Abstract
Alzheimer’s disease (AD), the most common age-dependent neurodegenerative disorder, is characterized neuropathologically by extracellular Aβ plaques and intracellular tau neurofibrillary tangles. While in AD tau pathology probably follows early alterations in Aβ metabolism, it develops independently in the so-called primary tauopathies, the main form being frontotemporal lobar degeneration with tau pathology. Tau pathology in AD brain is reflected in the cerebrospinal fluid (CSF) by elevated levels of the two AD tau biomarkers total and phosphorylated tau, which are now used for routine diagnostic purposes. On the contrary, no established neurochemical biomarkers exist for tau pathology in primary tauopathies. Thanks to recent technological advances, total and phosphorylated tau can now be quantified also on peripheral blood, and accumulating evidence shows that measurement of plasma phosphorylated tau species (P-tau181, P-tau217, and P-tau231) has high performances in discriminating AD patients from cognitively unimpaired subjects but also from patients with other dementias. Moreover, plasma P-tau levels are associated with tracer uptake on tau- and amyloid-PET as well as with brain atrophy, cognitive measures and longitudinal changes of these parameters. These features, together with the low invasiveness, scalability, and ease of longitudinal sampling, which differentiate plasma P-tau species from their CSF counterparts, make these proteins promising peripheral biomarkers for AD in both research and clinical setting. This review discusses the recent developments in the field of plasma tau proteins as diagnostic, pathophysiological and prognostic biomarkers of Alzheimer’s disease; additional findings from the fields of genetic forms of AD and of non-AD proteinopathies are also summarized.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ashton NJ, Pascoal TA, Karikari TK et al (2021) Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology. Acta Neuropathol 141(5):709–724. https://doi.org/10.1007/s00401-021-02275-6
Barthélemy NR, Horie K, Sato C, Bateman RJ (2020) Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease. J Exp Med. https://doi.org/10.1084/jem.20200861
Benussi A, Karikari TK, Ashton N et al (2020) Diagnostic and prognostic value of serum NfL and p-Tau181 in frontotemporal lobar degeneration. J Neurol Neurosurg Psychiatry 91(9):960–967. https://doi.org/10.1136/jnnp-2020-323487
Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82(4):239–259. https://doi.org/10.1007/BF00308809
Brickman AM, Manly JJ, Honig LS et al (2021) Plasma p-tau181, p-tau217, and other blood-based Alzheimer’s disease biomarkers in a multi-ethnic, community study. Alzheimers Dement 17(8):1353–1364. https://doi.org/10.1002/alz.12301
Cavedo E, Lista S, Houot M et al (2020) Plasma tau correlates with basal forebrain atrophy rates in people at risk for Alzheimer disease. Neurology 94(1):e30–e41. https://doi.org/10.1212/WNL.0000000000008696
Chen NC, Chen HL, Li SH et al (2020) Plasma levels of alpha-synuclein, abeta-40 and T-tau as biomarkers to predict cognitive impairment in Parkinson’s disease. Front Aging Neurosci 12:112. https://doi.org/10.3389/fnagi.2020.00112
Chen SD, Huang YY, Shen XN et al (2021) Longitudinal plasma phosphorylated tau 181 tracks disease progression in Alzheimer’s disease. Transl Psychiatry 11(1):356. https://doi.org/10.1038/s41398-021-01476-7
Chiu MJ, Yang SY, Chen TF et al (2021) Synergistic association between plasma Abeta1-42 and p-tau in Alzheimer’s disease but not in Parkinson’s disease or frontotemporal dementia. ACS Chem Neurosci 12(8):1376–1383. https://doi.org/10.1021/acschemneuro.1c00010
Chong JR, Ashton NJ, Karikari TK et al (2021) Blood-based high sensitivity measurements of beta-amyloid and phosphorylated tau as biomarkers of Alzheimer’s disease: a focused review on recent advances. J Neurol Neurosurg Psychiatry 92(11):1231–1241. https://doi.org/10.1136/jnnp-2021-327370
Chung DC, Roemer S, Petrucelli L, Dickson DW (2021) Cellular and pathological heterogeneity of primary tauopathies. Mol Neurodegen 16(1):57. https://doi.org/10.1186/s13024-021-00476-x
Clark C, Lewczuk P, Kornhuber J et al (2021) Plasma neurofilament light and phosphorylated tau 181 as biomarkers of Alzheimer’s disease pathology and clinical disease progression. Alzheimers Res Ther 13(1):65. https://doi.org/10.1186/s13195-021-00805-8
Dage JL, Wennberg AMV, Airey DC et al (2016) Levels of tau protein in plasma are associated with neurodegeneration and cognitive function in a population-based elderly cohort. Alzheimers Dement 12(12):1226–1234. https://doi.org/10.1016/j.jalz.2016.06.001
de Wolf F, Ghanbari M, Licher S et al (2020) Plasma tau, neurofilament light chain and amyloid-beta levels and risk of dementia; a population-based cohort study. Brain 143(4):1220–1232. https://doi.org/10.1093/brain/awaa054
Foiani MS, Woollacott IO, Heller C et al (2018) Plasma tau is increased in frontotemporal dementia. J Neurol Neurosurg Psychiatry 89(8):804–807. https://doi.org/10.1136/jnnp-2017-317260
Fortea J, Carmona-Iragui M, Benejam B et al (2018) Plasma and CSF biomarkers for the diagnosis of Alzheimer’s disease in adults with Down syndrome: a cross-sectional study. Lancet Neurol 17(10):860–869. https://doi.org/10.1016/S1474-4422(18)30285-0
Fortea J, Vilaplana E, Carmona-Iragui M et al (2020) Clinical and biomarker changes of Alzheimer’s disease in adults with Down syndrome: a cross-sectional study. Lancet 395(10242):1988–1997. https://doi.org/10.1016/S0140-6736(20)30689-9
Frisoni GB, Boccardi M, Barkhof F et al (2017) Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. Lancet Neurol 16(8):661–676. https://doi.org/10.1016/S1474-4422(17)30159-X
Gonzalez MC, Ashton NJ, Gomes BF et al (2021) Association of plasma p-tau181 and p-tau231 concentrations with cognitive decline in patients with probable dementia with Lewy bodies. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2021.4222
Grothe MJ, Moscoso A, Ashton NJ et al (2021) Associations of fully automated CSF and novel plasma biomarkers with Alzheimer disease neuropathology at autopsy. Neurology. https://doi.org/10.1212/WNL.0000000000012513
Hall S, Janelidze S, Londos E et al (2021) Plasma phospho-tau identifies Alzheimer’s co-pathology in patients with lewy body disease. Mov Disord 36(3):767–771. https://doi.org/10.1002/mds.28370
Hampel H, Buerger K, Zinkowski R et al (2004) Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch Gen Psychiatry 61(1):95–102. https://doi.org/10.1001/archpsyc.61.1.95
Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L (2006) Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 5(3):228–234. https://doi.org/10.1016/S1474-4422(06)70355-6
Hesse C, Rosengren L, Andreasen N et al (2001) Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke. Neurosci Lett 297(3):187–190. https://doi.org/10.1016/s0304-3940(00)01697-9
Illán-Gala I, Lleó A, Karydas A et al (2021) Plasma tau and neurofilament light in frontotemporal lobar degeneration and Alzheimer disease. Neurology 96(5):e671–e683. https://doi.org/10.1212/WNL.0000000000011226
Jack CR Jr, Bennett DA, Blennow K et al (2018) NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement 14(4):535–562. https://doi.org/10.1016/j.jalz.2018.02.018
Janelidze S, Mattsson N, Palmqvist S et al (2020a) Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med 26(3):379–386. https://doi.org/10.1038/s41591-020-0755-1
Janelidze S, Stomrud E, Smith R et al (2020b) Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease. Nat Commun 11(1):1683. https://doi.org/10.1038/s41467-020-15436-0
Janelidze S, Palmqvist S, Leuzy A et al (2021a) Detecting amyloid positivity in early Alzheimer’s disease using combinations of plasma Abeta42/Abeta40 and p-tau. Alzheimers Dement. https://doi.org/10.1002/alz.12395
Janelidze S, Berron D, Smith R et al (2021b) Associations of plasma phospho-Tau217 levels with tau positron emission tomography in early Alzheimer disease. JAMA Neurol 78(2):149–156. https://doi.org/10.1001/jamaneurol.2020.4201
Karikari TK, Pascoal TA, Ashton NJ et al (2020) 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 19(5):422–433. https://doi.org/10.1016/S1474-4422(20)30071-5
Karikari TK, Benedet AL, Ashton NJ et al (2021) Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer’s Disease Neuroimaging Initiative. Mol Psychiatry 26(2):429–442. https://doi.org/10.1038/s41380-020-00923-z
La Joie R, Bejanin A, Fagan AM et al (2018) Associations between [(18)F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample. Neurology 90(4):e282–e290. https://doi.org/10.1212/WNL.0000000000004860
Lantero Rodriguez J, Karikari TK, Suarez-Calvet M et al (2020) Plasma p-tau181 accurately predicts Alzheimer’s disease pathology at least 8 years prior to post-mortem and improves the clinical characterisation of cognitive decline. Acta Neuropathol 140(3):267–278. https://doi.org/10.1007/s00401-020-02195-x
Leuzy A, Mattsson-Carlgren N, Palmqvist S, Janelidze S, Dage JL, Hansson O (2021) Blood-based biomarkers for Alzheimer’s disease. EMBO Mol Med. https://doi.org/10.15252/emmm.202114408
Lin WT, Shaw JS, Cheng FY, Chen PH (2022) Plasma total tau predicts executive dysfunction in Parkinson’s disease. Acta Neurol Scand 145(1):30–37. https://doi.org/10.1111/ane.13517
Lleó A, Zetterberg H, Pegueroles J et al (2021) Phosphorylated tau181 in plasma as a potential biomarker for Alzheimer’s disease in adults with Down syndrome. Nat Commun 12(1):4304. https://doi.org/10.1038/s41467-021-24319-x
Lussier FZ, Benedet AL, Therriault J et al (2021) Plasma levels of phosphorylated tau 181 are associated with cerebral metabolic dysfunction in cognitively impaired and amyloid-positive individuals. Brain Commun 3(2):fcab073. https://doi.org/10.1093/braincomms/fcab073
Maia LF, Kaeser SA, Reichwald J et al (2013) Changes in amyloid-beta and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci Transl Med 5(194):194re2. https://doi.org/10.1126/scitranslmed.3006446
Marks JD, Syrjanen JA, Graff-Radford J et al (2021) Comparison of plasma neurofilament light and total tau as neurodegeneration markers: associations with cognitive and neuroimaging outcomes. Alzheimers Res Ther 13(1):199. https://doi.org/10.1186/s13195-021-00944-y
Mattsson N, Zetterberg H, Janelidze S et al (2016) Plasma tau in Alzheimer disease. Neurology 87(17):1827–1835. https://doi.org/10.1212/WNL.0000000000003246
Mattsson-Carlgren N, Janelidze S, Palmqvist S et al (2020) Longitudinal plasma p-tau217 is increased in early stages of Alzheimer’s disease. Brain 143(11):3234–3241. https://doi.org/10.1093/brain/awaa286
Mattsson-Carlgren N, Janelidze S, Bateman RJ et al (2021) Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau. EMBO Mol Med 13(6):e14022. https://doi.org/10.15252/emmm.202114022
Mengel D, Janelidze S, Glynn RJ, Liu W, Hansson O, Walsh DM (2020) Plasma NT1 tau is a specific and early marker of Alzheimer’s disease. Ann Neurol 88(5):878–892. https://doi.org/10.1002/ana.25885
Mielke MM, Hagen CE, Wennberg AMV et al (2017) 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(9):1073–1080. https://doi.org/10.1001/jamaneurol.2017.1359
Mielke MM, Hagen CE, Xu J et al (2018) Plasma phospho-tau181 increases with Alzheimer’s disease clinical severity and is associated with tau- and amyloid-positron emission tomography. Alzheimers Dement 14(8):989–997. https://doi.org/10.1016/j.jalz.2018.02.013
Mielke MM, Frank RD, Dage JL et al (2021) Comparison of plasma phosphorylated tau species with amyloid and tau positron emission tomography, neurodegeneration, vascular pathology, and cognitive outcomes. JAMA Neurol 78(9):1108–1117. https://doi.org/10.1001/jamaneurol.2021.2293
Moscoso A, Grothe MJ, Ashton NJ et al (2021a) Longitudinal associations of blood phosphorylated Tau181 and neurofilament light chain with neurodegeneration in Alzheimer disease. JAMA Neurol 78(4):396–406. https://doi.org/10.1001/jamaneurol.2020.4986
Moscoso A, Grothe MJ, Ashton NJ et al (2021b) Time course of phosphorylated-tau181 in blood across the Alzheimer’s disease spectrum. Brain 144(1):325–339. https://doi.org/10.1093/brain/awaa399
O’Connor A, Karikari TK, Poole T et al (2020) Plasma phospho-tau181 in presymptomatic and symptomatic familial Alzheimer’s disease: a longitudinal cohort study. Mol Psychiatry. https://doi.org/10.1038/s41380-020-0838-x
Olsson B, Lautner R, Andreasson U et al (2016) CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol 15(7):673–684. https://doi.org/10.1016/S1474-4422(16)00070-3
Ossenkoppele R, Reimand J, Smith R et al (2021) Tau PET correlates with different Alzheimer’s disease-related features compared to CSF and plasma p-tau biomarkers. EMBO Mol Med 13(8):e14398. https://doi.org/10.15252/emmm.202114398
Otto M, Wiltfang J, Cepek L et al (2002) Tau protein and 14-3-3 protein in the differential diagnosis of Creutzfeldt-Jakob disease. Neurology 58(2):192–197. https://doi.org/10.1212/wnl.58.2.192
Palmqvist S, Insel PS, Stomrud E et al (2019a) Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer’s disease. EMBO Mol Med 11(12):e11170. https://doi.org/10.15252/emmm.201911170
Palmqvist S, Janelidze S, Stomrud E et al (2019b) Performance of fully automated plasma assays as screening tests for Alzheimer disease-related beta-amyloid status. JAMA Neurol 76(9):1060–1069. https://doi.org/10.1001/jamaneurol.2019.1632
Palmqvist S, Janelidze S, Quiroz YT et al (2020) Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders. JAMA 324(8):772–781. https://doi.org/10.1001/jama.2020.12134
Palmqvist S, Tideman P, Cullen N et al (2021) Prediction of future Alzheimer’s disease dementia using plasma phospho-tau combined with other accessible measures. Nat Med 27(6):1034–1042. https://doi.org/10.1038/s41591-021-01348-z
Park JC, Han SH, Yi D et al (2019) Plasma tau/amyloid-beta1-42 ratio predicts brain tau deposition and neurodegeneration in Alzheimer’s disease. Brain 142(3):771–786. https://doi.org/10.1093/brain/awy347
Pase MP, Beiser AS, Himali JJ et al (2019) Assessment of plasma total tau level as a predictive biomarker for dementia and related endophenotypes. JAMA Neurol 76(5):598–606. https://doi.org/10.1001/jamaneurol.2018.4666
Pereira JB, Janelidze S, Stomrud E et al (2021) Plasma markers predict changes in amyloid, tau, atrophy and cognition in non-demented subjects. Brain 144(9):2826–2836. https://doi.org/10.1093/brain/awab163
Rauchmann BS, Schneider-Axmann T, Perneczky R (2021) Alzheimer’s Disease Neuroimaging I. Associations of longitudinal plasma p-tau181 and NfL with tau-PET, Abeta-PET and cognition. J Neurol Neurosurg Psychiatry 92(12):1289–1295. https://doi.org/10.1136/jnnp-2020-325537
Scheltens P, De Strooper B, Kivipelto M et al (2021) Alzheimer’s disease. Lancet 397(10284):1577–1590. https://doi.org/10.1016/S0140-6736(20)32205-4
Shaw LM, Arias J, Blennow K et al (2018) Appropriate use criteria for lumbar puncture and cerebrospinal fluid testing in the diagnosis of Alzheimer’s disease. Alzheimers Dement 14(11):1505–1521. https://doi.org/10.1016/j.jalz.2018.07.220
Shekhar S, Kumar R, Rai N et al (2016) Estimation of tau and phosphorylated Tau181 in serum of Alzheimer’s disease and mild cognitive impairment patients. PLoS ONE 11(7):e0159099. https://doi.org/10.1371/journal.pone.0159099
Shi Y, Lu X, Zhang L et al (2019) Potential value of plasma amyloid-beta, total tau, and neurofilament light for identification of early Alzheimer’s disease. ACS Chem Neurosci 10(8):3479–3485. https://doi.org/10.1021/acschemneuro.9b00095
Skillbäck T, Farahmand BY, Rosen C et al (2015) Cerebrospinal fluid tau and amyloid-beta1-42 in patients with dementia. Brain 138(Pt 9):2716–2731. https://doi.org/10.1093/brain/awv181
Tatebe H, Kasai T, Ohmichi T et al (2017) Quantification of plasma phosphorylated tau to use as a biomarker for brain Alzheimer pathology: pilot case-control studies including patients with Alzheimer’s disease and down syndrome. Mol Neurodegen 12(1):63. https://doi.org/10.1186/s13024-017-0206-8
Teunissen CE, Verberk IMW, Thijssen EH et al (2022) Blood-based biomarkers for Alzheimer’s disease: towards clinical implementation. Lancet Neurol 21(1):66–77. https://doi.org/10.1016/S1474-4422(21)00361-6
Thijssen EH, La Joie R, Wolf A et al (2020) Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med 26(3):387–397. https://doi.org/10.1038/s41591-020-0762-2
Thijssen EH, La Joie R, Strom A et al (2021) Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer’s disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study. Lancet Neurol 20(9):739–752. https://doi.org/10.1016/S1474-4422(21)00214-3
Vanmechelen E, Vanderstichele H, Davidsson P et al (2000) Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: a sandwich ELISA with a synthetic phosphopeptide for standardization. Neurosci Lett 285(1):49–52. https://doi.org/10.1016/s0304-3940(00)01036-3
Verberk IMW, Misdorp EO, Koelewijn J et al (2021) Characterization of pre-analytical sample handling effects on a panel of Alzheimer’s disease-related blood-based biomarkers: results from the Standardization of Alzheimer’s Blood Biomarkers (SABB) working group. Alzheimers Dement. https://doi.org/10.1002/alz.12510
Wallin AK, Blennow K, Zetterberg H, Londos E, Minthon L, Hansson O (2010) CSF biomarkers predict a more malignant outcome in Alzheimer disease. Neurology 74(19):1531–1537. https://doi.org/10.1212/WNL.0b013e3181dd4dd8
Wu L, Rosa-Neto P, Hsiung GY et al (2012) Early-onset familial Alzheimer’s disease (EOFAD). Can J Neurol Sci 39(4):436–445. https://doi.org/10.1017/s0317167100013949
Xiao Z, Wu X, Wu W et al (2021) Plasma biomarker profiles and the correlation with cognitive function across the clinical spectrum of Alzheimer’s disease. Alzheimers Res Ther 13(1):123. https://doi.org/10.1186/s13195-021-00864-x
Yang CC, Chiu MJ, Chen TF, Chang HL, Liu BH, Yang SY (2018) Assay of plasma phosphorylated tau protein (threonine 181) and total tau protein in early-stage Alzheimer’s disease. J Alzheimers Dis 61(4):1323–1332. https://doi.org/10.3233/JAD-170810
Zerr I, Villar-Pique A, Hermann P et al (2021) Diagnostic and prognostic value of plasma neurofilament light and total-tau in sporadic Creutzfeldt-Jakob disease. Alzheimers Res Ther 13(1):86. https://doi.org/10.1186/s13195-021-00815-6
Zetterberg H, Blennow K (2021) Moving fluid biomarkers for Alzheimer’s disease from research tools to routine clinical diagnostics. Mol Neurodegen 16(1):10. https://doi.org/10.1186/s13024-021-00430-x
Zetterberg H, Wilson D, Andreasson U et al (2013) Plasma tau levels in Alzheimer’s disease. Alzheimers Res Ther 5(2):9. https://doi.org/10.1186/alzrt163
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Verde, F. Tau proteins in blood as biomarkers of Alzheimer’s disease and other proteinopathies. J Neural Transm 129, 239–259 (2022). https://doi.org/10.1007/s00702-022-02471-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-022-02471-y