Bouteloup Vincent, Villain Nicolas, Vidal Jean Sebastien, Gonzalez-Ortiz Fernando, Yuksekel Idil, Santos Cristiano, Schraen-Maschken Susanna, Pellegrin Isabelle, Lehmann Sylvain, Blennow Kaj, Chêne Geneviève, Hanon Olivier, Dufouil Carole, Planche Vincent
Bordeaux Population Health, University of Bordeaux, Inserm, UMR1219, Bordeaux, France.
CIC 1401 EC, Pôle Santé Publique, CHU de Bordeaux, Bordeaux, France.
JAMA Neurol. 2025 May 1;82(5):506-515. doi: 10.1001/jamaneurol.2025.0142.
Blood phosphorylated tau 217 (p-tau217) showed good performance in predicting brain amyloidosis. However, the importance of detailed cognitive phenotyping in patients without dementia when interpreting p-tau217 results remains unclear.
To assess whether accuracy, negative predictive value (NPV), and positive predictive value (PPV) in predicting brain amyloidosis using p-tau217 varies across clinical presentations in patients without dementia.
DESIGN, SETTING, AND PARTICIPANTS: The study design included 2 observational, prospective cohort studies: The Cohort of Outpatients From French Research Memory Centers in Order to Improve Knowledge on Alzheimer's Disease and Related Disorders (MEMENTO), with enrollment from 2011 to 2014 and 5 years of follow-up, and the Biomarker of Amyloid Peptide and Alzheimer's Disease Risk (BALTAZAR) cohort study, with enrollment from 2010 to 2015 and 3 years of follow-up. Both are multicenter cohorts conducted in French memory clinics. Participants without dementia were included for analysis if they had baseline blood p-tau217 measurement and a known amyloid status through cerebrospinal fluid amyloid β (Aβ)-42/Aβ-40 ratio or positron emission tomography. They presented with either subjective cognitive impairment (SCI), mild cognitive impairment (MCI) with a common Alzheimer disease (AD) phenotype (cAD-MCI: amnestic syndrome of hippocampal type, posterior cortical atrophy, or logopenic primary progressive aphasia), or MCI with uncommon AD or other phenotypes (uAD-MCI). Data were analyzed from May to September 2024.
Blood p-tau217 concentrations.
Brain amyloidosis probabilities were derived from p-tau217 logistic regressions including age, gender, and APOE genotype. Published and internally developed cut points with 90% sensitivity and specificity were used.
A total of 776 participants from the MEMENTO cohort (N = 2323 participants) and 193 participants from the BALTAZAR cohort (N = 1040) were included in this analysis. In the MEMENTO cohort (median [IQR] age, 71 [65-76] years; 444 female [57%]), brain amyloidosis prevalence was 16.5% (20 of 121) in SCI, 45.9% (78 of 170) in cAD-MCI, and 24.5% (119 of 485) in uAD-MCI. Area under the receiver operating characteristic curve for predicting brain amyloidosis with p-tau217 models was 0.78 (95% CI, 0.66-0.89), 0.91 (95% CI, 0.86-0.95), and 0.87 (95% CI, 0.84-0.91) in the SCI, cAD-MCI, and uAD-MCI subgroups, respectively. External cut points resulted in a PPV of 60.0%, 90.0%, and 74.5% in the SCI, cAD-MCI, and uAD-MCI subgroups, respectively. NPV ranged from 84.2% to 90.2%. With internally developed cut points, PPVs were 52.6%, 84.0%, and 72.3% in the SCI, cAD-MCI, and uAD-MCI subgroups, respectively. NPVs were high (91.7%-94.6%) in all subgroups. Rates of incident dementia strongly increased with the probability of brain amyloidosis in the cAD-MCI subgroup. Replicated analyses in the BALTAZAR cohort provided similar results.
Results from 2 clinical cohorts suggest that amyloid prevalence varied across cognitive phenotypes and was associated with the diagnostic performance of blood p-tau217 models to determine brain amyloidosis. Comprehensive cognitive phenotyping beyond the basic characterization of SCI, MCI, or dementia should accompany the use of blood biomarkers in clinical practice to avoid misdiagnosis due to false positives.
血液磷酸化tau 217（p-tau217）在预测脑淀粉样变性方面表现良好。然而，在解释p-tau217结果时，无痴呆患者详细认知表型分析的重要性仍不明确。
评估使用p-tau217预测脑淀粉样变性的准确性、阴性预测值（NPV）和阳性预测值（PPV）在无痴呆患者的不同临床表现中是否存在差异。
设计、设置和参与者：该研究设计包括2项观察性前瞻性队列研究：法国研究记忆中心门诊患者队列以提高对阿尔茨海默病及相关疾病的认识（MEMENTO），于2011年至2014年招募并随访5年；以及淀粉样肽与阿尔茨海默病风险生物标志物（BALTAZAR）队列研究，于2010年至2015年招募并随访3年。两者均为在法国记忆诊所开展的多中心队列研究。如果无痴呆参与者进行了基线血液p-tau217测量且通过脑脊液淀粉样β（Aβ）-42/Aβ-40比值或正电子发射断层扫描已知淀粉样状态，则纳入分析。他们表现为主观认知障碍（SCI）、具有常见阿尔茨海默病（AD）表型的轻度认知障碍（MCI）（cAD-MCI：海马型遗忘综合征、后皮质萎缩或语义性原发性进行性失语）或具有不常见AD或其他表型的MCI（uAD-MCI）。数据于2024年5月至9月进行分析。
血液p-tau217浓度。
脑淀粉样变性概率通过包括年龄、性别和APOE基因型的p-tau217逻辑回归得出。使用已发表的以及内部制定的具有90%敏感性和特异性的切点。
本分析纳入了MEMENTO队列的776名参与者（该队列共2323名参与者）和BALTAZAR队列的193名参与者（该队列共1040名）。在MEMENTO队列中（年龄中位数[四分位间距]为71[65 - 76]岁；444名女性[57%]），SCI组脑淀粉样变性患病率为16.5%（121例中的20例），cAD-MCI组为45.9%（170例中的78例），uAD-MCI组为24.5%（485例中的119例）。在SCI、cAD-MCI和uAD-MCI亚组中，用p-tau217模型预测脑淀粉样变性的受试者操作特征曲线下面积分别为0.78（95%CI，0.66 - 0.89）、0.91（95%CI，0.86 - 0.95）和0.87（95%CI，0.84 - 0.91）。外部切点在SCI、cAD-MCI和uAD-MCI亚组中的PPV分别为60.0%、90.0%和74.5%。NPV范围为84.2%至90.2%。使用内部制定的切点时，SCI、cAD-MCI和uAD-MCI亚组的PPV分别为52.6%、84.0%和72.3%。所有亚组的NPV都很高（91.7% - 94.6%）。在cAD-MCI亚组中，痴呆发病率随脑淀粉样变性概率的增加而显著升高。在BALTAZAR队列中的重复分析提供了类似结果。
两项临床队列研究结果表明，淀粉样变性患病率在不同认知表型中存在差异，并且与血液p-tau217模型诊断脑淀粉样变性的性能相关。在临床实践中使用血液生物标志物时，除了对SCI、MCI或痴呆进行基本特征描述外，还应进行全面的认知表型分析，以避免因假阳性导致的误诊。
