近日，美国圣路易斯华盛顿大学Randall J. Bateman等研究人员完成gantenerumab或solanezumab治疗显性遗传性阿尔茨海默病的临床试验。2021年6月21日，《自然—医学》杂志在线发表了这项成果。

研究人员在显性遗传的阿尔茨海默病（DIAD）患者的无症状和有症状疾病阶段进行了一项关于gantenerumab或solanezumab的随机、安慰剂对照、多臂试验。突变携带者以3:1的比例分配给药物或安慰剂，并接受4-7年的治疗。主要结果是认知终点；次要结果包括临床、认知、成像和体液生物标志物测量。52名携带突变的参与者被分配接受gantenerumab、52名为solanezumab以及40名为安慰剂。

两种药物均使用其Aβ靶标，但与对照组相比，均未表现出对认知测量的有益影响。接受solanezumab治疗的组在某些指标上表现出更大的认知能力下降，并且未显示对下游生物标志物的益处。gantenerumab显著减少淀粉样斑块、脑脊液总tau和磷酸化tau181，并减弱神经丝轻链的增加。在gantenerumab组的19.2%（11个中有3个具有轻度症状）、安慰剂组的2.5%和solanezumab组的0%中观察到淀粉样蛋白相关的成像异常水肿。gantenerumab和solanezumab不能减缓有症状DIAD患者的认知能力下降。无症状组没有表现出认知能力下降；有症状的参与者在达到目标剂量之前已经下降。

据了解，DIAD会在临床症状出现前几十年引起可预测的生物学变化，从而能够在无症状和有症状阶段测试干预措施来延迟或减缓疾病进展。

附：英文原文

Title: A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease

Author: Stephen Salloway, Martin Farlow, Eric McDade, David B. Clifford, Guoqiao Wang, Jorge J. Llibre-Guerra, Janice M. Hitchcock, Susan L. Mills, Anna M. Santacruz, Andrew J. Aschenbrenner, Jason Hassenstab, Tammie L. S. Benzinger, Brian A. Gordon, Anne M. Fagan, Kelley A. Coalier, Carlos Cruchaga, Alison A. Goate, Richard J. Perrin, Chengjie Xiong, Yan Li, John C. Morris, B. Joy Snider, Catherine Mummery, G. Mustafa Surti, Didier Hannequin, David Wallon, Sarah B. Berman, James J. Lah, Ivonne Z. Jimenez-Velazquez, Erik D. Roberson, Christopher H. van Dyck, Lawrence S. Honig, Raquel Snchez-Valle, William S. Brooks, Serge Gauthier, Douglas R. Galasko, Colin L. Masters, Jared R. Brosch, Ging-Yuek Robin Hsiung, Suman Jayadev, Mait Formaglio, Mario Masellis, Roger Clarnette, Jrmie Pariente, Bruno Dubois, Florence Pasquier, Clifford R. Jack, Robert Koeppe, Peter J. Snyder, Paul S. Aisen, Ronald G. Thomas, Scott M. Berry, Barbara A. Wendelberger, Scott W. Andersen, Karen C. Holdridge, Mark A. Mintun, Roy Yaari, John R. Sims, Monika Baudler, Paul Delmar, Rachelle S. Doody, Paulo Fontoura, Caroline Giacobino, Geoffrey A. Kerchner, Randall J. Bateman

Issue&Volume: 2021-06-21

Abstract: Dominantly inherited Alzheimer’s disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4–7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.

DOI: 10.1038/s41591-021-01369-8

Source: https://www.nature.com/articles/s41591-021-01369-8