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Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer's disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study
Open accessAbstract
Background Plasma tau phosphorylated at threonine 217 (p-tau217) and plasma tau phosphorylated at threonine 181 (p-tau181) are associated with Alzheimer's disease tau pathology. We compared the diagnostic value of both biomarkers in cognitively unimpaired participants and patients with a clinical diagnosis of mild cognitive impairment, Alzheimer's disease syndromes, or frontotemporal lobar degeneration (FTLD) syndromes.Methods In this retrospective multicohort diagnostic performance study, we analysed plasma samples, obtained from patients aged 18-99 years old who had been diagnosed with Alzheimer's disease syndromes (Alzheimer's disease dementia, logopenic variant primary progressive aphasia, or posterior cortical atrophy), FTLD syndromes (corticobasal syndrome, progressive supranuclear palsy, behavioural variant frontotemporal dementia, non-fluent variant primary progressive aphasia, or semantic variant primary progressive aphasia), or mild cognitive impairment; the participants were from the University of California San Francisco (UCSF) Memory and Aging Center, San Francisco, CA, USA, and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL; 17 sites in the USA and two in Canada). Participants from both cohorts were carefully characterised, including assessments of CSF p-tau181, amyloid-PET or tau-PET (or both), and clinical and cognitive evaluations. Plasma p-tau181 and p-tau217 were measured using electrochemiluminescence-based assays, which differed only in the biotinylated antibody epitope specificity. Receiver operating characteristic analyses were used to determine diagnostic accuracy of both plasma markers using clinical diagnosis, neuropathological findings, and amyloid-PET and tau-PET measures as gold standards. Difference between two area under the curve (AUC) analyses were tested with the Delong test.Findings Data were collected from 593 participants (443 from UCSF and 150 from ARTFL, mean age 64 years [SD 13], 294 [50%] women) between July 1 and Nov 30, 2020. Plasma p-tau217 and p-tau181 were correlated (r=0·90, p<0·0001). Both p-tau217 and p-tau181 concentrations were increased in people with Alzheimer's disease syndromes (n=75, mean age 65 years [SD 10]) relative to cognitively unimpaired controls (n=118, mean age 61 years [SD 18]; AUC=0·98 [95% CI 0·95-1·00] for p-tau217, AUC=0·97 [0·94-0·99] for p-tau181; p diff=0·31) and in pathology-confirmed Alzheimer's disease (n=15, mean age 73 years [SD 12]) versus pathologically confirmed FTLD (n=68, mean age 67 years [SD 8]; AUC=0·96 [0·92-1·00] for p-tau217, AUC=0·91 [0·82-1·00] for p-tau181; p diff=0·22). P-tau217 outperformed p-tau181 in differentiating patients with Alzheimer's disease syndromes (n=75) from those with FTLD syndromes (n=274, mean age 67 years [SD 9]; AUC=0·93 [0·91-0·96] for p-tau217, AUC=0·91 [0·88-0·94] for p-tau181; p diff=0·01). P-tau217 was a stronger indicator of amyloid-PET positivity (n=146, AUC=0·91 [0·88-0·94]) than was p-tau181 (n=214, AUC=0·89 [0·86-0·93]; p diff=0·049). Tau-PET binding in the temporal cortex was more strongly associated with p-tau217 than p-tau181 (r=0·80 vs r=0·72; p diff<0·0001, n=230).Interpretation Both p-tau217 and p-tau181 had excellent diagnostic performance for differentiating patients with Alzheimer's disease syndromes from other neurodegenerative disorders. There was some evidence in favour of p-tau217 compared with p-tau181 for differential diagnosis of Alzheimer's disease syndromes versus FTLD syndromes, as an indication of amyloid-PET-positivity, and for stronger correlations with tau-PET signal. Pending replication in independent, diverse, and older cohorts, plasma p-tau217 and p-tau181 could be useful screening tools to identify individuals with underlying amyloid and Alzheimer's disease tau pathology.Funding US National Institutes of Health, State of California Department of Health Services, Rainwater Charitable Foundation, Michael J Fox foundation, Association for Frontotemporal Degeneration, Alzheimer's Association.
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“Nonetheless, plasma p‐tau217 often shows a superior association with temporal lobe tau load compared to other plasma biomarkers (including other p‐tau species), 13 , 25 , 36”
From Machine learning prediction of tau‐PET in Alzheimer's disease using plasma, MRI, and clinical data (2025) · cites this paper as [36]
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“Several recent studies have reported that plasma biomarkers have excellent diagnostic accuracy for AD, with sensitivity or specificity often exceeding 90% (refs. 4–10).”
From Diagnosis of Alzheimer's disease using plasma biomarkers adjusted to clinical probability (2024) · cites this paper as [7]
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“Although total tau and amyloid β concentrations are not sensitive or specific for any of the frontotemporal lobar degeneration proteinopathies, elevated phosphorylated tau concentrations in either CSF or plasma suggest that underlying Alzheimer's disease pathology is likely to be the cause of the frontotemporal dementia clinical syndrome.49,55,56”
From Advances and controversies in frontotemporal dementia: diagnosis, biomarkers, and therapeutic considerations (2022) · cites this paper as [56]
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“Notably, p-tau217 exhibits larger-fold changes compared with p-tau181 and p-tau231,10 often achieving high discrimination, with areas under the curve (AUC) exceeding 90%.19,23”
From Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology (2024) · cites this paper as [23]
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In the citing paper
“Although total tau and amyloid β concentrations are not sensitive or specific for any of the frontotemporal lobar degeneration proteinopathies, elevated phosphorylated tau concentrations in either CSF or plasma suggest that underlying Alzheimer's disease pathology is likely to be the cause of the frontotemporal dementia clinical syndrome.49,55,56”
From Advances and controversies in frontotemporal dementia: diagnosis, biomarkers, and therapeutic considerations (2022) · cites this paper as [56]
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“Like NfL (neurofilament light chain), plasma tau has emerged as a marker of neuronal distress. It appears in several different neurodegenerative diseases, including importantly even preclinical AD patients (76–85).”
From All the Tau We Cannot See (2023) · cites this paper as [85]
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“It appears to be more specific for AD pathology, at least compared to frontotemporal dementia and chronic traumatic encephalopathy (85, 91, 92), but it is increased in prion disease (83).”
From All the Tau We Cannot See (2023) · cites this paper as [85]
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Metadata
- Authors
- Thijssen, E. H., La Joie, R., Strom, A., Fonseca, C., Iaccarino, L., Wolf, A., Spina, S., Allen, I. E., Cobigo, Y., Heuer, H., VandeVrede, L., Proctor, N. K., Lago, A. L., Baker, S., Sivasankaran, R., Kieloch, A., Kinhikar, A., Yu, L., Valentin, M.-A., Jeromin, A., Zetterberg, H., Hansson, O., Mattsson-Carlgren, N., Graham, D., Blennow, K., Kramer, J. H., Grinberg, L. T., Seeley, W. W., Rosen, H., Boeve, B. F., Miller, B. L., Teunissen, C. E., Rabinovici, G. D., Rojas, J. C., Dage, J. L., & Boxer, A. L.
- Affiliations
- University of California, San Francisco (US)
- Eli Lilly (United States) (US)
- Lawrence Berkeley National Laboratory (US)
- Quanterix (United States) (US)
- Sahlgrenska University Hospital (SE)
- Lund University (SE)
- Biogen (United States) (US)
- Mayo Clinic (US)
- Amsterdam Neuroscience (NL)
- Corresponding author
- Boxer, Adam L
- ORCID
- Thijssen, Elisabeth H
- Strom, Amelia
- Fonseca, Corrina
- Iaccarino, Leonardo
- Wolf, Amy
- Spina, Salvatore
- Allen, Isabel E
- Cobigo, Yann
- Heuer, Hilary
- VandeVrede, Lawren
- Proctor, Nicholas K
- Lago, Argentina Lario
- Baker, Suzanne
- Sivasankaran, Rajeev
- Kinhikar, Arvind
- Yu, Lili
- Zetterberg, Henrik
- Hansson, Oskar
- Graham, Danielle
- Blennow, Kaj
- Kramer, Joel H
- Grinberg, Lea T
- Seeley, William W
- Rosen, Howard
- Boeve, Bradley F
- Miller, Bruce L
- Teunissen, Charlotte E
- Rabinovici, Gil D
- Rojas, Julio C
- Dage, Jeffrey L
- Boxer, Adam L
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2021-09
- Volume
- 20
- Issue
- 9
- Pages
- 739-752
- ISSN
- 1474-4422 (ISSN-L)
- PMC
- PMC8711249
- OpenAlex
- W3194829575
- Cited by
- 607
- References
- 40
- Citations by year
- 2026: 127 · 2025: 161 · 2024: 119 · 2023: 101 · 2022: 87 · 2021: 11
- FWCI
- 57.94
- Type
- journal article
- Language
- en
- Update notices
- erratum (2021-10-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The Lancet Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Alzheimer's Association (AARF-16\u2013443577, 443577)
- National Center for Advancing Translational Sciences (LEFFTDS U01 AG045390)
- National Institute of Neurological Disorders and Stroke (U54NS092089)
- National Institute on Aging
- American College of Radiology
- Association for Frontotemporal Degeneration
- Rainwater Charitable Foundation
- NIH (R01 AG045611, U24AG21886, K24AG053435, R01AG038791, P50AG016574, K99AG065501, U19AG063911, P50AG023501, P01AG019724)
- Vetenskapsrådet (2018\u201302532, 02532)
- Little Family Foundation
- European Research Council (681712)
- Michael J Fox Foundation for Parkinson's Research
- Alzheimer's Drug Discovery Foundation (201809\u20132016862, 2016862, 201809)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- Alzheimer's disease, frontotemporal lobar degeneration, plasma biomarkers, diagnostic accuracy, mild cognitive impairment, tau PET, amyloid PET, primary progressive aphasia, corticobasal syndrome, progressive supranuclear palsy, behavioral variant frontotemporal dementia, posterior cortical atrophy, logopenic variant primary progressive aphasia, semantic dementia, electrochemiluminescence assay
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Diagnosis, Differential, Female, Humans, Male, Middle Aged, Phosphorylation, Predictive Value of Tests, Retrospective Studies, Biomarkers, Amyloid beta-Peptides, tau Proteins, Positron-Emission Tomography, Frontotemporal Lobar Degeneration, Cognitive Dysfunction
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