γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS).

IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY
Lancet Neurology Pub Date : 2024-09-01 Epub Date: 2024-07-26 DOI:10.1016/S1474-4422(24)00236-9
Stephanie A Schultz, Lei Liu, Aaron P Schultz, Colleen D Fitzpatrick, Raina Levin, Jean-Pierre Bellier, Zahra Shirzadi, Nelly Joseph-Mathurin, Charles D Chen, Tammie L S Benzinger, Gregory S Day, Martin R Farlow, Brian A Gordon, Jason J Hassenstab, Clifford R Jack, Mathias Jucker, Celeste M Karch, Jae-Hong Lee, Johannes Levin, Richard J Perrin, Peter R Schofield, Chengjie Xiong, Keith A Johnson, Eric McDade, Randall J Bateman, Reisa A Sperling, Dennis J Selkoe, Jasmeer P Chhatwal
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Most pathogenic variants that cause autosomal dominant Alzheimer's disease are in presenilin 1 (PSEN1), 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 PSEN1 pathogenic variants could be predicted on the basis of the effects of individual PSEN1 variants on γ-secretase activity and amyloid β production.</p><p><strong>Methods: </strong>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 PSEN1 pathogenic variants for whom relevant genetic, clinical, imaging, and CSF data were available. PSEN1 pathogenic variants were characterised via genetically modified PSEN1 and PSEN2 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, [<sup>11</sup>C]Pittsburgh compound B (PiB)-PET and brain glucose metabolism using [<sup>18</sup>F] fluorodeoxyglucose (FDG)-PET, CSF Aβ42-to-Aβ40 ratio (Aβ42/40), CSF log<sub>10</sub> (phosphorylated tau 181), CSF log<sub>10</sub> (phosphorylated tau 217), and MRI-based hippocampal volume.</p><p><strong>Findings: </strong>Data were included from 190 people carrying PSEN1 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 PSEN1) were associated with earlier AAO (r=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).</p><p><strong>Interpretation: </strong>Our findings suggest that clinical heterogeneity in people with autosomal dominant Alzheimer's disease can be at least partly explained by different effects of PSEN1 variants on γ-secretase activity and amyloid β production. 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引用次数: 0

Abstract

Background: 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 (PSEN1), 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 PSEN1 pathogenic variants could be predicted on the basis of the effects of individual PSEN1 variants on γ-secretase activity and amyloid β production.

Methods: 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 PSEN1 pathogenic variants for whom relevant genetic, clinical, imaging, and CSF data were available. PSEN1 pathogenic variants were characterised via genetically modified PSEN1 and PSEN2 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, [11C]Pittsburgh compound B (PiB)-PET and brain glucose metabolism using [18F] fluorodeoxyglucose (FDG)-PET, CSF Aβ42-to-Aβ40 ratio (Aβ42/40), CSF log10 (phosphorylated tau 181), CSF log10 (phosphorylated tau 217), and MRI-based hippocampal volume.

Findings: Data were included from 190 people carrying PSEN1 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 PSEN1) were associated with earlier AAO (r=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).

Interpretation: Our findings suggest that clinical heterogeneity in people with autosomal dominant Alzheimer's disease can be at least partly explained by different effects of PSEN1 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.

Funding: 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.

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:显性遗传性阿尔茨海默病网络观察研究(DIAN-OBS)的横断面和纵向分析。
背景:导致常染色体显性阿尔茨海默病的基因变异具有很高的渗透性,但在发病年龄(AAO)、认知能力下降率和生物标志物变化方面却存在很大差异。导致常染色体显性阿尔茨海默病的大多数致病变异都发生在 presenilin 1(PSEN1)中,该基因编码γ-分泌酶的催化核心,而γ-分泌酶是产生淀粉样β的关键酶复合物。我们的目的是研究是否可以根据单个 PSEN1 变异对γ-分泌酶活性和淀粉样β产生的影响来预测 PSEN1 致病变异携带者 AAO 和生物标志物轨迹的异质性:在这项横断面和纵向分析中,我们使用了通过DIAN-OBS第15版数据冻结(2008年2月29日至2020年6月30日期间收集的数据)加入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。数据冻结包括来自欧洲、北美、南美、亚洲和大洋洲的研究机构、大学、医院和诊所的 20 个研究点的数据。我们纳入了具有 PSEN1 致病变异且可获得相关基因、临床、影像和脑脊液数据的个体。PSEN1致病变体通过基因修饰的PSEN1和PSEN2双基因敲除人胚肾293T细胞和Aβ37、Aβ38、Aβ40、Aβ42和Aβ43免疫测定进行鉴定。我们计算了每个变异体的γ-分泌酶活性的综合指标(γ-分泌酶复合指标[GSC]),并通过相关性分析将其与临床病史得出的 AAO 进行了比较。我们使用线性混合效应模型来评估 GSC 评分与 DIAN-OBS 的多模态生物标记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级方框总和(CDR-SB)、迷你精神状态检查(MMSE)和韦氏记忆量表-修订版(WMS-R)逻辑记忆延迟回忆之间的关联、[11C]匹兹堡化合物 B (PiB)-PET、使用[18F]氟脱氧葡萄糖 (FDG)-PET的脑葡萄糖代谢、CSF Aβ42 与 Aβ40 的比率 (Aβ42/40)、CSF log10 (磷酸化 tau 181)、CSF log10 (磷酸化 tau 217)以及基于 MRI 的海马体积。研究结果数据来自190名携带PSEN1致病变体的患者,其中中位年龄为39-0岁(IQR为32-0至48-0),AAO为44-5岁(40-6至51-4)。190名携带者中有109人(57%)为女性,81人(43%)为男性。较低的GSC值(即γ-分泌酶活性低于野生型PSEN1)与较早的AAO相关(r=0-58;p解释: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地通过 PSEN1 变体对γ-分泌酶活性和淀粉样β生成的不同影响来解释。他们支持以γ-分泌酶为靶点的治疗方法,并建议使用基于细胞的模型来改善对症状发作的预测:美国国家老龄化研究所、阿尔茨海默氏症协会、德国神经退行性疾病中心、劳尔-卡雷亚神经研究所、日本医学研究开发机构、韩国健康产业振兴院、韩国保健福祉部、韩国科学和信息通信技术部以及西班牙卡洛斯三世健康研究所。
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来源期刊
Lancet Neurology
Lancet Neurology 医学-临床神经学
CiteScore
58.70
自引率
1.00%
发文量
572
审稿时长
6-12 weeks
期刊介绍: The Lancet Neurology is the world-leading clinical neurology journal. It publishes original research that advocates for change in, or sheds light on, neurological clinical practice. The topics covered include cerebrovascular disease, Alzheimer's disease and other dementias, epilepsy, migraine, neurological infections, movement disorders, multiple sclerosis, neuromuscular disorders, peripheral nerve disorders, pediatric neurology, sleep disorders, and traumatic brain injury. The journal publishes a range of article types, including Articles (including randomized clinical trials and meta-analyses), Review, Rapid Review, Comment, Correspondence, and Personal View. It also publishes Series and Commissions that aim to shape and drive positive change in clinical practice and health policy in areas of need in neurology. The Lancet Neurology is an internationally trusted source of clinical, public health, and global health knowledge. It has an Impact Factor of 48.0, making it the top-ranked clinical neurology journal out of 212 journals worldwide.
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