James J. and Joan A. Gardner Family Center for Parkinson's disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH 45219, USA.
Division of Biostatistics & Epidemiology, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA.
Brain. 2024 Oct 3;147(10):3513-3521. doi: 10.1093/brain/awae216.
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.
新的抗淀粉样蛋白-β（Aβ）单克隆抗体在阿尔茨海默病（AD）中的积极作用归因于脑淀粉样蛋白的减少。然而，大多数抗 Aβ 抗体也会增加脑脊液中 42 个氨基酸同工型（Aβ42）的水平。我们评估了随机抗 Aβ药物试验中脑脊液 Aβ42 和脑 Aβ-PET 变化与认知和临床终点之间的相关性，这些药物降低（β-和 γ-分泌酶抑制剂）或增加脑脊液 Aβ42 水平（抗 Aβ 单克隆抗体），以检验治疗后脑脊液 Aβ42 水平升高与认知和临床结局独立相关的假设。我们从截至 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，计算了 ADAS-Cog（阿尔茨海默病评估量表的认知子量表）和 CDR-SB（临床痴呆评分-框总和）与脑脊液 Aβ42 和 Aβ-PET Centiloids（CL）的 z 标准化变化的治疗后与基线差异。我们使用随机效应荟萃回归模型估计 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（RCs）和置信区间（CIs）]和异质性（I2）。我们纳入了 24 项试验中 25966 名 AD 患者。在随机效应分析中，脑脊液 Aβ42 的增加与 ADAS-Cog 下降速度减缓相关（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%）。同样，Aβ-PET 的减少与 ADAS-Cog 下降速度减缓相关（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%）。敏感性分析得出了类似的结果。抗 Aβ 药物暴露后，脑脊液 Aβ42 水平升高与认知障碍和临床衰退速度减缓独立相关。Aβ42 的增加可能代表了抗 Aβ 单克隆抗体在 AD 中潜在益处的一种机制。
