Plasma Levels of an N‐terminal Tau Fragment Are Highly Associated with Future Cognitive Decline and Neurodegeneration in Clinically Normal Elderly

AbstractBackgroundAdvances in high‐sensitivity biofluid assays have accelerated the development of novel tools to study Alzheimer's disease (AD) pathobiology. Recent work demonstrates levels of an N‐terminal fragment of tau (NT1), measured in cerebrospinal fluid or plasma, can differentiate clinically‐normal people from those with clinically‐evident AD with high sensitivity and specificity. However, the potential of plasma NT1 to capture the earliest, preclinical signs of AD remains unclear. Accordingly, we examined the potential for plasma NT1 to predict prospective cognitive decline and neurodegeneration in a large, longitudinal cohort of clinically‐unimpaired elderly at‐risk of future cognitive decline.MethodBaseline plasma samples from participants in the Harvard Aging Brain Study (n=236) were assayed for NT1 and neurofilament light (NfL) using single‐molecule array (Quanterix Simoa). Baseline NT1 and NfL were assessed alone or interactively with β‐amyloid (11C‐Pittsburgh C‐mpound‐B PET; PiB‐PET) as predictors of longitudinal cognitive decline (Preclinical Alzheimer's Cognitive Composite; PACC) and neurodegeneration (vMRI) using linear mixed effects models. In participants with available longitudinal 18F‐Flortaucipir PET (FTP‐PET), we assessed plasma NT1 as a potential predictor of tau neurofibrillary tangle accumulation.ResultGreater plasma NT1 at baseline was highly predictive of greater cognitive decline during longitudinal follow‐up (median 5.04+/‐0.99 yr; p<0.0001; Figure 1). This effect was synergistic with baseline β‐amyloid burden (p<0.005). Greater NT1 was also associated with greater decreases in cortical gray matter and hippocampal volumes. In the subset of participants with longitudinal tau PET, plasma NT1 levels at the time of initial tau PET were predictive of increases in temporal tau PET signal over time in people with high b‐amyloid burden. Baseline plasma NT1 levels were strongly associated with neurofilament light chain (NfL) levels, but NfL was a much weaker predictor of future cognitive decline in this preclinical cohort.ConclusionThese results suggest plasma NT1 may be a novel, non‐invasive, and inexpensive biomarker that captures risk of imminent cognitive decline and neurodegeneration even in unimpaired, at‐risk elderly. The pattern of results further suggests NT1 may be a powerful compliment to existing biomarkers of β‐amyloid burden, as we observed synergistic associations between NT1 and β‐amyloid PET in predicting neurodegeneration, cognitive decline, and tau accumulation.