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

Abstract

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

Blood neurofilament light: a critical review of its application to neurologic disease

“…83 The core AD CSF biomarkers (Ab 42 , phospho-tau, total-tau) enabled the quantification of these pathological processes supporting the diagnosis of AD. 83,84 However, the complexity of the blood matrix, peripheral sources, and protein degradation have hampered the translation of this biomarker panel in the blood, 84,85 although new assays for tau and phosphotau are being investigated. 85,86 The pathological process of AD begins years before symptoms are manifest.…”

“…83,84 However, the complexity of the blood matrix, peripheral sources, and protein degradation have hampered the translation of this biomarker panel in the blood, 84,85 although new assays for tau and phosphotau are being investigated. 85,86 The pathological process of AD begins years before symptoms are manifest. 83 Thus, a biomarker that facilitates early detection of the disease would enable early treatment and better prognosis for AD patients with familial AD.…”

The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers

“…Plasma t-tau has also been investigated widely in AD [25,29,30], yet these studies have concluded that plasma t-tau, certainly in its current immunoassay format, only shows minor changes with large overlaps with disease controls to have clinical relevance for AD. Recent studies, despite being preliminary, have suggested that associations with AD can be achieved by measuring t-tau using an assay format directed toward the N-terminal region of the tau protein in blood [31,32].…”

Caspase-6-cleaved tau is relevant in Alzheimer’s disease but not in other tauopathies: diagnostic and therapeutic implications

“…Recent studies on fluid-based biomarkers with a N-terminal assay (NT1)—including the N-terminal mAbTau12 (amino acids 6– 13)—show that as NT1 levels increase, clinical decline in subjects with positivity for other AD biomarkers worsens. NT1 levels probably remain intact in non-AD dementia [36–38]. Supported by our quantitative neuropathological results and the success of other N-terminal truncated assays, mAbD13 may become an essential player in the arsenal of biofluid biomarkers against AD.…”