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)框架已被证实与 神经病理学、脑脊液(CSF)和神经影像生物标志物，在 血液是不完整的。我们现在有高性能的血浆A和T标记物，它们成为 根据AD病理生理学判断为异常。然而，目前的N标记物-神经丝光 (NFL)-是神经变性/神经元损伤的非疾病特异性指标。此外， 血浆总tau(t-tau)在诊断组间有很大重叠，与 脑脊液T-tau。我们已经开发并验证了一种新的AD类型神经退行性变生物标记物 (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/民族多样化的零星AD 通过临床、体内和死后评估的队列(n=2,594)来回答以下问题 具体目标：目的1.比较血浆BD-tau、NFL和t-tau与临床的关系 阿尔茨海默病的诊断和纵向认知改变；目的2.比较AT(N)波群和 血浆BD-tau与NFL和t-tau的相关性；目的3.比较(增加) 血浆BD-tau与NFL、t-tau对AD尸检确认的诊断价值 探索目标4：比较血浆BD-tau与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， 提高诊断和预测的准确性和置信度，以及预测 可直接转化为抗阿尔茨海默病临床试验的纵向认知变化。

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.