Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer’s continuum when only subtle changes in Aβ pathology are detected
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In Alzheimer’s disease (AD), tau phosphorylation in the brain and its subsequent release into cerebrospinal fluid (CSF) and blood is a dynamic process that changes during disease evolution. The main aim of our study was to characterize the pattern of changes in phosphorylated tau (p‐tau) in the preclinical stage of the Alzheimer’s continuum . We measured three novel CSF p‐tau biomarkers, phosphorylated at threonine‐181 and threonine‐217 with an N‐terminal partner antibody and at threonine‐231 with a mid‐region partner antibody. These were compared with an automated mid‐region p‐tau181 assay (Elecsys) as the gold standard p‐tau measure. We demonstrate that these novel p‐tau biomarkers increase more prominently in preclinical Alzheimer, when only subtle changes of amyloid‐β (Aβ) pathology are detected, and can accurately differentiate Aβ‐positive from Aβ‐negative cognitively unimpaired individuals. Moreover, we show that the novel plasma N‐terminal p‐tau181 biomarker is mildly but significantly increased in the preclinical stage. Our results support the idea that early changes in neuronal tau metabolism in preclinical Alzheimer, likely in response to Aβ exposure, can be detected with these novel p‐tau assays.
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Blood 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 [9]
The Results (Association of p-tau biomarkers and Aβ pathology; page unavailable) report higher plasma p-tau181 and NfL in Aβ-positive than Aβ-negative cognitively unimpaired participants; the ROC results also assess their discrimination. But this paper measures p-tau217 and p-tau231 in CSF, not blood, and uses CSF Aβ42/40 to define groups rather than testing it as a blood measure. It does not establish the claimed blood-biomarker discrimination from cognitively unimpaired people with non-AD pathological changes, or report GFAP results. (LLM, conf=0.89)
Experimental — accuracy not yet measuredPlasma ptau-217 changes are detectable in preclinical stages and predictive of progression to mild cognitive impairment and AD dementia in a dose-dependent relationship.
“These changes are detectable in preclinical stages and predictive of progression to mild cognitive impairment (MCI) and AD dementia in a dose-dependent relationship (16,23,27).”
From Amyloid-Independent Elevation of Plasma phosphorylated tau-217 Tracks Neurodegenerative Risk in Tuberous Sclerosis Complex: Implications for mTOR-Targeted Intervention (2026) · cites this paper as [27]
The Introduction reports that plasma p-tau217 predicts Aβ pathology in asymptomatic stages, supporting the preclinical-detection portion. The Discussion states that this study did not include plasma p-tau217 and that longitudinal studies are needed to assess whether its biomarkers predict cognitive impairment. It does not establish dose-dependent prediction of progression to MCI or AD dementia. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCSF p-tau231 showed the earliest change in association with Aβ pathology in the AD brain.
“CSF p-tau231 showed the earliest change in association with Aβ pathology in the AD brain9,14.”
From Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease (2022) · cites this paper as [9]
CSF p-tau231 increases early in the AD continuum and may detect preclinical AD among cognitively unimpaired individuals.
“We have recently reported that CSF p-tau231 increases early in the AD continuum and, therefore, may detect preclinical AD among cognitively unimpaired (CU) individuals.31”
From Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease (2022) · cites this paper as [31]
CSF p-tau epitopes increase in the preclinical phase of the disease, prior to symptom onset and before substantial tau PET ligand retention.
“Our data, like prior studies,18,28,31 shows an increase of CSF p-tau epitopes in the preclinical phase of the disease, prior to symptom onset and before substantial tau PET ligand retention.”
From Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease (2022) · cites this paper as [31]
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References 111 · Cited by 401
- Authors
- Suárez‐Calvet, M., Karikari, T. K., Ashton, N. J., Lantero Rodríguez, J., Milà‐Alomà, M., Gispert, J. D., Salvadó, G., Minguillon, C., Fauria, K., Shekari, M., Grau‐Rivera, O., Arenaza‐Urquijo, E. M., Sala‐Vila, A., Sánchez‐Benavides, G., González‐de‐Echávarri, J. M., Kollmorgen, G., Stoops, E., Vanmechelen, E., Zetterberg, H., Blennow, K., Molinuevo, J. L., Study, F. T. A., Beteta, A., Cacciaglia, R., Cañas, A., Deulofeu, C., Cumplido, I., Dominguez, R., Emilio, M., Falcon, C., Fuentes, S., Hernandez, L., Huesa, G., Huguet, J., Marne, P., Menchón, T., Operto, G., Polo, A., Pradas, S., Soteras, A., Vilanova, M., & Vilor‐Tejedor, N.
- Affiliations
- Pasqual Maragall Foundation (ES)
- University of Gothenburg (SE)
- King's College London (GB)
- Universitat Pompeu Fabra (ES)
- ADx NeuroSciences (BE)
- Sahlgrenska University Hospital (SE)
- Corresponding author
- Blennow, Kaj
- ORCID
- Suárez‐Calvet, Marc
- Karikari, Thomas K
- Ashton, Nicholas J
- Milà‐Alomà, Marta
- Gispert, Juan Domingo
- Salvadó, Gemma
- Fauria, Karine
- Shekari, Mahnaz
- Grau‐Rivera, Oriol
- Arenaza‐Urquijo, Eider M
- Sala‐Vila, Aleix
- Sánchez‐Benavides, Gonzalo
- Kollmorgen, Gwendlyn
- Stoops, Erik
- Vanmechelen, Eugeen
- Zetterberg, Henrik
- Blennow, Kaj
- Molinuevo, José Luis
- Cacciaglia, Raffaele
- Cañas, Alba
- Huguet, Jordi
- Operto, Grégory
- Soteras, Anna
- Venue
- EMBO Molecular Medicine
- Published
- 2020-11-10
- Volume
- 12
- Issue
- 12
- Pages
- e12921-e12921
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC7721364
- OpenAlex
- W3099667207
- Cited by
- 401
- References
- 111
- Citations by year
- 2026: 42 · 2025: 71 · 2024: 100 · 2023: 70 · 2022: 66 · 2021: 50 · 2020: 1
- FWCI
- 28.28
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, other-oa)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- “la Caixa” Foundation (LCF/PR/GN17/50300004)
- Alzheimer's Association (TriBEKa‐17‐519007)
- H2020 Marie Skłodowska-Curie Actions (752310)
- BrightFocus Foundation (A2020812F)
- H2020 European Research Council (681712)
- EU Joint Programme – Neurodegenerative Disease Research (JPND2019‐466‐236)
- Instituto de Salud Carlos III (PI19/00155, CP II 17/00029)
- Ministerio de Ciencia, Innovación y Universidades (IJC2018‐037478‐I, FJCI‐2017‐33437, RYC2018‐026053‐I)
- Ministerio de Economía y Competitividad (RYC‐2013‐13054, IEDI‐2016‐00690)
- Svenska Forskningsrådet Formas (2018‐02532, 2017‐00915)
- Alzheimer's Drug Discovery Foundation (201809‐2016862, RDAPB‐201809‐2016615)
- 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 phosphorylation, preclinical Alzheimer's disease, cerebrospinal fluid biomarkers, plasma biomarkers, amyloid-beta pathology, cognitively unimpaired individuals
- MeSH terms
- Aged, Alzheimer Disease, Brain, Female, Humans, Longitudinal Studies, Male, Middle Aged, Phosphorylation, Biomarkers, Amyloid beta-Peptides, tau Proteins, Prodromal Symptoms
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