Two novel blood-based biomarker candidates measuring degradation of tau are associated with dementia: A prospective study

Abstract

BackgroundTruncated tau appears to be specifically related to disease pathology and recent studies have shown the presence and elevation of several truncated tau species in Cerebrospinal fluid (CSF) of subjects with Alzheimer’s disease (AD); however, the relevance of truncated Tau measurements in blood is still being studied.ObjectiveThe aim of the current study was to assess the longitudinal associations between baseline levels of two novel blood biomarker candidates measuring truncated tau, Tau-A and Tau-C, and the risk of incident dementia and AD in elderly women.MethodsUsing solid phase competitive ELISA, two tau fragments were detected in serum of 5,309 women from the Prospective Epidemiological Risk Factor study. The study was an observational, prospective study of Danish postmenopausal women. Subjects were followed with registry-linkage for up to 15 years (median follow-up time 13.7 years). Cox regression was used to assess the utility of the biomarker candidates in relation to dementia and AD.ResultsHigh levels of Tau-A and Tau-C (above the median) in blood were associated with lower risk of dementia and AD (Tau-A: Dementia HR[95% CI] = 0.85[0.70–1.04]; AD 0.71[0.52–0.98] and Tau-C: Dementia 0.84[0.70–1.00]; AD 0.78[0.60–1.03]). Tau-C gave a very modest increase in the AUC in a 5-year prediction horizon as compared to a reference model with age and education, while a combination of the two did not improve their predictive capacity.ConclusionsMeasurement of tau in serum is feasible. The serological tau turnover profile may be related to the diagnosis and development of dementia and AD. The exact processing and profile in serum in relation to cognitive disorders remains to be further assessed to provide simple non-invasive tests to identify subjects with progressive cognitive disorders.

Serum tau fragments as predictors of death or poor neurological outcome after out-of-hospital cardiac arrest

“…Interactions of tau fragments with inflammation can be A c c e p t e d M a n u s c r i p t investigated in future studies. The methods used in this study have been used and validated in numerous previous studies with great reliability (Henriksen et al, 2013, Inekci et al, 2015, Shahim et al, 2016, Neergaard et al, 2018. We have showed that the two tau fragments increase as expected after OHCA in the same way as other biomarkers (Stammet et al, 2015, Mattsson et al, 2017, are correlated with each other and correlates with several other biomarkers in this study.…”

“…Tau fragments have proved beneficial in previous studies where serum-levels of tau-A and tau-C were associated with Alzheimer's disease and severity of sports-related head trauma (Shahim et al, 2014, Inekci et al, 2015, Shahim et al, 2016. Furthermore, cognitive function has been shown to be inversely related with serum-levels of tau-A and tau-C, (Henriksen et al, 2013) and tau-C levels were indicative of future dementia diagnosis in a study of over 5,500 elderly women (Neergaard et al, 2018). In our study of resuscitated, comatose, OHCA patients, we have measured tau-A and tau-C at several time points after resuscitation and found no association between serum levels of the tau fragments and brain injury.…”

Matrix metalloproteinase-degraded type I collagen is associated with APOE/TOMM40 variants and preclinical dementia

“…We have previously shown that biomarkers of ADAM10- and caspase-degraded tau (TAU-A and TAU-C) were negatively associated with dementia in PERF. 22 In the current study, we noted that there was a strong correlation between C1M and tau degradation biomarker levels ( r = 0.54 between TAU-C and C1M, r = 0.58 between TAU-A and C1M, figure 3, A and B ). By grouping dementia/Alzheimer disease incidences into 2 bins: (1) dementia/Alzheimer disease at baseline (diagnosed less than 2 years after baseline) and (2) preclinical dementia/Alzheimer disease (diagnosed more than 2 years after baseline), and looking at C1M levels, we observed that women with preclinical dementia/Alzheimer disease had lower levels of C1M compared with women with dementia/Alzheimer disease at baseline and women with no cognitive impairment (never diagnosed with dementia/Alzheimer disease, figure 3C ).…”

“…We have previously seen that high levels of the tau degradation markers were associated with a lower risk of preclinical dementia and Alzheimer disease. 22 A plausible explanation for this could be linked to microglial activation. In early stages of dementia and Alzheimer disease, microglial activation is believed to be neuroprotective by enhancing phagocytosis and degradation of β-amyloid and tau, 27 , 28 a process that may result in less release of tau degradation products to the periphery.…”

Truncation of Tau selectively facilitates its pathological activities

“…It was reported that ADAM10cleaved tau fragment (Tau-A) was elevated 10fold high in the brains of the Tg4510 mouse model of tau deposition (65). Although high levels of serum Tau-A were associated with lower risk of AD and dementia in a prospective study (66), Serum Tau-A levels did show a significant increase in AD and mild cognitive impairment (MCI) (67). In AD patients, Tau-A level in serum correlated inversely with the cognitive assessment score (Mattis Dementia Rating Scale) (65) and was related to the change of cognitive function over time in early AD patients (68), supporting that Tau-A could indicate the rate of clinical progression of AD.…”