ImportanceData from 2 phase 3 studies of gantenerumab, GRADUATE I/II, and their open-label extensions represent a resource to further characterize amyloid-related imaging abnormalities (ARIA), including long-term sequelae.ObjectivesTo describe the characteristics of ARIA and risk factors and clinical consequences of ARIA-edema (ARIA-E).Design, Setting, and ParticipantsSecondary data collection from the GRADUATE I/II phase 3 randomized, double-blind, placebo-controlled, 116-week parallel-group studies and their open-label extensions, including PostGraduate, with up to 210 (mean, 125) weeks of total gantenerumab treatment were conducted between 2018 and 2023. The study included multicenter trials at 288 sites across 30 countries. GRADUATE I/II enrolled 985 and 980 participants, respectively, with early symptomatic Alzheimer disease (AD) and amyloid-beta (Aβ) pathology who were aged 50 to 90 years. PostGraduate enrolled 1382 participants (671 previously randomized to gantenerumab). Data were analyzed from November 2, 2022, to October 10, 2023.InterventionsGRADUATE I/II participants were randomized 1:1 to gantenerumab or placebo. Nine-month uptitration was used to mitigate ARIA risk.Main outcomes and measuresPostbaseline safety monitoring, including brain magnetic resonance imaging (MRI) findings, and adverse events and cognitive assessments.ResultsThe safety-evaluable MRI population of GRADUATE I/II comprised 1939 participants (mean age, 71.7 years; 1105 female [57.0%]). Severity of AD–related Aβ neuropathology (lower cerebrospinal fluid [CSF] Aβ42, hazard ratio [HR] for CSF Aβ42: 0.4; 95% CI, 0.2-0.7) and comorbid cerebrovascular pathology (Fazekas score: HR, 1.6; 95% CI, 1.3-2.0; total superficial siderosis count: HR, 1.9; 95% CI, 1.3-2.6; total microhemorrhage count: HR, 1.3; 95% CI, 1.0-1.5) may be important baseline risk factors for ARIA-E, in addition to apolipoprotein E (APOE) ε4 status (APOE ε4 heterozygous carrier: HR, 2.0; 95% CI, 1.4-2.8 and APOE ε4 homozygous carrier: HR, 4.7; 95% CI, 3.2-6.7). At the group level, ARIA-E did not impact long-term cognitive and functional performance (relative difference in adjusted means for Clinical Dementia Rating–Sum of Boxes was −9% in pooled GRADUATE analysis at week 116 and when censored at first ARIA-E). While taking gantenerumab, ARIA-E and ARIA-hemosiderin occurred in 24.9% (247 of 993) and 22.9% (227 of 993) participants, respectively; first ARIA-E occurred by week 64 in 86.2% (213 of 247) of participants with ARIA-E. Narratives are provided for all serious symptomatic ARIA-E cases.Conclusions and RelevanceThese results show that in addition to APOE ε4 allele count, severity of Aβ neuropathology and comorbid cerebrovascular pathology may be relevant for clinicians prescribing anti-Aβ monoclonal antibodies for early AD and developing individualized safety monitoring plans. Evaluation of these risk factors in other anti-Aβ monoclonal antibodies is recommended.Trial registrationsClinicalTrials.gov Identifiers: NCT03444870, NCT03443973, NCT04374253.

中文翻译：

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Gantenerumab 治疗早期阿尔茨海默病临床试验中的淀粉样蛋白相关影像学异常 （ARIA）


重要性来自 gantenerumab 的 2 项 3 期研究、研究生 I/II 及其开放标签扩展的数据代表了进一步表征淀粉样蛋白相关影像学异常 （ARIA） 的资源，包括长期后遗症。目的描述 ARIA 的特征以及 ARIA-水肿 （ARIA-E） 的危险因素和临床后果。设计、设置和参与者研究生 I/II 期 3 期随机、双盲、安慰剂对照、116 周平行组研究及其开放标签扩展（包括研究生）的二次数据收集，最多 210 周（平均，125）周的总 gantenerumab 治疗在 2018 年至 2023 年期间进行。该研究包括在 30 个国家/地区的 288 个地点进行的多中心试验。GRADUATE I/II 分别招募了 985 名和 980 名参与者，他们患有早期症状性阿尔茨海默病 （AD） 和 β 淀粉样蛋白 （Aβ） 病理，年龄在 50 至 90 岁之间。研究生组招募了 1382 名参与者（671 名之前被随机分配到 gantenerumab）。数据分析时间为 2022 年 11 月 2 日至 2023 年 10 月 10 日。使用 9 个月的递增来减轻 ARIA 风险。主要结局和措施基线后安全性监测，包括脑磁共振成像 （MRI） 结果，以及不良事件和认知评估。结果GRADUATE I/II 的安全性可评估 MRI 人群包括 1939 名参与者 （平均年龄 71.7 岁;1105 名女性 [57.0%]）。AD 相关 Aβ 神经病理学的严重程度（下脑脊液 [CSF] Aβ42，CSF Aβ42 的风险比 [HR]：0.4;95% CI，0.2-0.7）和共病脑血管病变（Fazekas 评分：HR，1.6;95% CI，1.3-2.0;浅表铁质沉着症总计数：HR，1.9;95% CI，1.3-2。6;总微出血计数： HR， 1.3;95% CI，1.0-1.5）可能是 ARIA-E 的重要基线危险因素，此外还有载脂蛋白 E （APOE） ε4 状态（APOE ε4 杂合子携带者：HR，2.0;95% CI，1.4-2.8 和 APOE ε4 纯合子携带者：HR，4.7;95% CI，3.2-6.7）。在组水平上，ARIA-E 不会影响长期认知和功能表现（在第 116 周的汇总 GRADUATE 分析中，临床痴呆评分-方框总和的调整均值的相对差异为 -9%，并且在第一次 ARIA-E 时截尾）。在服用 gantenerumab 期间，ARIA-E 和 ARIA-含铁血黄素分别发生在 24.9% （993 人中的 247 人） 和 22.9% （993 人中的 227 人） 参与者中;86.2% （247 例中的 213 例） 的 ARIA-E 参与者在第 64 周时首次发生 ARIA-E。为所有有严重症状的 ARIA-E 病例提供叙述。结论和相关性这些结果表明，除了 APOE ε4 等位基因计数外，Aβ 神经病理学的严重程度和合并的脑血管病理学可能与临床医生为早期 AD 开具抗 Aβ 单克隆抗体和制定个体化安全监测计划有关。建议在其他抗 Aβ 单克隆抗体中评估这些危险因素。试验 registrationsClinicalTrials.gov 标识符：NCT03444870、NCT03443973、NCT04374253。