Increases in amyloid-β42 slow cognitive and clinical decline in Alzheimer’s disease trials

内科学 认知功能衰退 医学 痴呆 阿尔茨海默病 临床试验 置信区间 随机对照试验 肿瘤科 胃肠病学 疾病 心理学
作者
Jesus Abanto,Alok Dwivedi,Bruno Dubois,Alberto J. Espay
出处
期刊:Brain [Oxford University Press]
标识
DOI:10.1093/brain/awae216
摘要

Abstract 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.
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