline magnetic resonance imaging (MRI) screening; APOE-informed counseling; and standardized, front-loaded MRI surveillance with symptom-triggered evaluation. We summarize prevention trials in autosomal dominant and sporadic preclinical populations and consider prospects for combination or sequential regimens with tau-targeting therapies. Finally, we focus on biomarker-guided implementation: blood-based prescreening, confirmation pathways, monitoring of biological response, and treat-to-clear or stopping concepts, alongside unresolved issues of health-system readiness, equity, and budget impact. Registry-enabled learning is emphasized to generate real-world safety and effectiveness evidence.