Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Plasma phospho-tau181 in presymptomatic and symptomatic familial Alzheimer’s disease: a longitudinal cohort study

Molecular Psychiatry volume 26, pages 5967–5976 (2021)Cite this article

Subjects

Abstract

Blood biomarkers have great potential to advance clinical care and accelerate trials in Alzheimer’s disease (AD). Plasma phospho-tau181 (p-tau181) is a promising blood biomarker however, it is unknown if levels increase in presymptomatic AD. Therefore, we investigated the timing of p-tau181 changes using 153 blood samples from 70 individuals in a longitudinal study of familial AD (FAD). Plasma p-tau181 was measured, using an in-house single molecule array assay. We compared p-tau181 between symptomatic carriers, presymptomatic carriers, and non-carriers, adjusting for age and sex. We examined the relationship between p-tau181 and neurofilament light and estimated years to/from symptom onset (EYO), as well as years to/from actual onset in a symptomatic subgroup. In addition, we studied associations between p-tau181 and clinical severity, as well testing for differences between genetic subgroups. Twenty-four were presymptomatic carriers (mean baseline EYO −9.6 years) while 27 were non-carriers. Compared with non-carriers, plasma p-tau181 concentration was higher in both symptomatic (p < 0.001) and presymptomatic mutation carriers (p < 0.001). Plasma p-tau181 showed considerable intra-individual variability but individual values discriminated symptomatic (AUC 0.93 [95% CI 0.85–0.98]) and presymptomatic (EYO ≥ −7 years) (AUC 0.86 [95% CI 0.72–0.94]) carriers from non-carriers of the same age and sex. From a fitted model there was evidence (p = 0.050) that p-tau181 concentrations were higher in mutation carriers than non-carriers from 16 years prior to estimated symptom onset. Our finding that plasma p-tau181 concentration is increased in symptomatic and presymptomatic FAD suggests potential utility as an easily accessible biomarker of AD pathology.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Box and whisker plots for observed baseline plasma p-tau181 concentrations across the three groups.
Fig. 2: Age- and sex-adjusted receiver operating characteristic (ROC) curves.
Fig. 3: Trajectory of plasma biomarkers against estimated and actual years to/from onset.

Similar content being viewed by others

References

  1. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of alzheimer’s disease: Report of the NINCDS-ADRDA work group⋆ under the auspices of department of health and human services task force on alzheimer’s disease. Neurology. 1984;34:939–44.

    Article  CAS  Google Scholar 

  2. Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 2014;13:614–29.

    Article  Google Scholar 

  3. Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimer’s Dement. 2018;14:535–62.

    Article  Google Scholar 

  4. Knopman DS, Petersen RC, Jack CR. A brief history of “Alzheimer disease”: multiple meanings separated by a common name. Neurology. 2019;92:1053–9.

    Article  Google Scholar 

  5. Dubois B, Feldman HH, Jacova C, Cummings JL, DeKosky ST, Barberger-Gateau P, et al. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 2010;9:1118–27.

    Article  Google Scholar 

  6. Hampel H, O’Bryant SE, Molinuevo JL, Zetterberg H, Masters CL, Lista S, et al. Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic. Nat Rev Neurol. 2018;14:639–52.

    Article  Google Scholar 

  7. Zetterberg H, Bendlin BB. Biomarkers for Alzheimer’s disease—preparing for a new era of disease-modifying therapies. Mol Psychiatry. 2020;1–13. https://doi.org/10.1038/s41380-020-0721-9 [Online ahead of print].

  8. Janelidze S, Mattsson N, Palmqvist S, Smith R, Beach TG, Serrano GE, et al. Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med. 2020;26:379–86.

    Article  CAS  Google Scholar 

  9. Ryman DC, Acosta-Baena N, Aisen PS, Bird T, Danek A, Fox NC, et al. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology. 2014;83:253–60.

    Article  CAS  Google Scholar 

  10. Ryan NS, Nicholas JM, Weston PSJ, Liang Y, Lashley T, Guerreiro R, et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series. Lancet Neurol. 2016;15:1326–35.

    Article  Google Scholar 

  11. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–98.

    Article  CAS  Google Scholar 

  12. Morris JC. The clinical dementia rating (CDR): current version and scoring rules. Neurology. 1993;43:2412–4.

    Article  CAS  Google Scholar 

  13. Warrington E. Recognition Memory Test: Rmt.(Words). Test Booklet 1. Berkshire, UK, NFER-Nelson, 1984.

  14. Weschler D. Wechsler adult intelligence scale—4th ed. Stat Solut. Clearwater, Florida, US, 2008;1–3.

  15. Karikari TK, Pascoal TA, Ashton NJ, Janelidze S, Benedet AL, Rodriguez JL, et al. 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;19:1–12.

    Article  Google Scholar 

  16. White H. A heteroskedasticity-consistent covariance matrix estimator and a direct test for heteroskedasticity. Econometrica. 1980;48:817.

    Article  Google Scholar 

  17. Huber P. Behavior of maximum likelihood estimates under nonstandard conditions. In: Proc 5th Berkeley Sympt Math Statist Prob. 1967;1:221–33.

    Google Scholar 

  18. Weston PSJ, Poole T, O’Connor A, Heslegrave A, Ryan NS, Liang Y, et al. Longitudinal measurement of serum neurofilament light in presymptomatic familial Alzheimer’s disease. Alzheimers Res Ther. 2019;11:19.

    Article  Google Scholar 

  19. Fagan AM, Xiong C, Jasielec MS, Bateman RJ, Goate AM, Benzinger TLS, et al. Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer’s disease. Sci Transl Med. 2014;6:226ra30.

    Article  Google Scholar 

  20. Preische O, Schultz SA, Apel A, Kuhle J, Kaeser SA, Barro C, et al. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease. Nat Med. 2019;25:277–83.

    Article  CAS  Google Scholar 

  21. Palmqvist S, Insel PS, Stomrud E, Janelidze S, Zetterberg H, Brix B, et al. Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer’s disease. EMBO Mol Med. 2019;e11170. https://doi.org/10.15252/emmm.201911170.

  22. Quiroz YT, Zetterberg H, Reiman EM, Chen Y, Su Y, Fox-Fuller JT, et al. Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: a cross-sectional and longitudinal cohort study. Lancet Neurol. 2020;19:513–21.

    Article  CAS  Google Scholar 

  23. McDade E, Wang G, Gordon BA, Hassenstab J, Benzinger TL, Buckles V, et al. Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease CME course. Neurology. 2018;91:1295–306.

    Article  Google Scholar 

  24. Bateman RJ, Xiong C, Benzinger TLS, Fagan AM, Goate A, Fox NC, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367:795–804.

    Article  CAS  Google Scholar 

  25. Toledo JB, Xie SX, Trojanowski JQ, Shaw LM. Longitudinal change in CSF Tau and Aβ biomarkers for up to 48 months in ADNI. Acta Neuropathol. 2013;126:659–70.

    Article  CAS  Google Scholar 

  26. Blennow K, Zetterberg H, Minthon L, Lannfelt L, Strid S, Annas P, et al. Longitudinal stability of CSF biomarkers in Alzheimer’s disease. Neurosci Lett. 2007;419:18–22.

    Article  CAS  Google Scholar 

  27. Mielke MM, Hagen CE, Xu J, Chai X, Vemuri P, Lowe VJ, et al. Plasma phospho-tau181 increases with Alzheimer’s disease clinical severity and is associated with tau- and amyloid-positron emission tomography. Alzheimer’s Dement. 2018;14:989–97.

    Article  Google Scholar 

  28. Thijssen EH, La Joie R, Wolf A, Strom A, Wang P, Iaccarino L, et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med. 2020;26:387–97.

    Article  CAS  Google Scholar 

  29. Barthélemy NR, Liu H, Lu W, Kotzbauer PT, Bateman RJ, Lucey BP. Sleep deprivation affects tau phosphorylation in human cerebrospinal fluid. Ann Neurol. 2020;87:700–9.

    Article  Google Scholar 

  30. Gordon BA, Blazey TM, Christensen J, Dincer A, Flores S, Keefe S, et al. Tau PET in autosomal dominant Alzheimer’s disease: relationship with cognition, dementia and other biomarkers. Brain. 2019;142:1063–76.

    Article  Google Scholar 

  31. Mattsson N, Schöll M, Strandberg O, Smith R, Palmqvist S, Insel PS, et al. 18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer’s disease. EMBO Mol Med. 2017;9:1212–23.

    Article  CAS  Google Scholar 

  32. Sato C, Barthélemy NR, Mawuenyega KG, Patterson BW, Gordon BA, Jockel-Balsarotti J, et al. Tau kinetics in neurons and the human central nervous system. Neuron. 2018;97:1284–98.e7.

    Article  CAS  Google Scholar 

  33. Scahill RI, Ridgway GR, Bartlett JW, Barnes J, Ryan NS, Mead S, et al. Genetic influences on atrophy patterns in familial alzheimer’s disease: a comparison of APP and PSEN1 mutations. J Alzheimer’s Dis. 2013;35:199–212.

    Article  CAS  Google Scholar 

  34. Ringman JM, Monsell S, Ng DW, Zhou Y, Nguyen A, Coppola G, et al. Neuropathology of autosomal dominant Alzheimer disease in the national alzheimer coordinating center database. J Neuropathol Exp Neurol. 2016;75:284–90.

    Article  CAS  Google Scholar 

  35. Ryan NS, Biessels G-J, Kim L, Nicholas JM, Barber PA, Walsh P, et al. Genetic determinants of white matter hyperintensities and amyloid angiopathy in familial Alzheimer’s disease. Neurobiol Aging. 2015;36:3140–51.

    Article  CAS  Google Scholar 

  36. Ridha BH, Barnes J, Bartlett JW, Godbolt A, Pepple T, Rossor MN, et al. Tracking atrophy progression in familial Alzheimer’s disease: a serial MRI study. Lancet Neurol. 2006;5:828–34.

    Article  Google Scholar 

  37. Boccardi M, Gallo V, Yasui Y, Vineis P, Padovani A, Mosimann U, et al. The biomarker-based diagnosis of Alzheimer’s disease. 2—lessons from oncology. Neurobiology of Aging. 2017;52:141–52.

    Article  Google Scholar 

  38. Frisoni GB, Boccardi M, Barkhof F, Blennow K, Cappa S, Chiotis K, et al. Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. Lancet Neurol. 2017;16:661–76.

    Article  Google Scholar 

  39. Toledo JB, Zetterberg H, van Harten AC, Glodzik L, Martinez-Lage P, Bocchio-Chiavetto L, et al. Alzheimer’s disease cerebrospinal fluid biomarker in cognitively normal subjects. Brain. 2015;138:2701–15.

    Article  Google Scholar 

Download references

Acknowledgements

AOC is supported by an Alzheimer’s Society clinical research training fellowship. TKK was supported by the Swedish Alzheimer Foundation, the Swedish Dementia Foundation, Gamla Tjänarinnor, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, and the Anna Lisa and Brother Björnsson’s Foundation. NJA is funded by the Wallenburg Centre for Molecular and Translational. NSR is supported by a University of London Chadburn Academic Clinical Lectureship. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931) and the UK Dementia Research Institute at UCL. This work was supported by the NIHR UCLH/UCL Biomedical Research Centre, the Rosetrees Trust, the MRC Dementia Platform UK and the UK Dementia Research Institute at UCL which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK.

Author information

Author notes

  1. These authors contributed equally: Antoinette O’Connor, Thomas K. Karikari, Teresa Poole, Henrik Zetterberg, Nick C. Fox

Authors and Affiliations

  1. Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK

    Antoinette O’Connor, Teresa Poole, Ayesha Khatun, Philip S. J. Weston, Ivanna M. Pavisic, Natalie S. Ryan, Suzie Barker, Martin N. Rossor & Nick C. Fox

  2. UK Dementia Research Institute at UCL, London, UK

    Antoinette O’Connor, Imogen Swift, Amanda J. Heslegrave, Emily Abel, Elisha Chung, Natalie S. Ryan, Henrik Zetterberg & Nick C. Fox

  3. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden

    Thomas K. Karikari, Nicholas J. Ashton, Juan Lantero Rodriguez, Kaj Blennow & Henrik Zetterberg

  4. Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK

    Teresa Poole & Chris Frost

  5. Wallenberg Centre for Molecular and Translational Medicine, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London, UK

    Nicholas J. Ashton

  6. NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia, South London & Maudsley NHS Foundation, London, UK

    Nicholas J. Ashton

  7. Neurogenetics Laboratory, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK

    James M. Polke

  8. National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK

    Simon Mead

  9. MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, UK

    Simon Mead

  10. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden

    Kaj Blennow & Henrik Zetterberg

Authors
  1. Antoinette O’Connor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas K. Karikari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Teresa Poole
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nicholas J. Ashton
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Juan Lantero Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ayesha Khatun
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Imogen Swift
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Amanda J. Heslegrave
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Emily Abel
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Elisha Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Philip S. J. Weston
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ivanna M. Pavisic
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Natalie S. Ryan
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Suzie Barker
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Martin N. Rossor
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. James M. Polke
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Chris Frost
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Simon Mead
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Kaj Blennow
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Henrik Zetterberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Nick C. Fox
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AOC, NCF did the literature search. AOC, TKK, KB, HZ and NCF designed the study. AOC, PSJW, NSR, IP and AK contributed to recruitment. Data were collected by AOC, PSJW and NSR. Blood samples were processed and analysed by AJH, EA, EC, IS, NJA, JLR, TKK and HZ. TP and CF carried out the statistical analysis. SM and JP contributed to the genetic analysis. TP created the figures. All authors were involved in the interpretation of results and writing the report.

Corresponding authors

Correspondence to Henrik Zetterberg or Nick C. Fox.

Ethics declarations

Conflict of interest

KB has served as a consultant or at advisory boards for Abcam, Axon, Biogen, Lilly, MagQu, Novartis and Roche Diagnostics, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. The other authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

O’Connor, A., Karikari, T.K., Poole, T. et al. Plasma phospho-tau181 in presymptomatic and symptomatic familial Alzheimer’s disease: a longitudinal cohort study. Mol Psychiatry 26, 5967–5976 (2021). https://doi.org/10.1038/s41380-020-0838-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-020-0838-x

This article is cited by

Search

Advanced search

Quick links