Plasma brain-derived tau: a novel Alzheimer’s disease-type neurodegeneration biomarker with potential to complete the AT(N) scheme in blood

虽然淀粉样蛋白（A）/Tau（T）/神经变性（N）框架已被验证针对 神经病理学、脑脊液（CSF）和神经影像学生物标志物，其在 血不完整。我们现在有了高性能的血浆A和T标记物， 根据AD病理生理学异常。然而，目前的N标记-神经丝灯 (NfL)- 是神经变性/神经元损伤的非疾病特异性指标。此外，委员会认为， 血浆总-tau（t-tau）在诊断组之间有很大的重叠， 脑脊液t-tau蛋白。我们已经开发并验证了一种新的AD型神经退行性疾病生物标志物 （称为脑源性tau [BD-tau]），具有在血液中完成AT（N）框架的能力。 我们的总体目标是对血浆进行大规模的临床和病理生理学验证 BD-tau我们将利用五个纵向的，已经存在的，种族/民族多样化的散发性AD 队列（n = 2，594）进行临床、体内和尸检评价，以回答以下问题 具体目标：目标1。比较血浆BD-tau、NfL和t-tau与临床 AD的诊断和纵向认知变化;目的2.为了比较AT（N）曲线， 血浆BD-tau相对于NfL和t-tau的关联;目的3.比较（添加） 血浆BD-tau相对于NfL和t-tau对于AD的尸检确认的诊断价值;以及 探索性目的4：比较血浆BD-tau vs. NfL和t-tau的性能， 不同的种族/民族。如果得到证实，BD-tau将在血液中完成AT（N）方案， 提高诊断和预后的准确性和信心，以及预测 纵向认知变化，可直接转化为抗AD临床试验。

While the Amyloid(A)/Tau(T)/Neurodegeneration(N) framework has been validated against neuropathology, cerebrospinal fluid (CSF) and neuroimaging biomarkers, its implementation in blood is incomplete. We now have high-performance plasma A and T markers that become abnormal according to AD pathophysiology. However, the current N marker – neurofilament light (NfL) – is a non-disease-specific indicator of neurodegeneration/neuronal injury. Moreover, plasma total-tau (t-tau) has large overlaps between diagnostic groups and does not correlate with CSF t-tau. We have developed and validated a novel AD-type neurodegeneration biomarker (referred to as brain-derived tau [BD-tau]) with capacity to complete the AT(N) framework in blood. Our overall goal is to perform a large-scale clinical and pathophysiological validation of plasma BD-tau. We will leverage five longitudinal, already existing, racially/ethnically diverse sporadic AD cohorts (n = 2,594) with clinical, in vivo, and post-mortem evaluations to answer the following specific aims: Aim 1. To compare associations of plasma BD-tau, NfL and t-tau with clinical diagnosis of AD and longitudinal cognitive change; Aim 2. To compare AT(N) profiles and associations for plasma BD-tau vs. NfL and t-tau; Aim 3. To compare the (added) diagnostic value of plasma BD-tau vs. NfL and t-tau for autopsy confirmation of AD; and Exploratory Aim 4: To compare performances of plasma BD-tau vs. NfL and t-tau in different racial/ethnic groups. If proven, BD-tau will complete the AT(N) scheme in blood, improving diagnostic and prognostic accuracies and confidence, as well as the prediction of longitudinal cognitive change that are directly translatable to anti-AD clinical trials.