Levels of tau protein in plasma are associated with neurodegeneration and cognitive function in a population‐based elderly cohort

Dage, Jeffrey L.; Wennberg, Alexandra; Airey, David; Hagen, Clinton E.; Knopman, David S.; Machulda, Mary M.; Roberts, Rosebud O.; Jack, Clifford R.; Petersen, Ronald C.; Mielke, Michelle M.

doi:10.1016/j.jalz.2016.06.001

Cited by 110 publications

(137 citation statements)

References 23 publications

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“…14 Initial efforts focused on assays that did not differentiate between phosphorylated and unphosphorylated tau. [15][16][17][18][19][20][21] Some studies found that tau in plasma was increased in AD, 16,19,22,23 whereas others found no significant change. 19,24 The Quanterix Human Tau kit (erroneously referred to as "total tau") has been the most widely applied assay used to measure tau in plasma.…”

mentioning

confidence: 99%

Plasma NT1 Tau is a Specific and Early Marker of Alzheimer's Disease

Mengel

Bateman

Glynn

et al. 2020

Annals of Neurology

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Objective There is an urgent need for sensitive, widely available, blood‐based screening tests to identify presymptomatic individuals destined to develop Alzheimer's disease (AD). We investigated whether tau detected in plasma by our in‐house NT1 assay is specifically altered in AD, and when applied to patients with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) can serve to predict progression to AD dementia. The predictive value of NT1 versus tau measured using assays from Quanterix and Roche, and the specificity of NT1 for AD versus a nonspecific marker of neurodegeneration (neurofilament light [NfL]) were also examined. Methods NT1 tau and NfL were measured in plasma from prospectively followed patients with SCD or MCI who remained cognitively stable, converted to AD dementia, or converted to non‐AD dementias, and in cognitively unimpaired participants. Tau was measured using Quanterix and Roche assays in baseline subjects with SCD and MCI. Results Plasma NT1 tau was specifically elevated in AD, but not in non‐AD dementia compared with controls, whereas NfL was increased in both AD and non‐AD dementias. Baseline specimens from individuals who had SCD or MCI revealed that NT1 tau, but not tau measured using Quanterix or Roche assays, is elevated in subjects who progress to AD dementia. As expected, baseline plasma NfL is elevated in those who progress to AD and non‐AD dementias. Interpretation Plasma NT1 tau is a specific marker of AD, which is elevated early in disease and may prove useful as a first round screen to identify individuals at risk of developing AD. ANN NEUROL 2020;88:878–892

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confidence: 99%

Plasma NT1 Tau is a Specific and Early Marker of Alzheimer's Disease

Mengel

Bateman

Glynn

et al. 2020

Annals of Neurology

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“…This study compared AD with MCI and control subjects from a Swedish cohort, showing that while plasma t-tau differentiates AD from control, there is no significant effect for MCI versus control. The former finding has been replicated in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort and the Swedish BioFINDER study [ 40 ] and the latter finding has been independently replicated in a larger cohort from the Mayo Clinic Study of Aging [ 41 ], using the same platform. While the difference in plasma t-tau levels between MCI and control did not reach statistical significance, there was a significant inverse correlation between plasma tau and cognitive performance (in the global, memory and attention/executive function domains), as well as between plasma t-tau and cortical thickness in an AD region of interest defined on MRI.…”

Section: The Candidate Approachmentioning

confidence: 84%

Blood Biomarkers for Alzheimer’s Disease: Much Promise, Cautious Progress

Keshavan

Heslegrave²,

Zetterberg

et al. 2016

Mol Diagn Ther

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Biomarkers in Alzheimer's disease (AD) have the potential to allow early and more accurate diagnosis, predict disease progression, stratify individuals and track response to candidate therapies in drug trials. The first fluid biomarkers reflecting aspects of AD neuropathology were identified in cerebrospinal fluid (CSF) in the 1990s. Three CSF biomarkers (amyloid-β 1-42, total tau and phospho-tau) have consistently been shown to have diagnostic utility and are incorporated into the new diagnostic criteria for AD. These markers have also been shown in longitudinal studies to predict conversion of mild cognitive impairment to AD. However, a key issue with the use of CSF biomarkers as a screening test is the invasiveness of lumbar puncture. Over the last 20 years there has been an active quest for blood biomarkers, which could be easily acquired and tested repeatedly throughout the disease course. One approach to identifying such markers is to attempt to measure candidates that have already been identified in CSF. Until recently, this approach has been limited by assay sensitivity, but newer platforms now allow single molecule-level detection. Another approach is identification of candidates in large multiplex panels that allow for multiple analytes to be quantified in parallel. While both approaches show promise, to date no blood-based biomarker or combination of biomarkers has sufficient predictive value to have utility in clinical practice. In this review, an overview of promising blood protein candidates is provided, and the challenges of validating and converting these into practicable tests are discussed. AQ1H. Zetterberg and J. M. Schott are joint senior author of this article. Key PointsMany studies have identified candidates for blood biomarkers of Alzheimer's disease (AD) but replication has been problematic.The two main candidates showing promise currently are plasma total tau and serum neurofilament light chain.New techniques such as multiplexing and use of more sensitive assays are likely to expand and improve blood biomarker research.

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“…The detailed relationship between plasma t-tau and the pathological state of the brain during the course of the disease is not yet clear. The t-tau concentration in plasma has been associated to abnormal cortical thickness and memory performance in a cohort of MCI patients [165]. However, in another cohort of MCI and AD cases, plasma t-tau appeared unrelated to cortical thickness in AD-specific regions [166].…”

Section: Tau In Blood-based Biofluidsmentioning

confidence: 98%

Tau Protein as a Biological Fluid Biomarker in Neurodegenerative Dementias

Llorens¹,

Villar‐Piqué²,

Candelise³

et al. 2019

Cognitive Disorders

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Tau is a microtubule-associated protein, whose main function is the modulation of the stability of axonal microtubules. In physiological conditions tau is abundant in neurons while its expression in glial populations is low and restricted to astrocytes and oligodendrocytes. The aggregation of tau in neurofibrillary or gliofibrillary tangles is the main hallmark of tauopathies, a complex group of human neurodegenerative conditions where tau hyper-phosphorylation causes its increased insolubility and aggregation leading to tangle formation and microtubule destabilization. Tau can be detected in biological fluids in physiological and pathological conditions. In several neurodegenerative dementias, either associated or not to a primary tauopathy, tau levels are altered in a diseasespecific pattern, which can be used as a biomarker for disease diagnosis and prognosis. The study of tau levels in biological fluids has been mainly performed in the cerebrospinal fluid (CSF), although the recent development of ultrasensitive techniques allows the robust quantification of tau in blood-based biofluids such as serum and plasma. The presence of elevated total-tau in the CSF is assumed to reflect the degree of axonal damage in the brain tissue. Consequently, highest total-tau CSF levels are found in sporadic Creutzfeldt-Jakob disease, which is characterized by massive neuronal damage and a rapid progressive course. Elevated total-tau is also detected in Alzheimer's disease and dementia with Lewy bodies, while in other dementia conditions such as vascular dementia, frontotemporal dementia and corticobasal degeneration are unchanged, inconclusive or not determined. Additionally, total-tau rises temporarily due to cerebral infarction. In contrast, elevated phospho-tau levels seem to be restricted to Alzheimer's disease pathology, most likely mirroring the presence of the hyper-phosphorylated form in the brain tissue, although phospho-tau levels are mainly unaffected in tauopathies. Additionally, isoforms and different structural and truncated tau forms have also been reported to be altered in neurodegenerative dementias. In this complex scenario the diagnostic accuracy of diverse tau forms as disease-specific biomarkers needs to be established. In this chapter, we summarize the current knowledge on the alterations of diverse tau forms

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Levels of tau protein in plasma are associated with neurodegeneration and cognitive function in a population‐based elderly cohort

Cited by 110 publications

References 23 publications

Plasma NT1 Tau is a Specific and Early Marker of Alzheimer's Disease

Plasma NT1 Tau is a Specific and Early Marker of Alzheimer's Disease

Blood Biomarkers for Alzheimer’s Disease: Much Promise, Cautious Progress

Tau Protein as a Biological Fluid Biomarker in Neurodegenerative Dementias

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