Total and phosphorylated tau protein as biological markers of Alzheimer’s disease
Open accessAbstract
Advances in our understanding of tau-mediated neurodegeneration in Alzheimer's disease (AD) are moving this disease pathway to center stage for the development of biomarkers and disease modifying drug discovery efforts. Immunoassays were developed detecting total (t-tau) and tau phosphorylated at specific epitopes (p-tauX) in cerebrospinal fluid (CSF), methods to analyse tau in blood are at the experimental beginning. Clinical research consistently demonstrated CSF t- and p-tau increased in AD compared to controls. Measuring these tau species proved informative for classifying AD from relevant differential diagnoses. Tau phosphorylated at threonine 231 (p-tau231) differentiated between AD and frontotemporal dementia, tau phosphorylated at serine 181 (p-tau181) enhanced classification between AD and dementia with Lewy bodies. T- and p-tau are considered "core" AD biomarkers that have been successfully validated by controlled large-scale multi-center studies. Tau biomarkers are implemented in clinical trials to reflect biological activity, mechanisms of action of compounds, support enrichment of target populations, provide endpoints for proof-of-concept and confirmatory trials on disease modification. World-wide quality control initiatives are underway to set required methodological and protocol standards. Discussions with regulatory authorities gain momentum defining the role of tau biomarkers for trial designs and how they may be further qualified for surrogate marker status.
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Both total and phosphorylated tau are increased in the CSF of AD patients and can predict the progression of the disease.
“Furthermore, both total and phosphorylated tau (p-tau) are increased in the CSF of AD patients and can predict the progression of the disease [22,30,31].”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [31]
Phosphorylation of tau at T231 has been associated with AD.
“Phosphorylation of tau at T231 has been associated with AD [38], and levels of this peptide are moderately correlated with tau tangle burden (Additional file 10: Figure S3D).”
From Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease (2018) · cites this paper as [38]
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“…et al., 2009) and concentration of p-tau231 declined longitudinally from mild to moderate AD (Hampel et al., 2001) and correlated significantly at baseline with rate of hippocampal atrophy in mild to moderate AD, acting as an indicator of structural disease progression (Hampel et al., 2005).”
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Biological Marker Candidates of Alzheimer's Disease in Blood, Plasma, and Serum
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Self-citationMulticenter assessment of CSF-phosphorylated tau for the prediction of conversion of MCI
Ewers, M., Büerger, K., Teipel, S. J., Scheltens, P., Schröder, J., Zinkowski, R. P., Bouwman, F. H., Schönknecht, P., Schoonenboom, N. S. M., Andreasen, N. C., et al. (2007) · Neurology · doi:10.1212/01.wnl.0000286944.22262.ff · Cited by 142 · see citing works
Self-citationParnetti, L., Lanari, A., Amici, S., Gallai, V., Vanmechelen, E., & Hulstaert, F. (2001) · Neurological Sciences · doi:10.1007/s100720170055 · Cited by 141 · see citing works
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Self-citationKapaki, E., Paraskevas, G. P., Tzerakis, N. G., Sfagos, C., Seretis, A., Kararizou, E., & Vassilopoulos, D. (2007) · European Journal of Neurology · doi:10.1111/j.1468-1331.2006.01593.x · Cited by 140 · see citing works
Cerebrospinal fluid total tau as a marker of Alzheimer's disease intensity
Sämgård, K., Zetterberg, H., Blennow, K., Hansson, O., Minthon, L., & Londos, E. (2009) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.2353 · Cited by 133 · see citing works
Self-citationCerebrospinal Fluid Markers in Dementia With Lewy Bodies Compared With Alzheimer Disease
Gómez‐Tortosa, E., Gonzalo, I., Fanjul, S., Sainz, M. J., Cantarero, S., Cemillán, C. A., de Yébenes, J. G., & del Ser, T. (2003) · Archives of Neurology · doi:10.1001/archneur.60.9.1218 · Cited by 133 · see citing works
Low frequency of post-lumbar puncture headache in demented patients
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Self-citationBlood-based biomarkers of microvascular pathology in Alzheimer’s disease
Ewers, M., Mielke, M. M., & Hampel, H. J. (2009) · Experimental Gerontology · doi:10.1016/j.exger.2009.09.005 · Cited by 121 · see citing works
Self-citationChou, Y.-Y., Leporé, N., Avedissian, C., Madsen, S. K., Parikshak, N., Hua, X., Shaw, L. M., Trojanowski, J. Q., Weiner, M. W., Toga, A. W., et al. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.02.015 · Cited by 117 · see citing works
Self-citationSjögren, M. J. C., Davidsson, P., Gottfries, J., Vanderstichele, H., Edman, Å., Vanmechelen, E., Wallin, A., & Blennow, K. (2001) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000051268 · Cited by 116 · see citing works
Self-citationCSF Aβ42, Tau and phosphorylated Tau, APOE ɛ4 allele and MCI type in progressive MCI
Herukka, S., Helisalmi, S., Hallikainen, M., Tervo, S., Soininen, H. S., & Pirttilä, T. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.02.001 · Cited by 109 · see citing works
Serum Tau Protein Level as a Marker of Axonal Damage in Acute Ischemic Stroke
Bitsch, A., Horn, C., Kemmling, Y., Seipelt, M., Hellenbrand, U., Stiefel, M., Ciesielczyk, B., Cepek, L., Bahn, E., Ratzka, P., et al. (2002) · European Neurology · doi:10.1159/000047946 · Cited by 102 · see citing works
Hampel, H. J., Büerger, K., Kohnken, R. E., Teipel, S. J., Zinkowski, R. P., Moeller, H., Rapoport, S. I., & Davies, P. (2001) · Annals of Neurology · doi:10.1002/ana.111 · Cited by 102 · see citing works
Self-citationPattern of Tau forms in CSF is altered in progressive supranuclear palsy
Borroni, B., Gardoni, F., Parnetti, L., Magno, L., Malinverno, M., Saggese, E., Calabresi, P., Spillantini, M. G., Padovani, A., & Luca, M. D. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.05.009 · Cited by 100 · see citing works
Jia, J., Meng, R., Sun, Y., Sun, W., Ji, X., & Jia, L. (2005) · Neuroscience Letters · doi:10.1016/j.neulet.2005.03.051 · Cited by 96 · see citing works
Büerger, K., Zinkowski, R. P., Teipel, S. J., Arai, H., DeBernardis, J. F., Kerkman, D. J., McCulloch, C., Padberg, F., Faltraco, F., Goernitz, A., et al. (2003) · American Journal of Psychiatry · doi:10.1176/appi.ajp.160.2.376 · Cited by 92 · see citing works
Self-citationCharacterization of Tau in Cerebrospinal Fluid Using Mass Spectrometry
Portelius, E., Hansson, S., Tran, A. J., Zetterberg, H., Grognet, P., Vanmechelen, E., Höglund, K., Brinkmalm, G., Brinkmalm, A., Nordhoff, E., et al. (2008) · Journal of Proteome Research · doi:10.1021/pr7008669 · Cited by 79 · see citing works
Self-citationDefining and labeling disease‐modifying treatments for Alzheimer's disease
Cummings, J. L. (2009) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2008.12.003 · Cited by 72 · see citing works
Nägga, K., Gottfries, J., Blennow, K., & Marcusson, J. O. (2002) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000066023 · Cited by 71 · see citing works
Self-citationIbach, B., Binder, H., Dragon, M., Poljansky, S., Haen, E., Schmitz, E., Koch, H., Putzhammer, A., Kluenemann, H., Wieland, W. F., et al. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.06.005 · Cited by 67 · see citing works
Phosphorylated tau predicts rate of cognitive decline in MCI subjects: A comparative CSF study
Büerger, K., Ewers, M., Andreasen, N. C., Zinkowski, R. P., Ishiguro, K., Vanmechelen, E., Teipel, S. J., Graz, C., Blennow, K., & Hampel, H. J. (2005) · Neurology · doi:10.1212/01.wnl.0000183284.92920.f2 · Cited by 65 · see citing works
Self-citationBuch, K., Padberg, F., Nolde, T., Teipel, S. J., Stübner, S., Haslinger, A., Schwarz, M., Sunderland, T., Arai, H., Rapoport, S. I., et al. (1999) · Neuroscience Letters · doi:10.1016/s0304-3940(99)00845-9 · Cited by 65 · see citing works
Self-citationBüerger, K., Frisoni, G. B., Uspenskaya, O., Ewers, M., Zetterberg, H., Geroldi, C., Binetti, G. G., Johannsen, P., Rossini, P. M., Wahlund, L., et al. (2009) · Experimental Gerontology · doi:10.1016/j.exger.2009.06.003 · Cited by 63 · see citing works
Self-citationHampel, H. J., & Teipel, S. J. (2004) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000077170 · Cited by 60 · see citing works
Self-citationBlennow, K., Johansson, A., & Zetterberg, H. (2005) · International Journal of Molecular Medicine · doi:10.3892/ijmm.16.6.1147 · Cited by 55 · see citing works
Self-citationHaense, C., Büerger, K., Kalbe, E., Drzezga, A. E., Teipel, S. J., Markiewicz, P. J., Herholz, K., Heiß, W.-D., & Hampel, H. J. (2008) · European Journal of Neurology · doi:10.1111/j.1468-1331.2008.02274.x · Cited by 55 · see citing works
Self-citationSchönknecht, P., Pantel, J., Hartmann, T., Werle, E., Volkmann, M., Essig, M., Amann, M., Zanabili, N., Bardenheuer, H. J., Hunt, A., et al. (2003) · Psychiatry Research · doi:10.1016/s0165-1781(03)00197-5 · Cited by 55 · see citing works
Biological markers for early detection and pharmacological treatment of Alzheimer's disease
Hampel, H. J., Broich, K., Hoessler, Y. C., & Pantel, J. (2009) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2009.11.2/hhampel · Cited by 50 · see citing works
Self-citationTau Immunoreactivity Detected in Human Plasma, But No Obvious Increase in Dementia
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Self-citationCerebrospinal fluid markers in differential diagnosis of Alzheimer's disease and vascular dementia.
Boban, M., Grbić, K., Mladinov, M., et al. (2008) · PubMed · Cited by 23 · see citing works
Hampel, H., & Broich, K. (2009) · The Journal of Nutrition, Health & Aging · doi:10.1007/s12603-009-0048-3 · Cited by 23 · see citing works
Self-citationMaximizing the Alzheimer's Disease Neuroimaging Initiative II
Carrillo, M. C., Sanders, C. A., & Katz, R. G. (2009) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2009.02.005 · Cited by 20 · see citing works
Cerebrospinal fluid markers for prediction of Alzheimer's disease
Zetterberg, H. (2003) · Neuroscience Letters · doi:10.1016/s0304-3940(03)00984-4 · Cited by 15 · see citing works
Self-citationHampel, H. J., Büerger, K., Kohnken, R. E., et al. (2001) · Annals of Neurology · doi:10.1002/ana.111.abs · Cited by 14 · see citing works
Self-citation
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Preclinical Alzheimer’s Disease: Definition, Natural History, and Diagnostic Criteria
Dubois, B., Hampel, H., Feldman, H. H., Scheltens, P., Aisen, P., Andrieu, S., Bakardjian, H., Benali, H., Bertram, L., Blennow, K., et al. (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.02.002 · Cited by 1,925 · see citing works
Self-citationTau Kinetics in Neurons and the Human Central Nervous System
Sato, C., Barthélemy, N. R., Mawuenyega, K. G., Patterson, B. W., Gordon, B. A., Jockel-Balsarotti, J., Sullivan, M., Crisp, M. J., Kasten, T., Kirmess, K. M., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.02.015 · Cited by 586 · see citing works
Identifying and validating biomarkers for Alzheimer's disease
Humpel, C. (2011) · Trends in Biotechnology · doi:10.1016/j.tibtech.2010.09.007 · Cited by 484 · see citing works
Amyloid biomarkers in Alzheimer's disease
Blennow, K., Mattsson, N., Schöll, M., Hansson, O., & Zetterberg, H. (2015) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2015.03.002 · Cited by 470 · see citing works
Self-citationAntibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy
Kondo, A., Shahpasand, K., Mannix, R., Qiu, J., Moncaster, J., Chen, C.-H., Yao, Y., Lin, Y.-M., Driver, J. A., Sun, Y., et al. (2015) · Nature · doi:10.1038/nature14658 · Cited by 445 · see citing works
Liss, J. L., Seleri Assunção, S., Cummings, J., Atri, A., Geldmacher, D. S., Candela, S. F., Devanand, D. P., Fillit, H. M., Susman, J., Mintzer, J., et al. (2021) · Journal of Internal Medicine · doi:10.1111/joim.13244 · Cited by 312 · see citing works
Tau Oligomers: Cytotoxicity, Propagation, and Mitochondrial Damage
Shafiei, S. S., Guerrero-Muñoz, M. J., & Castillo-Carranza, D. L. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00083 · Cited by 314 · see citing works
Mechanisms of secretion and spreading of pathological tau protein
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Self-citationHampel, H., O’Bryant, S. E., Durrleman, S., Younesi, E., Rojkova, K., Escott-Price, V., Corvol, J.-C., Broich, K., Dubois, B., Lista, S., et al. (2017) · Climacteric · doi:10.1080/13697137.2017.1287866 · Cited by 147 · see citing works
Self-citationAlzheimer’s disease profiled by fluid and imaging markers: tau PET best predicts cognitive decline
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Clinical appraisal of chronic traumatic encephalopathy: current perspectives and future directions
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Self-citationTreatment of Alzheimer’s Disease: Beyond Symptomatic Therapies
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“Furthermore, both total and phosphorylated tau (p-tau) are increased in the CSF of AD patients and can predict the progression of the disease [22,30,31].”
BackgroundMisfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway
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Derakhshankhah, H., Sajadimajd, S., Jafari, S., Izadi, Z., Sarvari, S., Sharifi, M., Falahati, M., Moakedi, F., Muganda, W. C. A., Müller, M., et al. (2020) · Nanomedicine: Nanotechnology, Biology and Medicine · doi:10.1016/j.nano.2020.102149 · Cited by 48 · see citing works
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Peng, Y., Tao, H., Wang, S., Xiao, J., Wang, Y., & Su, H. (2021) · Journal of Functional Foods · doi:10.1016/j.jff.2021.104463 · Cited by 31 · see citing works
- Authors
- Hampel, H., Blennow, K., Shaw, L. M., Hoessler, Y. C., Zetterberg, H., & Trojanowski, J. Q.
- Affiliations
- Goethe University Frankfurt (DE)
- University of Gothenburg (SE)
- University of Pennsylvania (US)
- Ludwig-Maximilians-Universität München (DE)
- Corresponding author
- Hampel, Harald
- Venue
- Experimental Gerontology
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 45
- Issue
- 1
- Pages
- 30-40
- ISSN
- 0531-5565 (ISSN-L)
- PMC
- PMC2815003
- OpenAlex
- W2147576743
- Cited by
- 389
- References
- 114
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 32 · 2023: 15 · 2022: 32 · 2021: 25 · 2020: 25 · 2019: 23 · 2018: 20 · 2017: 30 · 2016: 27 · 2015: 24 · 2014: 29 · 2013: 17 · 2012: 24
- FWCI
- 13.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Experimental Gerontology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-sa)
- HAL (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Lenus, The Irish Health Repository (Dr Steevens Hospital Library) (submittedVersion)
- Funders
- National Institutes of Health (5u01ag024904-10)
- National Institute on Aging (U01-AG-024904, P30AG010124, AG-10124, AG24904)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Keywords
- tau protein, phosphorylated tau, Alzheimer's disease, cerebrospinal fluid biomarkers, frontotemporal dementia, dementia with Lewy bodies, differential diagnosis, surrogate endpoints, disease-modifying trials, quality control standards
- MeSH terms
- Aged, Alzheimer Disease, Humans, Nerve Degeneration, Phosphorylation, Predictive Value of Tests, Biomarkers, tau Proteins
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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