Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration

Abstract

With the potential development of new disease-modifying Alzheimer’s disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals, who are experiencing symptoms of cognitive or behavioral decline, should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved cerebrospinal fluid or amyloid β positron emission tomography (PET) diagnostic tests. We examined whether plasma tau phosphorylated at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration. Plasma pTau181 concentrations were increased by 3.5-fold in AD compared to controls and differentiated AD from both clinically diagnosed (receiver operating characteristic area under the curve of 0.894) and autopsy-confirmed frontotemporal lobar degeneration (area under the curve of 0.878). Plasma pTau181 identified individuals who were amyloid β-PET-positive regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18F-flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Plasma pTau181 and plasma NfL per clinical diagnosis.
Fig. 2: Plasma pTau181 in pathology-confirmed cases and MAPT mutation carriers.
Fig. 3: Association of pTau181 and NfL, PiB-PET SUVR, FTP-PET SUVR and amyloid and FTP-PET status.
Fig. 4: Voxelwise correlations of plasma pTau181 and plasma NfL with FTP-PET and gray matter atrophy.

Data availability

All requests for raw and analyzed data and materials will be promptly reviewed by the corresponding author and the University of California, San Francisco to verify whether the request is subject to any intellectual property or confidentiality obligations. Some participant data not included in the paper were generated as part of clinical trials and may be subject to patient confidentiality limitations. Data and materials from participants with FTLD enrolled in ARTFL are accessible via forms that can be found on the ARTFL website (https://www.rarediseasesnetwork.org/cms/artfl/Healthcare-Professionals/Collaborating). Other data and materials that can be shared will be released via a material transfer agreement.

Code availability

All requests for code used for data analyses and data visualization will be promptly reviewed by the corresponding author and the UCSF to verify whether the request is subject to any intellectual property, confidentiality or other licensing obligations. If there are no limitations, the corresponding author will communicate with the requester to share the code.

References

  1. 1.

    Nature News Round-up. Swine flu snipers, Alzheimer’s drug push and Google’s latest gaming bot. Nature 574 602–603 (2019).

  2. 2.

    Rabinovici, G. D. et al. Association of amyloid positron emission tomography with subsequent change in clinical management among Medicare beneficiaries with mild cognitive impairment or dementia. J. Am. Med. Assoc. 94158, 1286–1294 (2019).

  3. 3.

    Landau, S. M. et al. Comparing positron emission tomography imaging and cerebrospinal fluid measurements of β-amyloid. Ann. Neurol. 74, 826–836 (2013).

  4. 4.

    Palmqvist, S. et al. Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease. Neurology 85, 1240–1249 (2015).

  5. 5.

    Rabinovici, G. D. & Miller, B. L. Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management. CNS Drugs 24, 375–398 (2010).

  6. 6.

    Bahia, V. S., Takada, L. T. & Deramecourt, V. Neuropathology of frontotemporal lobar degeneration: a review. Dement. Neuropsychol. 7, 19–26 (2013).

  7. 7.

    Buerger, K. et al. CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer’s disease. Brain 129, 3035–3041 (2006).

  8. 8.

    Tapiola, T. et al. Cerebrospinal fluid β-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Arch. Neurol. 66, 382–389 (2009).

  9. 9.

    Schöll, M. et al. Biomarkers for tau pathology. Mol. Cell. Neurosci. 97, 18–33 (2019).

  10. 10.

    Marquié, M. et al. Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue. Ann. Neurol. 78, 787–800 (2015).

  11. 11.

    Ossenkoppele, R. et al. Discriminative accuracy of [18F]flortaucipir positron emission tomography for Alzheimer disease vs other neurodegenerative disorders. J. Am. Med. Assoc. 320, 1151–1162 (2018).

  12. 12.

    Bacioglu, M. et al. Neurofilament light chain in blood and CSF as marker of disease progression in mouse models and in neurodegenerative diseases. Neuron 91, 56–66 (2016).

  13. 13.

    Meeter, L. H., Kaat, L. D., Rohrer, J. D. & Van Swieten, J. C. Imaging and fluid biomarkers in frontotemporal dementia. Nat. Rev. Neurol. 13, 406–419 (2017).

  14. 14.

    Khalil, M. et al. Neurofilaments as biomarkers in neurological disorders. Nat. Rev. Neurol. 14, 577–589 (2018).

  15. 15.

    Meeter, L. H. H. et al. Clinical value of neurofilament and phospho-tau/tau ratio in the frontotemporal dementia spectrum. Neurology 90, e1231–e1239 (2018).

  16. 16.

    Ljubenkov, P. A. et al. Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory. Ann. Clin. Transl. Neurol. 5, 1250–1263 (2018).

  17. 17.

    Scherling, C. S. et al. CSF neurofilament concentration reflects disease severity in frontotemporal degeneration. Ann. Neurol. 75, 116–126 (2014).

  18. 18.

    Rojas, J. C. et al. CSF neurofilament light chain and phosphorylated tau 181 predict disease progression in PSP. Neurology 90, e273–e281 (2018).

  19. 19.

    Rohrer, J. D. et al. Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia. Neurology 87, 1329–1336 (2016).

  20. 20.

    Steinacker, P. et al. Serum neurofilament light chain in behavioral variant frontotemporal dementia. Neurology 91, e1390–e1401 (2018).

  21. 21.

    Bridel, C., van Wieringen, W. N. & Zetterberg, H. Diagnostic value of cerebrospinal fluid neurofilament light protein in neurology: a systematic review and meta-analysis. JAMA Neurol. 76, 1035–1048 (2019).

  22. 22.

    Preische, O. et al. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease. Nat. Med. 25, 277–283 (2019).

  23. 23.

    Mattsson, N., Cullen, N. C., Andreasson, U., Zetterberg, H. & Blennow, K. Association between longitudinal plasma neurofilament light and neurodegeneration in patients with Alzheimer disease. JAMA Neurol. 76, 791–799 (2019).

  24. 24.

    Nakamura, A. et al. High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature 554, 249–254 (2018).

  25. 25.

    Ovod, V. et al. Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement. 13, 841–849 (2017).

  26. 26.

    Janelidze, S. et al. Plasma β-amyloid in Alzheimer’s disease and vascular disease. Sci. Rep. 6, 26801 (2016).

  27. 27.

    Mielke, M. M. et al. Association of plasma total tau level with cognitive decline and risk of mild cognitive impairment or dementia in the Mayo Clinic study on aging. JAMA Neurol. 74, 1073–1080 (2017).

  28. 28.

    Mattsson, N. et al. Plasma tau in Alzheimer disease. Neurology 87, 1827–1835 (2016).

  29. 29.

    Chen, Z. et al. Learnings about the complexity of extracellular tau aid development of a blood-based screen for Alzheimer’s disease. Alzheimers Dement. 15, 487–496 (2018).

  30. 30.

    Hampel, H. et al. Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic. Nat. Rev. Neurol. 14, 639–652 (2018).

  31. 31.

    Mielke, M. M. 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. 14, 989–997 (2018).

  32. 32.

    Ghetti, B. et al. Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging. Neuropathol. Appl. Neurobiol. 41, 24–46 (2015).

  33. 33.

    Maass, A. et al. NeuroImage comparison of multiple tau-PET measures as biomarkers in aging and Alzheimer’ s disease. Neuroimage 157, 448–463 (2017).

  34. 34.

    Braak, H. & Braak, E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).

  35. 35.

    Braak, H., Thal, D. R., Ghebremedhin, E. & Del Tredici, K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J. Neuropathol. Exp. Neurol. 70, 960–969 (2011).

  36. 36.

    Rabinovici, G. D. et al. Distinct MRI atrophy patterns in autopsy-proven Alzheimer’s disease and frontotemporal lobar degeneration. Am. J. Alzheimers Dis. Other Demen. 22, 474–488 (2007).

  37. 37.

    Halabi, C. et al. Patterns of striatal degeneration in frontotemporal dementia. Alzheimer Dis. Assoc. Disord. 27, 74–83 (2013).

  38. 38.

    Doraiswamy, P. M. et al. Florbetapir F 18 amyloid PET and 36-month cognitive decline: a prospective multicenter study. Mol. Psychiatry 19, 1044–1051 (2014).

  39. 39.

    Clark, C. M. et al. Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-β plaques: a prospective cohort study. Lancet Neurol. 11, 669–678 (2012).

  40. 40.

    La Joie, R. et al. Multisite study of the relationships between antemortem [11C] PIB-PET centiloid values and postmortem measures of Alzheimer’s disease neuropathology. Alzheimers Dement. 15, 205–216 (2019).

  41. 41.

    Rabinovici, G. D. et al. Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD. Neurology 77, 2034–2042 (2011).

  42. 42.

    Knopman, D. S. et al. Entorhinal cortex tau, amyloid-β, cortical thickness and memory performance in non-demented subjects. Brain 142, 1148–1160 (2019).

  43. 43.

    van Harten, A. C. et al. Tau and p-tau as CSF biomarkers in dementia: a meta-analysis. Clin. Chem. Lab. Med. 49, 353–366 (2011).

  44. 44.

    Rivero-Santana, A. et al. Cerebrospinal fluid biomarkers for the differential diagnosis between Alzheimer’s disease and frontotemporal lobar degeneration: systematic review, HSROC analysis, and confounding factors. J. Alzheimers Dis. 55, 625–644 (2017).

  45. 45.

    del Campo, M. et al. Novel CSF biomarkers to discriminate FTLD and its pathological subtypes. Ann. Clin. Transl. Neurol. 5, 1163–1175 (2018).

  46. 46.

    Jones, D. T. et al. In vivo 18F-AV-1451 tau PET signal in MAPT mutation carriers varies by expected tau isoforms. Neurology 90, e947–e954 (2018).

  47. 47.

    Smith, R. et al. 18F-AV-1451 tau PET imaging correlates strongly with tau neuropathology in MAPT mutation carriers. Brain 139, 2372–2379 (2016).

  48. 48.

    La Joie, R. et al. Associations between [18 F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample. Neurology 90, e282–e290 (2018).

  49. 49.

    Pontecorvo, M. J. et al. Relationships between flortaucipir PET tau binding and amyloid burden, clinical diagnosis, age and cognition. Brain 140, 748–763 (2017).

  50. 50.

    Jack, C. R. et al. Longitudinal tau PET in ageing and Alzheimer’s disease. Brain 141, 1517–1528 (2018).

  51. 51.

    Palmqvist, S. et al. Performance of fully automated plasma assays as screening tests for Alzheimer disease-related β-amyloid status. JAMA Neurol. 76, 1060–1069 (2019).

  52. 52.

    Lee, S. E. et al. Clinicopathological correlations in corticobasal degeneration. Ann. Neurol. 70, 327–340 (2011).

  53. 53.

    McKhann, G. M. et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers. Dement. 7, 263–269 (2011).

  54. 54.

    Albert, M. S. et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers. Dement. 7, 270–279 (2011).

  55. 55.

    Hoglinger, G. U. et al. Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria HHS public access author manuscript. Mov. Disord. 32, 853–864 (2017).

  56. 56.

    Rascovsky, K. et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134, 2456–2477 (2011).

  57. 57.

    Gorno-Tempini, M. L. et al. Classification of primary progressive aphasia and its variants. Neurology 76, 1006–1014 (2011).

  58. 58.

    Lynch, C. A. et al. The clinical dementia rating sum of box score in mild dementia. Dement. Geriatr. Cogn. Disord. 21, 40–43 (2006).

  59. 59.

    Folstein, M. F., Folstein, S. E. & McHugh, P. R. ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 12, 189–198 (1975).

  60. 60.

    Kramer, J. H. et al. Distinctive neuropsychological patterns in frontotemporal dementia, semantic dementia, and Alzheimer disease. Cogn. Behav. Neurol. 16, 211–218 (2003).

  61. 61.

    D’Elia, L. F., Satz, P., Uchiyama, C. & White, T. Color Trails Test. Professional Manual (Psychological Assessment Resources, 1996).

  62. 62.

    Heaton, R., Miller, S., Taylor, M. & Grant, I. Revised Comprehensive Norms for an Expanded Halstead-Reitan Battery: Demographically Adjusted Neuropsychological Norms for African American and Caucasian Adults (Psychological Assessment Resources, 2004).

  63. 63.

    Kaplan, E., Goodglass, H. & Weintraub, S. Boston Naming Test (Lea & Febiger, 1983).

  64. 64.

    Yesavage, J. A. et al. Development and validation of a geriatric depression screening scale: a preliminary report. J. Psychiatr. Res. 17, 37–49 (1982).

  65. 65.

    Pfeffer, R. I., Kurosaki, T. T., Harrah, C. H. J., Chance, J. M. & Filos, S. Measurement of functional activities in older adults in the community. J. Gerontol. 37, 323–329 (1982).

  66. 66.

    Schwab, R. & England, A. in Third Symposium on Parkinson’s Disease (eds Billingham, F. H. & Donaldson, M. C.) (Churchill Livingstone, 1969).

  67. 67.

    Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. B 57, 289–300 (1995).

  68. 68.

    Youden, W. J. Index for rating diagnostic tests. Cancer 3, 32–35 (1950).

  69. 69.

    Alzheimer’s Disease Neuroimaging Initiative (ADNI). ADNI2 Procedures Manual (2010). https://adni.loni.usc.edu/wp-content/uploads/2008/07/adni2-procedures-manual.pdf

  70. 70.

    Ashburner, J. & Friston, K. J. Unified segmentation. Neuroimage 26, 839–851 (2005).

  71. 71.

    Malone, I. B. et al. Accurate automatic estimation of total intracranial volume: a nuisance variable with less nuisance. Neuroimage 104, 366–372 (2015).

  72. 72.

    Ashburner, J. & Friston, K. J. NeuroImage diffeomorphic registration using geodesic shooting and Gauss–Newton optimisation. Neuroimage 55, 954–967 (2011).

  73. 73.

    Southekal, S. et al. Flortaucipir F18 quantitation using parametric estimation of reference signal intensity. J. Nucl. Med. 59, 944–951 (2018).

  74. 74.

    Devous, M. D. et al. Test–retest reproducibility for the tau PET imaging agent flortaucipir F 18. J. Nucl. Med. 59, 937–943 (2018).

  75. 75.

    Villeneuve, S. et al. Existing Pittsburgh Compound-B positron emission tomography thresholds are too high: statistical and pathological evaluation. Brain 138, 2020–2033 (2015).

  76. 76.

    Xia, M., Wang, J. & He, Y. BrainNet Viewer: a network visualization tool for human brain connectomics. PLoS One 8, e68910 (2013).

Download references

Acknowledgements

S. Lowe designed and conducted Eli Lilly’s study (NCT02624778) and provided a critical review of the manuscript. Data collection and dissemination of the data presented in this manuscript was supported by the LEFFTDS and ARTFL Consortium (LEFFTDS, U01 AG045390 (B.F.B. and H.R.)), funded by the National Institute on Aging and the National Institute of Neurological Diseases and Stroke (ARTFL, U54-NS092089 (A.L.B.)), part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Science (NCATS), and funded through a collaboration between NCATS and the National Institute of Neurological Disorders and Stroke, the Larry L. Hillblom Network and grant P01-AG019724-17 (B.L.M.). Samples from the National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886 (T. Foroud)), were used in this study. Imaging analyses were funded by the Tau Consortium, National Institute on Aging grants (R01-AG045611 (G.D.R.), P50-AG023501 (B.L.M.), P50-AG016574 (B.F.B.), P01-AG19724 (B.L.M.), R01-AG038791 (A.L.B.), U54-NS092089 (A.L.B.), State of California Department of Health Services Alzheimer’s Disease Research Center of California grant (04-33516 (B.L.M.)); Michael J. Fox Foundation (G.D.R.); Alzheimer’s Association (AARF-16-443577, R.L.J.) and K08AG052648 (S.S.). L.T.G. receives support from K24AG053435. J.C.R. receives support from K23AG059888. Avid Radiopharmaceuticals enabled use of the 18F-AV-1451 tracer by providing a precursor, but did not provide direct funding and was not involved in data analysis or interpretation. The funding agencies had no role in the design and conduct of the study, collection, management, analysis or interpretation of the data, preparation, review or approval of the manuscript or decision to submit the manuscript for publication.

Author information

E.H.T. and J.C.R. had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. E.H.T., J.L.D., J.C.R. and A.L.B. were responsible for concept development and design. All authors contributed to acquisition, analysis or interpretation of data. E.H.T. drafted the manuscript. E.H.T., R.L.J., J.L.D., J.C.R. and A.L.B. critically revised the manuscript. E.H.T., R.L.J., P.W., D.C.A. and J.C.R. conducted statistical analyses. A.L.B., B.F.B., H.R., B.L.M., G.D.R., J.H.K. and J.L.D. obtained funding. J.L.D., J.C.R. and A.L.B. supervised the research.

Correspondence to Adam L. Boxer.

Ethics declarations

Competing interests

E.H.T, R.L.J., A.W., A.S., P.W., L.I., V.B., Y.C., H.H., S.S., A.M.K., C.E.T., J.H.K., W.W.S., H.R., B.F.B. and B.L.M. declare no conflict of interest. J.L.D., X.C., N.K.P., D.C.A., S.S., C.D.E. and J.R.S. are employees of Eli Lilly and Company. H.Z. has served on scientific advisory boards for Roche Diagnostics, Wave, Samumed and CogRx, has given lectures in symposia sponsored by Alzecure and Biogen and is a cofounder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. K.B. served as a consultant or on advisory boards for Alector, Biogen, CogRx, Eli Lilly, MagQu, Novartis and Roche Diagnostics and is a cofounder of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg, all unrelated to the work presented in this paper. L.T.G. receives research support from Avid Radiopharmaceuticals and Eli Lilly. She has received consulting fees from the Simon Foundation and Cura Sen. She serves as Associate Editor for Frontiers in Aging Neurosciences, Frontiers in Dementia and the Journal of Alzheimer Disease. G.D.R. receives research support from the National Institutes of Health (NIH), Alzheimer’s Association, American College of Radiology, Tau Research Consortium, Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare and Life Molecular Imaging. He has served as a consultant for Eisai, Merck and Axon Neurosciences. He received speaking honoraria from GE Healthcare. He serves as Associate Editor for JAMA Neurology. J.C.R. is a Site Principal Investigator for clinical trials supported by Eli Lilly and receives support from NIH. A.L.B. receives research support from NIH, the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimer’s Drug Discovery Foundation and the Alzheimer’s Association. He has served as a consultant for Aeton, Abbvie, Alector, AGTC, Amgen, Arkuda, Arvinas, Asceneuron, Eisai, Ionis, Lundbeck, Novartis, Passage BIO, Sangamo, Samumed, Third Rock, Toyama and UCB, and received research support from Avid, Biogen, BMS, C2N, Cortice, Eisai, Eli Lilly, Forum, Genentech, Janssen, Novartis, Pfizer, Roche and TauRx.

Additional information

Peer review information Brett Benedetti and Kate Gao were the primary editors on this article, and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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

Extended data

Extended Data Fig. 1 Plasma pTau/NfL ratio per clinical diagnosis.

The ratio of pTau181/NfL was decreased in all FTLD diagnoses compared to controls, ADclin and MCI patients (n=212). **p<0.001 *p<0.05.

Extended Data Fig. 2 Plasma Aβ 42/40 ratio per clinical diagnosis and Amyloid PET and FTP-PET status.

a. There was no difference in plasma Aβ 42/40 ratio between the different phenotypes(n=178). b. The Aβ 42/40 ratio was decreased in Amyloid PET positive cases (n=135). c. The Aβ 42/40 ratio was decreased in FTP-PET positive cases (n=76).

Extended Data Fig. 3 Plasma NfL concentrations per autopsy determined Braak stage.

There was no difference in plasma NfL concentrations between the different Braak stages (n=69).

Extended Data Fig. 4 Plasma pTau181 and plasma NfL concentrations in mutation carriers.

a. Plasma pTau181 concentrations did not differ between mutation carriers (n=120). b. Plasma NfL concentrations were elevated in GRN and C9orf72 mutation carriers compared to the control group (p<0.0001) and MAPT mutation carriers (p<0.01) (n=59). **p<0.01.

Extended Data Fig. 5 Association between plasma pTau181 and CSF pTau181.

CSF pTau181 is associated with plasma pTau181 (β=0.51, p<0.0001; n=74), and is also associated within the AD/MCI (β=0.41, p=0.042; n=25), and the FTLD group (β=0.49, p<0.0001; n=29), but not in controls.

Extended Data Fig. 6 Receiver Operating Characteristic analyses of plasma pTau181 for Aβ-PET status in MCI patients and in controls.

a. Plasma pTau181 concentrations are increased in Aβ-PET positive MCI cases. pTau181 could differentiate between Aβ-PET positive and negative cases (visual read). AUC=0.944 (95% CI: 0.873-1.000, p<0.0001, n= 18 Aβ-PET positive, 21 negative), with a cut-off of 8.4 pg/mL (0.944 sensitivity and 0.857 specificity). b. Plasma pTau181 concentrations are increased in Aβ-PET positive NC cases. pTau181 could differentiate between Aβ-PET positive and negative cases (visual read). AUC=0.859 (95% CI: 0.732-0.986, p=0.001, n=11 Aβ-PET positive, 29 negative), with a cut-off of 7.1 pg/mL (0.818 sensitivity and 0.828 specificity). Notch displays the confidence interval around the median. ***p<0.0001 **p<0.01.

Extended Data Fig. 7 Plasma pTau181 and plasma NfL concentrations per FTP-PET estimated Braak stage.

a. Plasma pTau181 was increased in Braak stage 5-6, and Braak stage 3-4 compared to Braak stage 0 (n=97). b. There was no difference in plasma NfL concentrations between the different Braak stages (n=61). ***p<0.0001.

Supplementary information

Supplementary Information

Supplementary Results; Supplementary Tables 1–5; STARD 2015 Checklist

Reporting Summary

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Thijssen, E.H., La Joie, R., Wolf, A. et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med 26, 387–397 (2020). https://doi.org/10.1038/s41591-020-0762-2

Download citation

Further reading