- September 13, 2025
- Pedro Rosa-Neto, et al., McGill University
Topic/Product:
CNS Disease Panel 120, Neurology
Disease Area:
Alzheimer's Disease
Sample Type:
Plasma
Abstract
Background: Plasma phosphorylated tau (p-tau) biomarkers show promise to transform the clinical management of Alzheimer’s disease by providing more accessible and cost-effective diagnostic tools. p-tau biomarkers have emerged as leading contenders for clinical implementation; however, there have been no comprehensive meta-analyses of their diagnostic performance. We aimed to evaluate the diagnostic performance of plasma p-tau biomarkers and individual p-tau assays to identify biologically defined Alzheimer’s disease.
Methods: For this systematic review and meta-analysis, we searched Embase, MEDLINE, PubMed, Scopus, and Web of Science for articles published from July 1, 1984 up to Dec 9, 2024, that reported on the discriminative accuracy of plasma p-tau biomarkers for amyloid-PET, tau-PET, CSF, and neuropathological reference standards. We included cohort, case-control, cross-sectional, and randomised controlled studies that recruited adults from any setting. Articles were excluded if they did not contain data on a p-tau blood biomarker, did not contain an appropriate biological reference standard, did not report diagnostic accuracy data, included participants younger than 18 years, or reported duplicate or overlapping data from another publication. Summary data were independently extracted by eight authors. Risk of bias was assessed using QUADAS-2. The primary outcome was the diagnostic performance of plasma p-tau biomarkers for Alzheimer’s disease. We used a bivariate random-effects meta-analysis to estimate pooled sensitivity, specificity, diagnostics odds ratio and area under the receiver operating characteristic curve. We assessed the certainty of evidence using GRADE. This study was done following PRISMA-DTA guidelines and is registered with PROSPERO as CRD42023422143.
Findings: Of the 6429 studies identified by our search, 312 studies were assessed for eligibility, with 113 studies included in the final analysis, comprising 29 625 unique individuals. Plasma p-tau217 was the highest-performing biomarker for identifying biologically defined Alzheimer’s disease, with pooled sensitivity of 88·1% (95% CI 86·7-89·5, moderate certainty of evidence), specificity of 88·7% (87·4-89·9, moderate certainty of evidence), area under the receiver operating characteristic curve (AUROC) of 91·1% (88·9-92·4, moderate certainty of evidence), and diagnostic odds ratio of 50·7 (40·6-63·4). p-tau181 pooled sensitivity was 80·5% (78·4-82·4, low certainty of evidence), specificity was 76·4% (74·1-78·6, low certainty of evidence), AUROC was 81·5% (80·2-82·9, low certainty of evidence), and diagnostic odds ratio was 13·4 (11·4-16·7). p-tau205 pooled sensitivity was 76·6% (70·7-81·6, moderate certainty of evidence), specificity was 86·0% (78·6-91·2, moderate certainty of evidence), AUROC was 85·1% (80·7-89·6, moderate certainty of evidence), and diagnostic odds ratio was 20·2 (10·5-38·7). p-tau212 pooled sensitivity was 84·5% (75·5-90·6, moderate certainty of evidence), specificity was 87·3% (79·5-92·5, moderate certainty of evidence), AUROC was 90·3% (86·6-94·1, moderate certainty of evidence), and diagnostic odds ratio was 41·2 (22·0-77·3). p-tau231 pooled sensitivity was 75·2% (71·3-78·8, moderate certainty of evidence), specificity was 75·3% (71·2-78·9, moderate certainty of evidence), AUROC was 80·2 (77·6-82·7, moderate certainty of evidence), and diagnostic odds ratio was 9·3 (7·0-12·2). Approximately 90% of studies were rated as high risk of bias for not having used predefined or externally derived thresholds.
Interpretation: Plasma p-tau217 is a highly sensitive and specific biomarker for Alzheimer’s disease pathology, despite the high risk of bias of many studies. Prospective clinical implementation studies in real-world settings are needed to characterise the effect of plasma p-tau217 on Alzheimer’s disease diagnosis and clinical management.
Authors & Affiliations
Joseph Therriault¹, Wagner S Brum², Lydia Trudel³, Arthur C Macedo⁴, Fernando Valentim Bitencourt⁵, Carolina Castro Martins-Pfeifer⁶, Martin Nakouzi⁴, Ilaria Pola⁷, Matthew Wong⁴, Przemysław R Kac⁷, Ana Paula Real³, Chloë Witherow⁴, Thomas K Karikari⁸, Alexis Moscoso⁹, Eduardo R Zimmer¹⁰, Michael Schöll¹¹, Tharick Pascoal¹², Andrea L Benedet⁷, Nicholas J Ashton¹³, Suzanne E Schindler¹⁴, Henrik Zetterberg¹⁵, Kaj Blennow¹⁶, Pedro Rosa-Neto¹⁷
¹ Translational Neuroimaging Laboratory, Montreal Neurological Institute, Montreal, Canada
² Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden; Graduate Programme in Biological Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
³ Translational Neuroimaging Laboratory, Montreal Neurological Institute, Montreal, Canada; Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, Canada
⁴ Translational Neuroimaging Laboratory, Montreal Neurological Institute, Montreal, Canada
⁵ Department of Dentistry and Oral Health, Section for Oral Ecology, Aarhus University, Aarhus, Denmark; Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
⁶ School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
⁷ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
⁸ Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
⁹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
¹⁰ Graduate Programme in Biological Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Graduate Programme in Biological Sciences: Pharmacology and Therapeutics, Department of Pharmacology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Brain Institute of Rio Grande do Sul, PUCRS, Porto Alegre, Brazil
¹¹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Neuropsychiatry, Region Västra Götaland, Sahlgrenska University Hospital, Götaland, Sweden; Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK
¹² Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
¹³ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden; Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London, UK; NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK; Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway
¹⁴ Washington University School of Medicine, St Louis, MO, USA
¹⁵ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden; Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; UK Dementia Research Institute at UCL, University College London, London, UK; Hong Kong Centre for Neurodegenerative Diseases, Hong Kong, China; Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin–Madison, Madison, WI, USA
¹⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden; Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France
¹⁷ Translational Neuroimaging Laboratory, Montreal Neurological Institute, Montreal, Canada; Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, Canada; Department of Neuroscience, Department of Neurology, and Department of Radiology, The Peter O’Donnell Jr Brain Institute, University of Texas Southwestern Medical Centre, Dallas, TX, USA