Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.
Memory Clinic, Skåne University Hospital, Malmö, Sweden.
JAMA. 2020 Aug 25;324(8):772-781. doi: 10.1001/jama.2020.12134.
There are limitations in current diagnostic testing approaches for Alzheimer disease (AD).
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).
Plasma P-tau217.
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]).
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).
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.
目前阿尔茨海默病（AD）的诊断检测方法存在局限性。
研究血浆 tau 磷酸化在苏氨酸 217 位（P-tau217）作为 AD 的诊断生物标志物。
设计、地点和参与者：三个横断面队列：一个位于亚利桑那州的神经病理学队列（队列 1），包括 34 名 AD 患者和 47 名非 AD 患者（入组日期为 2007 年 5 月至 2019 年 1 月）；瑞典 BioFINDER-2 队列（队列 2），包括认知正常的参与者（n=301）和临床诊断为轻度认知障碍（MCI）（n=178）、AD 痴呆（n=121）和其他神经退行性疾病（n=99）的患者（2017 年 4 月至 2019 年 9 月）；以及一个哥伦比亚常染色体显性 AD 家族（队列 3），包括 365 名 PSEN1 E280A 突变携带者和 257 名非突变携带者（2013 年 12 月至 2017 年 2 月）。
血浆 P-tau217。
主要结果是血浆 P-tau217 对 AD（临床或神经病理学诊断）的区分准确性。次要结果是与 tau 病理学的关联（通过神经病理学或正电子发射断层扫描 [PET] 确定）。
队列 1 的平均年龄为 83.5（标准差，8.5）岁，队列 2 为 69.1（标准差，10.3）岁，队列 3 为 35.8（标准差，10.7）岁；队列 1 中 38%为女性，队列 2 中 51%为女性，队列 3 中 57%为女性。在队列 1 中，生前血浆 P-tau217 区分了神经病理学定义的 AD 与非 AD（曲线下面积 [AUC]，0.89 [95%CI，0.81-0.97]），其准确性明显高于血浆 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]）明显高于血浆 P-tau181、血浆 NfL 和 MRI 测量（AUC 范围，0.50-0.81；P<.001），但与脑脊液（CSF）P-tau217、CSF P-tau181 和 tau-PET 相比无显著差异（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 水平从大约 25 岁开始显著升高，这比突变携带者发生 MCI 的估计发病年龄早 20 年。在队列 1 中，血浆 P-tau217 水平与参与者的 tau 缠结相关（Spearman ρ=0.64；P<.001），但与β-淀粉样斑块无关（Spearman ρ=0.15；P=0.33）。在队列 2 中，血浆 P-tau217 区分了异常与正常 tau-PET 扫描（AUC，0.93 [95%CI，0.91-0.96]），其准确性明显高于血浆 P-tau181、血浆 NfL、CSF P-tau181、CSF Aβ42:Aβ40 比值和 MRI 测量（AUC 范围，0.67-0.90；P<.05），但与 CSF P-tau217 相比无显著差异（AUC，0.96；P=0.22）。
在来自 3 个选定队列的 1402 名参与者中，血浆 P-tau217 区分了 AD 与其他神经退行性疾病，其准确性明显高于已建立的基于血浆和 MRI 的生物标志物，且其性能与关键的基于 CSF 或 PET 的测量方法无显著差异。需要进一步研究来优化检测方法，验证在未选择和多样化人群中的发现，并确定其在临床护理中的潜在作用。
