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Plasma levels of an N‐terminal tau fragment are highly associated with future cognitive decline and neurodegeneration in clinically normal elderly
Author(s) -
Chhatwal Jasmeer P.,
Schultz Aaron P.,
Dang Yifan,
Ostaszewski Beth,
Liu Lei,
Yang HyunSik,
Johnson Keith A.,
Sperling Reisa A.,
Selkoe Dennis J
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.045261
Subject(s) - neurodegeneration , cognitive decline , medicine , alzheimer's disease , pittsburgh compound b , cognition , cerebrospinal fluid , neuroscience , psychology , oncology , dementia , pathology , disease
Background Advances 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. Method Baseline 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. Result Greater 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. Conclusion These 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.