Chhatwal JP, Schultz AP, Dang Y, Ostaszewski B, Liu L, Yang HS, Johnson KA, Sperling RA, Selkoe DJ. Plasma N-terminal tau fragment levels predict future cognitive decline and neurodegeneration in healthy elderly individuals. Nat Commun. 2020 Nov 27;11(1):6024. PubMed.

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  1. This is a remarkable study, clearly demonstrating the value of NT1 tau to predict cognitive decline (worsening PACC score), neurodegeneration (gray matter and hippocampal atrophy and cortical thinning), and pathological tau accumulation (FTP tau PET).

    It is a nice complementary extension of prior work demonstrating that distinct fragments of tau, specifically forms of tau captured with the NT1 tau assay (with the minimal sequence requirement spanning amino acids 6–198) are specific for AD pathology (Chen et al., 2019; Mengel et al., 2020). 

    The findings also provide corroborative evidence to the recent study in the Swedish Biofinder cohort that NT1 tau is elevated early in disease and helps to identify individuals with future cognitive decline (Mengel et al., 2020). Interestingly, in that study we had found that NT1 tau, but not tau measured using ultrasensitive Quanterix or Roche assays, is elevated in subjects with SCD and MCI who progressed to AD dementia (but not to non-AD dementia), thereby demonstrating the specificity of NT1 tau for AD pathobiology.

    Taken together, these studies provide a strong body of evidence that NT1 tau should be tested in combination with markers of phospho-tau, particularly tau T181P and T217P, to study the (temporal) relationship of these markers, and whether a combination might further improve their diagnostic and predictive usefulness.

    References:

    Chen Z, Mengel D, Keshavan A, Rissman RA, Billinton A, Perkinton M, Percival-Alwyn J, Schultz A, Properzi M, Johnson K, Selkoe DJ, Sperling RA, Patel P, Zetterberg H, Galasko D, Schott JM, Walsh DM. Learnings about the complexity of extracellular tau aid development of a blood-based screen for Alzheimer's disease. Alzheimers Dement. 2019 Mar;15(3):487-496. Epub 2018 Nov 9 PubMed.

    Mengel D, Liu W, Glynn RJ, Selkoe DJ, Strydom A, Lai F, Rosas HD, Torres A, Patsiogiannis V, Skotko B, Walsh DM. Dynamics of plasma biomarkers in Down syndrome: the relative levels of Aβ42 decrease with age, whereas NT1 tau and NfL increase. Alzheimers Res Ther. 2020 Mar 19;12(1):27. PubMed.

    Mengel D, Janelidze S, Glynn RJ, Liu W, Hansson O, Walsh DM. Plasma NT1 Tau is a Specific and Early Marker of Alzheimer's Disease. Ann Neurol. 2020 Nov;88(5):878-892. Epub 2020 Sep 25 PubMed.

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