Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts
Open accessAbstract
Background CSF and PET biomarkers of amyloid β and tau accurately detect Alzheimer's disease pathology, but the invasiveness, high cost, and poor availability of these detection methods restrict their widespread use as clinical diagnostic tools. CSF tau phosphorylated at threonine 181 (p-tau181) is a highly specific biomarker for Alzheimer's disease pathology. We aimed to assess whether blood p-tau181 could be used as a biomarker for Alzheimer's disease and for prediction of cognitive decline and hippocampal atrophy.Methods We developed and validated an ultrasensitive blood immunoassay for p-tau181. Assay performance was evaluated in four clinic-based prospective cohorts. The discovery cohort comprised patients with Alzheimer's disease and age-matched controls. Two validation cohorts (TRIAD and BioFINDER-2) included cognitively unimpaired older adults (mean age 63-69 years), participants with mild cognitive impairment (MCI), Alzheimer's disease, and frontotemporal dementia. In addition, TRIAD included healthy young adults (mean age 23 years) and BioFINDER-2 included patients with other neurodegenerative disorders. The primary care cohort, which recruited participants in Montreal, Canada, comprised control participants from the community without a diagnosis of a neurological condition and patients referred from primary care physicians of the Canadian National Health Service for specialist care. Concentrations of plasma p-tau181 were compared with established CSF and PET biomarkers and longitudinal measurements using Spearman correlation, area under the curve (AUC), and linear regression analyses.Findings We studied 37 individuals in the discovery cohort, 226 in the first validation cohort (TRIAD), 763 in the second validation cohort (BioFINDER-2), and 105 in the primary care cohort (n=1131 individuals). In all cohorts, plasma p-tau181 showed gradual increases along the Alzheimer's disease continuum, from the lowest concentrations in amyloid β-negative young adults and cognitively unimpaired older adults, through higher concentrations in the amyloid β-positive cognitively unimpaired older adults and MCI groups, to the highest concentrations in the amyloid β-positive MCI and Alzheimer's disease groups (p<0·001, Alzheimer's disease vs all other groups). Plasma p-tau181 distinguished Alzheimer's disease dementia from amyloid β-negative young adults (AUC=99·40%) and cognitively unimpaired older adults (AUC=90·21-98·24% across cohorts), as well as other neurodegenerative disorders, including frontotemporal dementia (AUC=82·76-100% across cohorts), vascular dementia (AUC=92·13%), progressive supranuclear palsy or corticobasal syndrome (AUC=88·47%), and Parkinson's disease or multiple systems atrophy (AUC=81·90%). Plasma p-tau181 was associated with PET-measured cerebral tau (AUC=83·08-93·11% across cohorts) and amyloid β (AUC=76·14-88·09% across cohorts) pathologies, and 1-year cognitive decline (p=0·0015) and hippocampal atrophy (p=0·015). In the primary care cohort, plasma p-tau181 discriminated Alzheimer's disease from young adults (AUC=100%) and cognitively unimpaired older adults (AUC=84·44%), but not from MCI (AUC=55·00%).Interpretation Blood p-tau181 can predict tau and amyloid β pathologies, differentiate Alzheimer's disease from other neurodegenerative disorders, and identify Alzheimer's disease across the clinical continuum. Blood p-tau181 could be used as a simple, accessible, and scalable test for screening and diagnosis of Alzheimer's disease.Funding Alzheimer Drug Discovery Foundation, European Research Council, Swedish Research Council, Swedish Alzheimer Foundation, Swedish Dementia Foundation, Alzheimer Society Research Program.
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Among existing plasma biomarkers, P-tau has shown the highest predictive accuracy for Aβ positivity.
“Among the existing plasma biomarkers, P-tau has shown the highest predictive accuracy for Aβ positivity11,12.”
From Integrated algorithm combining plasma biomarkers and cognitive assessments accurately predicts brain β-amyloid pathology (2023) · cites this paper as [12]
The Findings (page not provided) report that plasma p-tau181 outperformed the other plasma biomarkers tested in predicting Aβ PET positivity. The claim extends that comparison to all existing plasma biomarkers, whereas the Discussion (page not provided) describes its performance as comparable to high-performance mass spectrometry-based plasma Aβ assays. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSeveral recent studies have reported that plasma biomarkers have excellent diagnostic accuracy for AD, with sensitivity or specificity often exceeding 90%.
“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 [6]
The Results (page not available in our copy) report excellent diagnostic performance for plasma p-tau181, including an AUC of 90.06% for Alzheimer’s diagnosis and AUC and accuracy above 95% for some comparisons. The cited passages do not establish the claim’s specific measure—that sensitivity or specificity often exceeds 90%; AUC and overall accuracy are different measures. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPlasma levels of p-tau are strongly associated with PET and CSF biomarkers of AD pathology, neuropathological changes associated with AD, and subsequent development of AD dementia.
“Plasma levels of p-tau are strongly associated with PET and CSF biomarkers of AD pathology19–25, neuropathological changes associated with AD20,23,26,27 and the subsequent development of AD dementia20,23,28.”
From Highly accurate blood test for Alzheimer's disease is similar or superior to clinical cerebrospinal fluid tests (2024) · cites this paper as [21]
The Results report strong associations of plasma p-tau181 with tau and amyloid PET, while the Results and Discussion report correlations with CSF biomarkers. PET findings reflect AD-related pathology, but this study did not directly assess neuropathological changes by postmortem examination. Its one-year follow-up measured cognitive decline and hippocampal atrophy, not subsequent development of AD dementia. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPlasma measures of p-tau181, p-tau217 and p-tau231 have high diagnostic accuracy in differentiating AD from other neurodegenerative disorders in clinical studies, validated by postmortem neuropathological studies.
“Plasma measures of phosphorylated tau at Thr181 (p-tau181), Thr217 (p-tau217) and Thr231 (p-tau231) have high diagnostic accuracy in differentiating AD from other neurodegenerative disorders in clinical studies1–3, which are validated by postmortem neuropathological studies1,2,4.”
From Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease (2022) · cites this paper as [3]
The Findings and Results (page not available in our copy) report high diagnostic accuracy for plasma p-tau181 in distinguishing Alzheimer’s disease from several other neurodegenerative disorders. The paper does not report diagnostic results for p-tau217 or p-tau231, or validation of its findings in postmortem neuropathological studies; its pathology comparisons use PET and CSF measures. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBlood measures of p-tau181, p-tau217, p-tau231, GFAP, NfL and Aβ42/40 have been shown to change in preclinical AD and can discriminate this state from CU individuals with non-AD pathological changes.
“Indeed, blood measures of p-tau181, p-tau217, p-tau231, glial fibrillary acid protein (GFAP), neurofilament light (NfL) and Aβ42/40 have been shown to change in preclinical AD and can discriminate this state from CU individuals with non-AD pathological changes1,3,6–13.”
From Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease (2022) · cites this paper as [3]
The Results report that plasma p-tau181 is elevated in Aβ-positive cognitively unimpaired (CU) elderly people and distinguishes them from Aβ-negative CU elderly people (AUC 81.02%). This supports the p-tau181 portion of the multiply cited sentence, but the study does not establish discrimination specifically from CU people with non-AD pathological changes; its comparison group is described as Aβ-negative CU. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Plasma Aβ42/Aβ40 ratios have demonstrated potential for reflecting cerebral amyloid burden.
“In addition, plasma Aβ42/Aβ40 ratios have demonstrated potential for reflecting cerebral amyloid burden88, while NfL, a marker of axonal damage, is elevated in AD and provides prognostic insight into ongoing neurodegeneration89.”
From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [88]
Protein biomarkers in CSF and blood/plasma/serum have been developed or are under development according to amyloid cascade and tau hypotheses, including Aβ level, Aβ42/Aβ40 ratio, total tau level, and phosphorylated tau isoform accumulation.
“According to the amyloid cascade and tau hypotheses, protein biomarkers in cerebrospinal fluid (CSF) and blood/plasma/serum have also been developed or under development, including amyloid-β (Aβ) level, Aβ42/Aβ40 ratio, total tau level, and the accumulation of phosphorylated tau isoform [6–9].”
From Integrated analysis of ultra-deep proteomes in cortex, cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer’s disease (2020) · cites this paper as [9]
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Self-citationMoving fluid biomarkers for Alzheimer’s disease from research tools to routine clinical diagnostics
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Self-citationDesigning the next-generation clinical care pathway for Alzheimer’s disease
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Fluid Biomarkers for Synaptic Dysfunction and Loss
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Self-citationDiagnosis of Alzheimer's disease using plasma biomarkers adjusted to clinical probability
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Self-citationThe informed road map to prevention of Alzheimer Disease: a call to arms
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Current trends in blood biomarker detection and imaging for Alzheimer’s disease
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<i>APOE</i> ε4 associates with microglial activation independently of Aβ plaques and tau tangles
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Self-citationDiagnostic value of serum versus plasma phospho-tau for Alzheimer’s disease
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Self-citationAssociations of longitudinal plasma p-tau181 and NfL with tau-PET, Aβ-PET and cognition
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Detection of Brain Tau Pathology in Down Syndrome Using Plasma Biomarkers
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Association of plasma P-tau181 with memory decline in non-demented adults
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“Among the existing plasma biomarkers, P-tau has shown the highest predictive accuracy for A β positivity 11,12 .”
Phosphorylated Tau 181 Serum Levels Predict Alzheimer’s Disease in the Preclinical Stage
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- Authors
- Karikari, T. K., Pascoal, T. A., Ashton, N. J., Janelidze, S., Benedet, A. L., Rodriguez, J. L., Chamoun, M., Savard, M., Kang, M. S., Therriault, J., Schöll, M., Massarweh, G., Soucy, J.-P., Höglund, K., Brinkmalm, G., Mattsson, N., Palmqvist, S., Gauthier, S., Stomrud, E., Zetterberg, H., Hansson, O., Rosa-Neto, P., & Blennow, K.
- Affiliations
- University of Gothenburg (SE)
- Montreal Neurological Institute and Hospital (CA)
- King's College London (GB)
- Lund University (SE)
- McGill University Research Centre for Studies in Aging (CA)
- Wallenberg Centre for Molecular and Translational Medicine (SE)
- Sahlgrenska University Hospital (SE)
- Corresponding author
- Blennow, Kaj
- ORCID
- Karikari, Thomas K
- Pascoal, Tharick A
- Ashton, Nicholas J
- Janelidze, Shorena
- Benedet, Andréa Lessa
- Chamoun, Mira
- Kang, Min Su
- Therriault, Joseph
- Schöll, Michael
- Massarweh, Gassan
- Soucy, Jean-Paul
- Höglund, Kina
- Brinkmalm, Gunnar
- Mattsson, Niklas
- Palmqvist, Sebastian
- Gauthier, Serge
- Stomrud, Erik
- Zetterberg, Henrik
- Hansson, Oskar
- Blennow, Kaj
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 19
- Issue
- 5
- Pages
- 422-433
- ISSN
- 1474-4422 (ISSN-L)
- OpenAlex
- W3018431352
- Cited by
- 1,316
- References
- 30
- Citations by year
- 2026: 161 · 2025: 248 · 2024: 244 · 2023: 203 · 2022: 204 · 2021: 190 · 2020: 64
- FWCI
- 122.04
- Type
- journal article
- Language
- en
- Open access
- green
- discovery.ucl.ac.uk
- Licence
- Locations
- The Lancet Neurology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Fonds de Recherche du Québec - Santé
- Canada Foundation for Innovation (34874)
- Consortium canadien en neurodégénérescence associée au vieillissement
- Canadian Institutes of Health Research
- Alzheimer Society
- Vetenskapsrådet
- European Research Council (681712)
- Lunds Universitet
- Hjärnfonden
- Knut och Alice Wallenbergs Stiftelse
- University Hospital Foundation
- Alzheimer's Drug Discovery Foundation (2017-00915, AF-742881, ALFGBG-715986, FO2017-0243, RDAPB-201809–2016615)
- Association for Frontotemporal Degeneration (2018-02532)
- Sahlgrenska Universitetssjukhuset
- Alzheimerfonden
- Marcus och Amalia Wallenbergs minnesfond
- Wallenberg Centre for Molecular and Translational Medicine
- Weston Brain Institute
- Montreal Neurological Institute and Hospital
- Parkinson Research Foundation
- Roche (RO948)
- GE Healthcare
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Keywords
- phosphorylated tau 181, blood biomarkers, Alzheimer's disease, immunoassay, mild cognitive impairment, cognitive decline prediction, hippocampal atrophy, amyloid-beta, cerebrospinal fluid biomarkers, PET biomarkers, frontotemporal dementia, neurodegeneration, diagnostic accuracy, primary care referral
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Female, Humans, Male, Middle Aged, Models, Theoretical, Phosphorylation, Prospective Studies, Biomarkers, tau Proteins, Young Adult, Cognitive Dysfunction
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