Plasma N-terminal tau fragment levels predict future cognitive decline and neurodegeneration in healthy elderly individuals

Abstract

The availability of blood-based assays detecting Alzheimer’s disease (AD) pathology should greatly accelerate AD therapeutic development and improve clinical care. This is especially true for markers that capture the risk of decline in pre-symptomatic stages of AD, as this would allow one to focus interventions on participants maximally at risk and at a stage prior to widespread synapse loss and neurodegeneration. Here we quantify plasma concentrations of an N-terminal fragment of tau (NT1) in a large, well-characterized cohort of clinically normal elderly who were followed longitudinally. Plasma NT1 levels at study entry (when all participants were unimpaired) were highly predictive of future cognitive decline, pathological tau accumulation, neurodegeneration, and transition to a diagnosis of MCI/AD. These predictive effects were particularly strong in participants with even modestly elevated brain β-amyloid burden at study entry, suggesting plasma NT1 levels capture very early cognitive, pathologic and neurodegenerative changes along the AD trajectory.

Plasma biomarkers of Alzheimer’s disease improve prediction of cognitive decline in cognitively unimpaired elderly populations

“…The strengths of this study include the standardized collection and measurement of relevant biomarkers in both plasma and CSF—which allowed for direct comparison between biomarkers and across the two modalities—and the availability of multi-year follow-up data in a large number of participants. Our study improves in particular on previous studies linking plasma P-tau levels on their own with cognitive decline and neurodegeneration in similar populations 22 , 36 . Understanding the overlapping contributions of biomarkers is therefore a major contribution of our results.…”

Plasma biomarkers of Alzheimer’s disease predict cognitive decline and could improve clinical trials in the cognitively unimpaired elderly

“…39 The strengths of this study include the standardized collection and measurement of relevant biomarkers in both plasma and CSF-which allowed for direct comparison between biomarkers and across the two modalities-and the availability of multi-year follow-up data in a large number of participants. Our study improves in particular on previous studies linking novel plasma tau levels on their own with cognitive decline and neurodegeneration in similar populations 43,44 . Understanding the overlapping contributions of novel tau biomarkers is therefore a major contribution of our results.…”

The Use, Standardization, and Interpretation of Brain Imaging Data in Clinical Trials of Neurodegenerative Disorders

“…Second, the more widespread availability and site-to-site standardization of high-quality automated assays (e.g., Roche Elecsys [208]) has put the measurement of some widely-used fluid biomarkers on a firmer footing. Third, it is now possible to measure from blood plasma a number of analytes previously requiring a CSF draw; these include Aβ and tau species, along with NfL [209][210][211][212][213][214][215].…”