Importance There are limitations in current diagnostic testing approaches for Alzheimer disease (AD). Objective To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD. Design, Setting, and Participants Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n = 301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017). Exposures Plasma P-tau217. Main Outcomes and Measures Primary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET]). Results Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P < .05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P < .001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P > .15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman ρ = 0.64; P < .001), but not without (Spearman ρ = 0.15; P = .33), β-amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96]) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF Aβ42:Aβ40 ratio, and MRI measures (AUC range, 0.67-0.90; P < .05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P = .22). Conclusions and Relevance Among 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care.

中文翻译：

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血浆 Phospho-tau217 对阿尔茨海默病与其他神经退行性疾病的区分准确性


重要性 当前阿尔茨海默病 (AD) 的诊断测试方法存在局限性。目的 检测血浆 tau 苏氨酸 217 磷酸化 (P-tau217) 作为 AD 的诊断生物标志物。设计、设置和参与者三个横断面队列：亚利桑那州的神经病理学队列（队列 1），包括 34 名患有 AD 的参与者和 47 名没有 AD 的参与者（入组日期，2007 年 5 月至 2019 年 1 月）；瑞典 BioFINDER-2 队列（队列 2），包括认知未受损的参与者 (n = 301) 和临床诊断患有轻度认知障碍 (MCI) (n = 178)、AD 痴呆 (n = 121) 和其他神经退行性疾病的患者（ n = 99)（2017 年 4 月至 2019 年 9 月）；以及哥伦比亚常染色体显性AD亲属（队列3），包括365名PSEN1 E280A突变携带者和257名突变非携带者（2013年12月至2017年2月）。暴露血浆 P-tau217。主要结果和措施 主要结果是血浆 P-tau217 对 AD（临床或神经病理学诊断）的辨别准确性。次要结果是与 tau 病理学的关联（使用神经病理学或正电子发射断层扫描 [PET] 确定）。结果队列 1 的平均年龄为 83.5（SD，8.5）岁，队列 2 的平均年龄为 69.1（SD，10.3）岁，队列 3 的平均年龄为 35.8（SD，10.7）岁；第 1 组中 38% 为女性，第 2 组中 51%，第 3 组中 57%。在第 1 组中，生前血浆 P-tau217 将神经病理学定义的 AD 与非 AD 区分开来（曲线下面积 [AUC]，0.89 [95] % CI，0.81-0.97]），其准确度明显高于血浆 P-tau181 和神经丝轻链 (NfL)（AUC 范围，0.50-0.72；P < .05）。队列 2 中血浆 P-tau217 对临床 AD 痴呆与其他神经退行性疾病的区分准确性（AUC，0.96 [95% CI，0.93-0.98]）显着高于血浆 P-tau181、血浆 NfL 和 MRI 测量值（AUC 范围，0.50-0.81；P < .001），但与脑脊液 (CSF) P-tau217、CSF P-tau181 相比没有显着差异和 tau-PET（AUC 范围，0.90-0.99；P > .15）。在队列 3 中，与非携带者相比，PSEN1 突变携带者的血浆 P-tau217 水平显着更高，年龄约为 25 岁及以上，即突变携带者估计出现 MCI 的前 20 年。在队列 1 中，有（Spearman ρ = 0.64；P < .001）而非没有（Spearman ρ = 0.15；P = .33）β-淀粉样斑块的参与者中，血浆 P-tau217 水平与 tau 缠结相关。在队列 2 中，血浆 P-tau217 区分异常与正常 tau-PET 扫描（AUC，0.93 [95% CI，0.91-0.96]），准确度显着高于血浆 P-tau181、血浆 NfL、CSF P-tau181、CSF Aβ42:Aβ40 比率，和 MRI 测量（AUC 范围，0.67-0.90；P < .05），但其性能与 CSF P-tau217 相比没有显着差异（AUC，0.96；P = .22）。结论和相关性 在来自 3 个选定队列的 1402 名参与者中，血浆 P-tau217 可将 AD 与其他神经退行性疾病区分开来，其准确度明显高于已建立的基于血浆和 MRI 的生物标志物，并且其性能与关键 CSF 或 PET 没有显着差异。为基础的措施。需要进一步的研究来优化检测方法，在未经选择的不同人群中验证结果，并确定其在临床护理中的潜在作用。