Whilst cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers for amyloid-beta and tau pathologies are accurate for the diagnosis of Alzheimer's disease (AD), their broad implementation in clinical and trial settings are restricted by high cost and limited accessibility. Plasma phosphorylated-tau181 (p-tau181) is a promising blood-based biomarker that is specific for AD, correlates with cerebral amyloid-beta and tau pathology, and predicts future cognitive decline. In this study, we report the performance of p-tau181 in >1,000 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU), mild cognitive impairment (MCI) and AD dementia patients characterized by amyloid-beta PET. We confirmed that plasma p-tau181 is increased at the preclinical stage of Alzheimer and further increases in MCI and AD dementia. Individuals clinically classified as AD dementia but having negative amyloid-beta PET scans did not show increased plasma p-tau181. Despite being a multicenter study, plasma p-tau181 demonstrated high diagnostic accuracy to identify AD dementia (AUC=85.3%; 95% CI, 81.4%-89.2%), as well as to distinguish between amyloid-beta-negative and amyloid-beta-positive individuals along the Alzheimer's continuum (AUC=76.9%; 95% CI, 74.0%-79.8%). Higher baseline concentrations of plasma p-tau181 accurately predicted future dementia and performed comparably to the baseline prediction of CSF p-tau181. Longitudinal measurements of plasma p-tau181 revealed low intra-individual variability, which could be of potential benefit in disease-modifying trials seeking a measurable response to a therapeutic target. This study adds significant weight to the growing body of evidence in the use of plasma p-tau181 as a non-invasive diagnostic and prognostic tool for AD, regardless of clinical stage, which would be of great benefit in clinical practice and a large cost-saving in clinical trial recruitment.

中文翻译：

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血浆磷酸化tau181在阿尔茨海默氏病神经影像学计划中的诊断性能和临床进展预测

尽管用于淀粉样β和tau病理的脑脊液（CSF）和正电子发射断层扫描（PET）生物标志物对于阿尔茨海默病（AD）的诊断是准确的，但它们在临床和试验环境中的广泛实施受到成本高和可及性有限的限制。血浆磷酸化-tau181（p-tau181）是一种有前途的基于血液的生物标志物，对AD特异，与脑淀粉样蛋白β和tau病理相关，并预测未来的认知能力下降。在这项研究中，我们报告了p-tau181在阿尔茨海默氏病神经影像学倡议（ADNI）的> 1,000名患者中的表现，包括以淀粉样β-PET为特征的认知无障碍（CU），轻度认知障碍（MCI）和AD痴呆患者。我们证实血浆p-tau181在阿尔茨海默氏症的临床前阶段增加，并在MCI和AD痴呆症中进一步增加。临床分类为AD痴呆但淀粉样β-PET扫描阴性的个体未显示血浆p-tau181升高。尽管是一项多中心研究，但血浆p-tau181仍具有较高的诊断准确性，可识别AD痴呆症（AUC = 85.3％； 95％CI，81.4％-89.2％），并可区分β-淀粉样蛋白阴性和β-淀粉样蛋白-沿阿尔茨海默氏症连续体呈阳性的个体（AUC = 76.9％； 95％CI，74.0％-79.8％）。血浆p-tau181的较高基线浓度可准确预测未来的痴呆症，其表现与CSF p-tau181的基线预测相当。血浆p-tau181的纵向测量显示个体内变异性低，在寻求对治疗靶点进行可测量反应的疾病缓解试验中可能具有潜在的益处。这项研究将血浆p-tau181用作AD的非侵入性诊断和预后工具的证据越来越多，而不论其临床阶段如何，这在临床实践中将大有裨益，而且成本高昂，节省临床试验招募。