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

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.