A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease.
A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease.
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DOI：
10.1038/s41591-021-01369-8
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发表时间：
2021-07
期刊：
影响因子：
82.9
通讯作者：
Dominantly Inherited Alzheimer Network–Trials Unit
中科院分区：
文献类型：
--
作者：
Salloway S;Farlow M;McDade E;Clifford DB;Wang G;Llibre-Guerra JJ;Hitchcock JM;Mills SL;Santacruz AM;Aschenbrenner AJ;Hassenstab J;Benzinger TLS;Gordon BA;Fagan AM;Coalier KA;Cruchaga C;Goate AA;Perrin RJ;Xiong C;Li Y;Morris JC;Snider BJ;Mummery C;Surti GM;Hannequin D;Wallon D;Berman SB;Lah JJ;Jimenez-Velazquez IZ;Roberson ED;van Dyck CH;Honig LS;Sánchez-Valle R;Brooks WS;Gauthier S;Galasko DR;Masters CL;Brosch JR;Hsiung GR;Jayadev S;Formaglio M;Masellis M;Clarnette R;Pariente J;Dubois B;Pasquier F;Jack CR Jr;Koeppe R;Snyder PJ;Aisen PS;Thomas RG;Berry SM;Wendelberger BA;Andersen SW;Holdridge KC;Mintun MA;Yaari R;Sims JR;Baudler M;Delmar P;Doody RS;Fontoura P;Giacobino C;Kerchner GA;Bateman RJ;Dominantly Inherited Alzheimer Network–Trials Unit
显性遗传性阿尔茨海默病（DIAD）在临床症状出现前几十年就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，以延迟或减缓疾病进展。我们在无症状和有症状疾病阶段的DIAD受试者中进行了一项gantenerumab或solanezumab的随机、安慰剂对照、多组试验。突变携带者以3：1的比例分配到药物或安慰剂组，并接受4-7年的治疗。主要结局是认知终点;次要结局包括临床、认知、影像学和液体生物标志物测量。52名携带突变的参与者被分配接受gantenerumab，52名接受solanezumab，40名接受安慰剂。这两种药物都与Aβ靶点有关，但与对照组相比，都没有表现出对认知测量的有益作用。solanezumab治疗组在某些指标上表现出更大的认知下降，并且在下游生物标志物上没有表现出获益。Gantenerumab显著减少淀粉样斑块、脑脊液总tau蛋白和磷酸化tau 181，并减弱神经丝轻链的增加。在gantenerumab组、安慰剂组和solanezumab组分别有19.2%（3/11例为轻度症状）、2.5%和0%的患者中观察到淀粉样蛋白相关影像学异常水肿。Gantenerumab和solanezumab未减缓症状性DIAD患者的认知功能下降。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。
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.
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影响因子：
6.4
作者：
Klein, Gregory;Delmar, P.;Doody, R.
通讯作者：
Doody, R.
影响因子：
4.7
作者：
Karran, Eric;De Strooper, Bart
通讯作者：
De Strooper, Bart
影响因子：
14
作者：
Farlow, Martin;Amold, Steven E.;Siemers, Eric R.
通讯作者：
Siemers, Eric R.
影响因子：
9.9
作者：
McDade, Eric;Wang, Guoqiao;Bateman, Randall J.
通讯作者：
Bateman, Randall J.
DOI：
10.1111/cts.12491
发表时间：
2018-03
期刊：
Clinical and translational science
影响因子：
--
作者：
Cummings J
通讯作者：
Cummings J