Ackley Sarah F, Flanders Michael, Murchland Audrey, Chen Ruijia, Wang Jingxuan, Shah Sachin J, Huey Edward D, Glymour M Maria
Department of Epidemiology, Brown University, 121 S. Main St., Providence, RI 02903.
Department of Epidemiology, Boston University, 715 Albany St., Boston, MA 02118.
medRxiv. 2025 Jul 22:2025.07.21.25331942. doi: 10.1101/2025.07.21.25331942.
Amyloid removal has been used as a surrogate outcome in Alzheimer's disease trials, allowing accelerated approval of aducanumab and lecanemab. The A4 (Alzheimer's Clinical Trial Consortium A4/LEARN) trial's individual-level data supports novel methods to evaluate amyloid's validity as a surrogate for cognitive decline.
In 812 participants, cognitive and functional change was measured using the CDR-SB score. Instrumental-variable analysis estimated the effect of amyloid reduction; mediation analysis quantified solanezumab's cognitive effect mediated by amyloid reduction.
Each 10 centiloid reduction due to randomization to treatment was associated with 0.026 higher CDR-SB (95% CI: -0.013, 0.065). 14.6% of solanezumab's effect on cognition was mediated by amyloid reduction (95% CI: -122%, 208%).
Estimates showing near-zero effects of amyloid reduction on cognitive decline suggest minimal impact of amyloid reduction in populations with little disease progression. Replication in anti-amyloid trials with larger treatment effects could guide treatment and regulatory decisions.
淀粉样蛋白清除已在阿尔茨海默病试验中用作替代结局，这使得阿杜卡努单抗和乐卡奈单抗得以加速获批。A4（阿尔茨海默病临床试验联盟A4/LEARN）试验的个体水平数据支持采用新方法来评估淀粉样蛋白作为认知衰退替代指标的有效性。
在812名参与者中，使用CDR-SB评分来测量认知和功能变化。工具变量分析估计了淀粉样蛋白减少的效果；中介分析量化了由淀粉样蛋白减少介导的索拉努单抗的认知效果。
因随机分组接受治疗导致的每10个百分位数的降低与CDR-SB升高0.026相关（95%置信区间：-0.013，0.065）。索拉努单抗对认知的影响有14.6%是由淀粉样蛋白减少介导的（95%置信区间：-122%，208%）。
显示淀粉样蛋白减少对认知衰退影响近乎为零的估计结果表明，在疾病进展很少的人群中，淀粉样蛋白减少的影响极小。在具有更大治疗效果的抗淀粉样蛋白试验中进行重复研究可能会为治疗和监管决策提供指导。
