Genetic variants that cause autosomal dominant Alzheimer's disease are highly penetrant but vary substantially regarding age at symptom onset (AAO), rates of cognitive decline, and biomarker changes. Most pathogenic variants that cause autosomal dominant Alzheimer's disease are in presenilin 1 (), which encodes the catalytic core of γ-secretase, an enzyme complex that is crucial in production of amyloid β. We aimed to investigate whether the heterogeneity in AAO and biomarker trajectories in carriers of pathogenic variants could be predicted on the basis of the effects of individual variants on γ-secretase activity and amyloid β production. For this cross-sectional and longitudinal analysis, we used data from participants enrolled in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) via the DIAN-OBS data freeze version 15 (data collected between Feb 29, 2008, and June 30, 2020). The data freeze included data from 20 study sites in research institutions, universities, hospitals, and clinics across Europe, North and South America, Asia, and Oceania. We included individuals with pathogenic variants for whom relevant genetic, clinical, imaging, and CSF data were available. pathogenic variants were characterised via genetically modified and double-knockout human embryonic kidney 293T cells and immunoassays for Aβ37, Aβ38, Aβ40, Aβ42, and Aβ43. A summary measure of γ-secretase activity (γ-secretase composite [GSC]) was calculated for each variant and compared with clinical history-derived AAO using correlation analyses. We used linear mixed-effect models to assess associations between GSC scores and multimodal-biomarker and clinical data from DIAN-OBS. We used separate models to assess associations with Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), and Wechsler Memory Scale-Revised (WMS-R) Logical Memory Delayed Recall, [C]Pittsburgh compound B (PiB)–PET and brain glucose metabolism using [F] fluorodeoxyglucose (FDG)–PET, CSF Aβ42-to-Aβ40 ratio (Aβ42/40), CSF log (phosphorylated tau 181), CSF log (phosphorylated tau 217), and MRI-based hippocampal volume. Data were included from 190 people carrying pathogenic variants, among whom median age was 39·0 years (IQR 32·0 to 48·0) and AAO was 44·5 years (40·6 to 51·4). 109 (57%) of 190 carriers were female and 81 (43%) were male. Lower GSC values (ie, lower γ-secretase activity than wild-type ) were associated with earlier AAO (=0·58; p<0·0001). GSC was associated with MMSE (β=0·08, SE 0·03; p=0·0043), CDR-SB (–0·05, 0·02; p=0·0027), and WMS-R Logical Memory Delayed Recall scores (0·09, 0·02; p=0·0006). Lower GSC values were associated with faster increase in PiB–PET signal (p=0·0054), more rapid decreases in hippocampal volume (4·19, 0·77; p<0·0001), MMSE (0·02, 0·01; p=0·0020), and WMS-R Logical Memory Delayed Recall (0·004, 0·001; p=0·0003). Our findings suggest that clinical heterogeneity in people with autosomal dominant Alzheimer's disease can be at least partly explained by different effects of variants on γ-secretase activity and amyloid β production. They support targeting γ-secretase as a therapeutic approach and suggest that cell-based models could be used to improve prediction of symptom onset. US National Institute on Aging, Alzheimer's Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Korea Health Industry Development Institute, South Korean Ministry of Health and Welfare, South Korean Ministry of Science and ICT, and Spanish Institute of Health Carlos III.

中文翻译：

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常染色体显性阿尔茨海默病的 γ 分泌酶活性、临床特征和生物标志物：显性遗传阿尔茨海默病网络观察性研究 (DIAN-OBS) 的横断面和纵向分析


导致常染色体显性阿尔茨海默病的遗传变异具有高度渗透性，但在症状出现年龄 (AAO)、认知能力下降率和生物标志物变化方面差异很大。导致常染色体显性阿尔茨海默病的大多数致病变异位于早老素 1 () 中，它编码 γ-分泌酶的催化核心，γ-分泌酶是一种酶复合物，对于β淀粉样蛋白的产生至关重要。我们的目的是研究是否可以根据个体变异对 γ 分泌酶活性和淀粉样蛋白 β 产生的影响来预测致病变异携带者中 AAO 和生物标志物轨迹的异质性。对于这项横断面和纵向分析，我们使用了通过 DIAN-OBS 数据冻结版本 15 参加显性遗传性阿尔茨海默病网络观察研究 (DIAN-OBS) 的参与者的数据（数据收集于 2008 年 2 月 29 日至 6 月 30 日之间， 2020）。数据冻结包括来自欧洲、南北美洲、亚洲和大洋洲研究机构、大学、医院和诊所的 20 个研究中心的数据。我们纳入了具有致病性变异的个体，这些个体可以获得相关的遗传、临床、影像和脑脊液数据。通过转基因和双敲除人胚胎肾 293T 细胞以及 Aβ37、Aβ38、Aβ40、Aβ42 和 Aβ43 的免疫测定来表征致病变异。计算每个变体的 γ-分泌酶活性（γ-分泌酶复合物 [GSC]）的汇总测量值，并使用相关分析与临床病史得出的 AAO 进行比较。我们使用线性混合效应模型来评估 GSC 评分与来自 DIAN-OBS 的多模式生物标志物和临床数据之间的关联。 我们使用单独的模型来评估与临床痴呆评定总和 (CDR-SB)、简易精神状态检查 (MMSE) 和韦克斯勒记忆量表修订版 (WMS-R) 逻辑记忆延迟回忆、[C]匹兹堡化合物的关联B (PiB)–PET 和脑葡萄糖代谢，使用 [F] 氟脱氧葡萄糖 (FDG)–PET、CSF Aβ42 与 Aβ40 比率 (Aβ42/40)、CSF log（磷酸化 tau 181）、CSF log（磷酸化 tau 217）、和基于 MRI 的海马体积。数据包括 190 名携带致病性变异的人，其中中位年龄为 39·0 岁（IQR 32·0 至 48·0），AAO 为 44·5 岁（40·6 至 51·4）。 190 名携带者中，109 名（57%）为女性，81 名（43%）为男性。较低的 GSC 值（即，比野生型更低的 γ 分泌酶活性）与较早的 AAO 相关（=0·58；p<0·0001）。 GSC 与 MMSE (β=0·08, SE 0·03; p=0·0043)、CDR-SB (–0·05, 0·02; p=0·0027) 和 WMS-R 逻辑内存相关延迟回忆分数（0·09、0·02；p=0·0006）。较低的 GSC 值与 PiB-PET 信号更快增加 (p=0·0054)、海马体积更快减少 (4·19, 0·77; p<0·0001)、MMSE (0·02, 0 ·01；p=0·0020) 和 WMS-R 逻辑内存延迟调用 (0·004、0·001；p=0·0003)。我们的研究结果表明，常染色体显性阿尔茨海默病患者的临床异质性至少可以部分解释为变异体对 γ 分泌酶活性和淀粉样蛋白 β 产生的不同影响。他们支持以γ-分泌酶为目标的治疗方法，并建议基于细胞的模型可用于改善对症状发作的预测。 美国国家老龄化研究所、阿尔茨海默病协会、德国神经退行性疾病中心、劳尔·卡雷亚神经学研究所、日本医学研究开发机构、韩国健康产业发展研究所、韩国卫生福利部、韩国科学技术部ICT 和西班牙卡洛斯三世健康研究所。