Ashton NJ, Pascoal TA, Karikari TK, Benedet AL, Lantero-Rodriguez J, Brinkmalm G, Snellman A, Schöll M, Troakes C, Hye A, Gauthier S, Vanmechelen E, Zetterberg H, Rosa-Neto P, Blennow K. Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology. Acta Neuropathol. 2021 May;141(5):709-724. Epub 2021 Feb 14 PubMed.

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  1. Plasma p-tau has the potential to revolutionize the diagnostic work-up of Alzheimer’s disease in the near future. Plasma p-tau181 and p-tau217 can with very high accuracy differentiate AD dementia from other neurodegenerative diseases, with similar accuracies as those observed when using CSF or PET imaging (Thijssen et al., 2020; Janelidze et al., 2020; Karikari et al., 2020; Palmqvist et al., 2020). Further, these two biomarkers can be used for individualized prognosis of cognitive decline and AD dementia in patients with MCI (Cullen et al., 2021). Now Nicholas Ashton, Kaj Blennow and collaborators have developed a highly sensitive assay for quantification of plasma p-tau231, which exhibits an amazing performance for differential diagnosis of AD dementia on par with plasma p-tau181.

    This study is truly well-performed. For example, in an autopsy cohort, the levels of p-tau231 in plasma samples collected antemortem were able to differentiate cases with significant AD pathology from those without with an AUC of 0.99. Further, a cross-sectional analysis against amyloid-PET imaging provided preliminary evidence that plasma p-tau231 might increase very early in AD, when Aβ-fibrils are just starting to accumulate in the cortex.

    A next step could be to compare the longitudinal changes of plasma p-tau231 with the changes of plasma p-tau181 and p-tau217 in cognitively unimpaired subjects with repeated blood sampling over at least five to six years. Further, it would be interesting to study the clinical performance of different p-tau isoforms when using antibody-free mass spectrometry-based assays.

    In summary, I think it is very important for the field to have access to several different high-performing P-tau assays for use in research but also subsequently in clinical practice and trials. The current paper by Nicholas Ashton, Kaj Blennow, and collaborators has really contributed to this development in an important way.

    References:

    Thijssen EH, La Joie R, Wolf A, Strom A, Wang P, Iaccarino L, Bourakova V, Cobigo Y, Heuer H, Spina S, VandeVrede L, Chai X, Proctor NK, Airey DC, Shcherbinin S, Duggan Evans C, Sims JR, Zetterberg H, Blennow K, Karydas AM, Teunissen CE, Kramer JH, Grinberg LT, Seeley WW, Rosen H, Boeve BF, Miller BL, Rabinovici GD, Dage JL, Rojas JC, Boxer AL, Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) investigators. Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration. Nat Med. 2020 Mar;26(3):387-397. Epub 2020 Mar 2 PubMed.

    Janelidze S, Mattsson N, Palmqvist S, Smith R, Beach TG, Serrano GE, Chai X, Proctor NK, Eichenlaub U, Zetterberg H, Blennow K, Reiman EM, Stomrud E, Dage JL, Hansson O. Plasma P-tau181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer's dementia. Nat Med. 2020 Mar;26(3):379-386. Epub 2020 Mar 2 PubMed.

    Karikari TK, Pascoal TA, Ashton NJ, Janelidze S, Benedet AL, Rodriguez JL, Chamoun M, Savard M, Kang MS, Therriault J, Schöll M, Massarweh G, Soucy JP, Höglund K, Brinkmalm G, Mattsson N, Palmqvist S, Gauthier S, Stomrud E, Zetterberg H, Hansson O, Rosa-Neto P, Blennow K. Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol. 2020 May;19(5):422-433. PubMed.

    Palmqvist S, Janelidze S, Quiroz YT, Zetterberg H, Lopera F, Stomrud E, Su Y, Chen Y, Serrano GE, Leuzy A, Mattsson-Carlgren N, Strandberg O, Smith R, Villegas A, Sepulveda-Falla D, Chai X, Proctor NK, Beach TG, Blennow K, Dage JL, Reiman EM, Hansson O. Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA. 2020 Aug 25;324(8):772-781. PubMed.

    Cullen NC, Leuzy A, Palmqvist S, Janelidze S, Stomrud E, Pesini P, Sarasa L, Allué JA, Proctor NK, Zetterberg H, Dage JL, Blennow K, Mattsson-Carlgren N, Hansson O. Individualized prognosis of cognitive decline and dementia in mild cognitive impairment based on plasma biomarker combinations. Nat Aging 1, 114–123 (2021).

    View all comments by Oskar Hansson

  2. Ashton et al. provide a very complete picture of the performance of p-tau231, including technical validation. What truly stands out is the stepwise increase of p-tau231 per amyloid-PET quartile and per pathology-confirmed Braak stage, which we did not observe with plasma p-tau181 or p-tau217. It looks like p-tau231 is an indicator of early AD tau pathology and could as such be valuable for early treatment and could potentially contribute to accurate prognosis.

    Looking at the results in the biomarker-confirmed TRIAD cohort, it does seem like the overlap between the clinical groups is quite large. This might translate to a significant number of false negatives, though the combination with clinical diagnosis might mitigate this concern.

    The study included the primary care setting, which offers translation to the real world that we are all very excited about. Additional biomarker confirmation in such populations will further advance our understanding of the value of plasma p-tau as a screening marker.

    View all comments by Elisabeth Thijssen

  3. Plasma p-tau231 is a welcome measure in the growing list of highly specific blood-based measures. The comprehensive analysis to amyloid and tau PET as well as CSF and neuropathology are great strengths of this study, as are the number of cohorts evaluated, including primary care.

    It will be interesting and important to understand the exact relationship of p-tau231, as well as other p-tau species, with the AD pathophysiologic process. For example, what does this measure tell us about tau pathology as measured in the brain or tau PET? Is the phosphorylation at a specific site a cause, effect, or not directly related to tau pathology? Is the phosphorylation at a specific site a consequence of a reaction to amyloid plaques or some other process? 

    The answers to these questions will have an impact on interpretation for clinical utility, and especially for clinical trial results where interpreting novel tau-targeted drugs is a major need.

    View all comments by Randall Bateman

  4. This interesting article demonstrates the promise of a new plasma p-tau231 assay in helping to inform the diagnosis, prognosis, and unusually early detection of Alzheimer’s disease. It builds on findings using CSF and plasma p-tau181, complements recent findings by our collaborative team and others using p-tau217 (e.g., Palmqvist et al., 2020). It underscores the growing promise of blood-based biomarkers in AD research, disease-modifying and prevention therapy development, and clinical care.

    Additional studies are needed to further characterize, compare, and establish the potentially complementary roles of these and other emerging blood-based biomarkers, and set the stage to fulfill their promise in each of these endeavors. I congratulate this outstanding research team on their extremely important work.

    In the interest of transparency, I am a co-founder and chief medical officer of ALZPath, a startup company that will be trying to advance the role of p-tau217 and other BBBs in research, drug development, and clinical settings.

    References:

    Palmqvist S, Janelidze S, Quiroz YT, Zetterberg H, Lopera F, Stomrud E, Su Y, Chen Y, Serrano GE, Leuzy A, Mattsson-Carlgren N, Strandberg O, Smith R, Villegas A, Sepulveda-Falla D, Chai X, Proctor NK, Beach TG, Blennow K, Dage JL, Reiman EM, Hansson O. Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA. 2020 Aug 25;324(8):772-781. PubMed.

    View all comments by Eric M. Reiman

  5. This remarkable paper seems to be opening a new horizon. Often such landmark reports raise more questions. For example, where is the detected tau coming from, and why? Is it the first sawdust visible as termites attack a majestic oak? And eventually the grand tree falls? Or is it a byproduct of an invasion, as cardiolipin was when the Wassermann test first detected syphilis in 1906; it then took 40 years for curative penicillin to be discovered and utilized. The researchers are to be congratulated, but where this ship lands remains to be determined.

    View all comments by Leslie Norins

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