Tonegawa-Kuji Reina, Hou Yuan, Hu Bo, Lorincz-Comi Noah, Pieper Andrew A, Tousi Babak, Leverenz James B, Cheng Feixiong
Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
PLoS Med. 2025 Mar 31;22(3):e1004568. doi: 10.1371/journal.pmed.1004568. eCollection 2025 Mar.
While recently U.S. FDA-approved anti-amyloid beta (anti-Aβ) monoclonal antibodies (mAbs) offer new treatment approaches for patients suffering from Alzheimer's disease (AD), these medications also carry potential safety concerns and uncertainty about their efficacy for improving cognitive function. This study presents an updated meta-analysis of cognitive outcomes and side effects of anti-Aβ mAbs from phase III randomized controlled trials (RCTs) in patients with sporadic AD.
Phase III randomized, placebo-controlled blinded trials evaluating the efficacy and safety of anti-Aβ mAbs in patients with AD were identified through a search in clinicaltrials.gov, PubMed and Embase on January 14th, 2024. The retrieved studies were further screened from January 15th, 2024, to February 14th, 2024. We included studies that had been published in any language. Quality of trials was assessed using the Jadad score and publication bias was assessed using Egger's test and Funnel plot. Primary outcomes were mean changes from baseline to post-treatment in Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) and AD Assessment Scale-Cognitive Subscale (ADAS-Cog) scores, and secondary outcomes were adverse events, including amyloid-related imaging abnormalities with edema (ARIA-E), and ARIA with hemorrhage (ARIA-H). Random-effects meta-analysis and meta-regression analyses were conducted. The literature search identified 13 phase III RCTs, which included 18,826 patients with mild cognitive impairment or dementia due to AD. Compared with placebo, treatment with mAbs significantly improved cognitive performance on CDR-SB (mean difference -0.25, 95% confidence interval [CI] [-0.38, -0.11]) and ADAS-Cog (standardized mean difference -0.09, 95% CI [-0.12, -0.06]), in which a negative change indicates improvement for both scores. Meta-regression analysis suggested that trials enrolling patients with early-stage AD were associated with better efficacy. Elevated risk of ARIA-E (risk ratio [RR] 9.79, 95% CI [5.32,18.01]), ARIA-H (RR 1.94, 95% CI [1.47,2.57]), and headaches (RR 1.21, 95% CI [1.10,1.32]) were noted. Statistical heterogeneity was relatively high for ARIA-E and ARIA-H, leading to wide confidence intervals and considerable variability in effect sizes, though meta-regression was conducted to address this. Furthermore, differences in trial designs introduce limitations in cross-trial comparisons.
Anti-Aβ mAb therapy slows cognitive decline, but with small effect sizes, and raises potential concerns about ARIA and headaches.
虽然美国食品药品监督管理局（FDA）最近批准的抗淀粉样蛋白β（抗Aβ）单克隆抗体（mAb）为阿尔茨海默病（AD）患者提供了新的治疗方法，但这些药物也存在潜在的安全问题，且其改善认知功能的疗效存在不确定性。本研究对散发性AD患者的III期随机对照试验（RCT）中抗Aβ mAb的认知结果和副作用进行了更新的荟萃分析。
通过在clinicaltrials.gov、PubMed和Embase上检索，确定了2024年1月14日评估抗Aβ mAb在AD患者中的疗效和安全性的III期随机、安慰剂对照双盲试验。从2024年1月15日至2024年2月14日对检索到的研究进行进一步筛选。我们纳入了以任何语言发表的研究。使用Jadad评分评估试验质量，使用Egger检验和漏斗图评估发表偏倚。主要结局是从基线到治疗后临床痴呆评定量表-方框总和（CDR-SB）和AD评估量表-认知子量表（ADAS-Cog）评分的平均变化，次要结局是不良事件，包括伴有水肿的淀粉样蛋白相关成像异常（ARIA-E）和伴有出血的ARIA（ARIA-H）。进行了随机效应荟萃分析和荟萃回归分析。文献检索确定了13项III期RCT，其中包括18826例因AD导致轻度认知障碍或痴呆的患者。与安慰剂相比，mAb治疗显著改善了CDR-SB（平均差异-0.25，95%置信区间[CI][-0.38，-0.11]）和ADAS-Cog（标准化平均差异-0.09，95%CI[-0.12，-0.06]）的认知表现，其中负向变化表明两个评分均有所改善。荟萃回归分析表明，纳入早期AD患者的试验疗效更好。观察到ARIA-E（风险比[RR]9.79，95%CI[5.32，18.01]）、ARIA-H（RR 1.94，95%CI[1.47，2.57]）和头痛（RR 1.21，95%CI[1.10，1.32]）的风险升高。ARIA-E和ARIA-H的统计异质性相对较高，导致置信区间较宽且效应大小存在相当大的变异性，尽管进行了荟萃回归以解决此问题。此外，试验设计的差异在跨试验比较中引入了局限性。
抗Aβ mAb治疗可减缓认知衰退，但效应大小较小，并引发了对ARIA和头痛的潜在担忧。
