Positive effects of new anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer’s disease (AD) have been attributed to brain amyloid reduction. However, most anti-Aβ antibodies also increase the CSF levels of the 42-amino acid isoform (Aβ42). We evaluated the associations of changes in CSF Aβ42 and brain Aβ-PET with cognitive and clinical end points in randomized trials of anti-Aβ drugs that lowered (β- and γ-secretase inhibitors) or increased CSF Aβ42 levels (anti-Aβ monoclonal antibodies) to test the hypothesis that post-treatment increases in CSF Aβ42 levels are independently associated with cognitive and clinical outcomes. From long-term (≥12 months) randomized placebo-controlled clinical trials of anti-Aβ drugs published until November 2023, we calculated the post-treatment versus baseline difference in ADAS-Cog (cognitive subscale of the Alzheimer’s Disease Assessment Scale) and CDR-SB (Clinical Dementia Rate-Sum of Boxes) and z-standardized changes in CSF Aβ42 and Aβ-PET Centiloids (CL). We estimated the effect size [regression coefficients (RCs) and confidence intervals (CIs)] and the heterogeneity (I2) of the associations between AD biomarkers and cognitive and clinical end points using random-effects meta-regression models. We included 25 966 subjects with AD from 24 trials. In random-effects analysis, increases in CSF Aβ42 were associated with slower decline in ADAS-Cog (RC: −0.55; 95% CI: −0.89, −0.21, P = 0.003, I2 = 61.4%) and CDR-SB (RC: −0.16; 95% CI: −0.26, −0.06, P = 0.002, I2 = 34.5%). Similarly, decreases in Aβ–PET were associated with slower decline in ADAS-Cog (RC: 0.69; 95% CI: 0.48, 0.89, P < 0.001, I2 = 0%) and CDR-SB (RC: 0.26; 95% CI: 0.18, 0.33, P < 0.001, I2 = 0%). Sensitivity analyses yielded similar results. Higher CSF Aβ42 levels after exposure to anti-Aβ drugs are independently associated with slowing cognitive impairment and clinical decline. Increases in Aβ42 may represent a mechanism of potential benefit of anti-Aβ monoclonal antibodies in AD.

中文翻译：

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淀粉样蛋白-β42 的增加可减缓阿尔茨海默病试验中的认知和临床下降


新的抗淀粉样蛋白β （Aβ） 单克隆抗体对阿尔茨海默病 （AD） 的积极作用归因于脑淀粉样蛋白的减少。然而，大多数抗 Aβ 抗体也会增加 42 个氨基酸亚型 （Aβ42） 的 CSF 水平。在降低 （β 和 γ-分泌酶抑制剂） 或增加 CSF Aβ 42 水平 （抗 Aβ 单克隆抗体） 的抗 Aβ 药物随机试验中，我们评估了 CSF Aβ42 和脑 Aβ-PET 变化与认知和临床终点的关联，以检验治疗后 CSF Aβ 42 水平增加与认知和临床结果独立相关的假设。从截至 2023 年 11 月发表的抗 Aβ 药物的长期 （≥12 个月） 随机安慰剂对照临床试验中，我们计算了 ADAS-Cog（阿尔茨海默病评估量表的认知分量表）和 CDR-SB （临床痴呆率-盒子总和） 的治疗后与基线差异以及 CSF Aβ42 和 Aβ-PET Centiloids （CL） 的 z 标准化变化。我们使用随机效应 meta 回归模型估计了 AD 生物标志物与认知和临床终点之间关联的效应大小 [回归系数 （regression coefficients， RCs） 和置信区间 （CIs）] 和异质性 （I2）。我们纳入了来自 24 项试验的 25 966 名 AD 受试者。在随机效应分析中，CSF Aβ42 的增加与 ADAS-Cog （RC： -0.55;95% CI： -0.89， -0.21， P = 0.003， I2 = 61.4%） 和 CDR-SB （RC： -0.16;95% CI： -0.26， -0.06， P = 0.002， I2 = 34.5%） 的下降缓慢相关。同样，Aβ-PET 的降低与 ADAS-Cog （RC： 0.69;95% CI： 0.48， 0.89， P < 0.001， I2 = 0%） 和 CDR-SB （RC： 0.26;95% CI： 0.18， 0.33， P < 0.001， I2 = 0%） 的较慢下降有关。敏感性分析得出了类似的结果。 暴露于抗 Aβ 药物后较高的 CSF Aβ 42 水平与认知障碍减缓和临床衰退独立相关。Aβ42 的增加可能代表了抗 Aβ 单克隆抗体在 AD 中的潜在益处机制。