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

Jasmeer P Chhatwal,Dennis J Selkoe,Aaron P Schultz,Keith A Johnson,Lei Liu,Yifan Dang,Reisa A Sperling,Hyun-Sik Yang,Beth Ostaszewski

doi:10.1038/s41467-020-19543-w

Jasmeer P Chhatwal, Dennis J Selkoe + Show 7 more

Open Access

https://doi.org/10.1038/s41467-020-19543-w

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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.

Highlights

The availability of blood-based assays detecting Alzheimer’s disease (AD) pathology should greatly accelerate AD therapeutic development and improve clinical care
We systematically examined whether plasma NT1 predicts prospective cognitive change, neurodegeneration, and tau accumulation in a well-characterized cohort of cognitively normal older adults participating in the Harvard Aging Brain Study (HABS)
The association of baseline plasma NT1 with cognitive decline remained robust even after simultaneously correcting for PiB PET and hippocampal volume (d = −0.63, p < 0.0005 with correction for these measures; Supplementary Table 2), indicating that NT1 is capturing variance relevant to cognitive decline that is largely independent of these well-established AD biomarkers

Summary

Introduction

The availability of blood-based assays detecting Alzheimer’s disease (AD) pathology should greatly accelerate AD therapeutic development and improve clinical care. Preclinical stages of Alzheimer’s disease (AD) are characterized by elevated brain β-amyloid (Aβ) burden as assessed by PET imaging, cerebrospinal fluid (CSF) testing, and most recently, by biochemical analyses of blood1–5 As a group, those with evidence of elevated brain β-amyloid burden generally show greater rates of cognitive decline, but numerous cohort studies demonstrate that many individuals with elevated brain β-amyloid do not show clear cognitive decline, at least during the available follow-up. Coupled with findings demonstrating that N-terminal containing tau fragments may be actively secreted from neurons when exposed to Aβ (as opposed to passively released in response to general cell injury, as occurs with some other tau species), the work to date suggests that N-terminal containing tau fragments may provide particular insight into early Aβ-driven neurodegenerative processes20,22 In this context, we examine the extent to which alterations in plasma NT1 can predict future cognitive decline and neuronal injury and loss along an AD trajectory in cognitively unimpaired older adults. We went on to compare NT1 and NfL as predictors of cognitive and neurodegenerative trajectories and of AD pathologic changes

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