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Tau biomarkers in Alzheimer's disease: towards implementation in clinical practice and trials
Open accessAbstract
Background Deposition of tau aggregates is a pathological hallmark of Alzheimer's disease that is closely linked both spatially and temporally to emergence of neurodegeneration and manifestation of clinical symptoms. There is an urgent need for accurate PET, CSF, and plasma biomarkers of tau pathology to improve the diagnostic process in clinical practice and the selection of participants and monitoring of treatment effects in trials.Recent developments Innovative second-generation tau-PET tracers with high affinity and selectivity to tau pathology in Alzheimer's disease have enabled detection of tau pathology in medial temporal lobe subregions that are affected in the earliest disease stages. Furthermore, novel but common tau spreading subtypes have been discovered using tau-PET, suggesting much greater interindividual differences in the distribution of tau pathology across the brain than previously assumed. In the CSF biomarker field, novel phosphorylated tau (p-tau) assays have been introduced that better reflect tau tangle load than established CSF biomarkers of tau pathology. The advent of cost-effective and accessible blood-based biomarkers for tau pathophysiology (ie, p-tau181, p-tau217, and p-tau231) might transform the Alzheimer's disease field, as these biomarkers correlate with post-mortem Alzheimer's disease pathology, differentiate Alzheimer's disease from other types of dementia, and predict future progression from normal cognition and mild cognitive impairment to Alzheimer's disease. In controlled investigational settings, improvements in tau-PET and biofluid p-tau markers have led to earlier disease detection, more accurate diagnostic methods, and refinement of prognosis. The anti-tau therapy landscape is rapidly evolving, with multiple ongoing phase 1 and 2 trials of post-translational modification of tau, tau immunotherapy, tau aggregation inhibitors, and targeting production of tau and reduction of intracellular tau levels. Neuroimaging and biofluid tau markers hold potential for optimising such clinical trials by augmenting participant selection, providing evidence of target engagement, and monitoring treatment efficacy. WHERE NEXT?: Major challenges to overcome are the high cost of tau-PET, partial sensitivity to detect early-stage Alzheimer's disease pathology, and off-target tracer binding. Prospective validation studies of biofluid p-tau markers are needed, and assay-related preanalytical and analytical factors need further refinement. Future studies should focus on demonstrating the diagnostic and prognostic accuracy of tau biomarkers-blood-based markers in particular-in non-tertiary settings, such as primary care, which is characterised by a diverse population with medical comorbidities. Large-scale head-to-head studies are needed across different stages of Alzheimer's disease to determine which tau biomarker is optimal in various clinical scenarios, such as early diagnosis, differential diagnosis, and prognosis, and for aspects of clinical trial design, such as proving target engagement, optimising participant selection, and refining monitoring of treatment effects.
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“it is crucial to find ways to reduce the need for PET scans due to their relative inaccessibility and costliness, while still preserving the ability to estimate the load and distribution of AD pathology as accurately and comprehensively. 12 , 13”
From Machine learning prediction of tau‐PET in Alzheimer's disease using plasma, MRI, and clinical data (2025) · cites this paper as [12]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Tau‐PET is often considered a state‐of‐the‐art outcome in AD research studies, a very accurate prognostic tool in patients with AD, and frequently used in clinical trials for AD during screening and to monitor treatment effects. 12 , 14 , 15 , 16”
From Machine learning prediction of tau‐PET in Alzheimer's disease using plasma, MRI, and clinical data (2025) · cites this paper as [12]
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“As a major component of NFTs, tau protein exhibits a spatial and temporal distribution that strongly correlates with clinical symptoms, making it a highly specific pathological biomarker in AD patients.152”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [152]
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“Tau‐PET is often considered a state‐of‐the‐art outcome in AD research studies, a very accurate prognostic tool in patients with AD, and frequently used in clinical trials for AD during screening and to monitor treatment effects. 12 , 14 , 15 , 16”
From Machine learning prediction of tau‐PET in Alzheimer's disease using plasma, MRI, and clinical data (2025) · cites this paper as [12]
The cited source says what the claim attributes to it.
In the citing paper
“Tau‐PET is often considered a state‐of‐the‐art outcome in AD research studies, a very accurate prognostic tool in patients with AD, and frequently used in clinical trials for AD during screening and to monitor treatment effects. 12 , 14 , 15 , 16”
From Machine learning prediction of tau‐PET in Alzheimer's disease using plasma, MRI, and clinical data (2025) · cites this paper as [12]
In the citing paper
“Plasma tau measurement could thus be used as a screening test in early-stage clinical trials to enrich trial participation with individuals more likely to have AD pathology (76, 77, 90).”
From All the Tau We Cannot See (2023) · cites this paper as [90]
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Cites
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Self-citationPET Imaging of Tau Deposition in the Aging Human Brain
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Self-citationThe Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease
Spires-Jones, T. L., & Hyman, B. T. (2014) · Neuron · doi:10.1016/j.neuron.2014.05.004 · Cited by 1,201
Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease
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Self-citationBiomarkers for neurodegenerative diseases
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Zhang, J., Zhang, Y., Wang, J., Xia, Y., Zhang, J., & Chen, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01911-3 · Cited by 1,138
“152 In recent years, there has been a heightened focus on tau deposition, including the correlation between tau deposition, brain atrophy, and glucose metabolism in both typical and atypical AD, 167,168 as well as the effects of tau deposition at the molecular and cellular levels.”
BackgroundMitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances
Xu, X., Pang, Y., & Fan, X. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02253-4 · Cited by 1,016
A biological classification of Parkinson's disease: the SynNeurGe research diagnostic criteria
Höglinger, G. U., Adler, C. H., Berg, D., Klein, C., Outeiro, T. F., Poewe, W. H., Postuma, R. B., Stoessl, A. J., & Lang, A. E. (2024) · The Lancet Neurology · doi:10.1016/s1474-4422(23)00404-0 · Cited by 607
Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer’s disease
Janelidze, S., Bali, D., Ashton, N. J., Barthélemy, N. R., Vanbrabant, J., Stoops, E., Vanmechelen, E., He, Y., Dolado, A. O., Triana-Baltzer, G., et al. (2023) · Brain · doi:10.1093/brain/awac333 · Cited by 522
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Metadata
- Authors
- Ossenkoppele, R., van der Kant, R., & Hansson, O.
- Affiliations
- Lund University (SE)
- Corresponding author
- Ossenkoppele, Rik
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2022-08
- Volume
- 21
- Issue
- 8
- Pages
- 726-734
- ISSN
- 1474-4422 (ISSN-L)
- OpenAlex
- W4281564421
- Cited by
- 557
- References
- 79
- Citations by year
- 2026: 127 · 2025: 174 · 2024: 142 · 2023: 98 · 2022: 15
- FWCI
- 14.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The Lancet Neurology (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- VU Research Portal (publishedVersion, other-oa)
- Pure Amsterdam UMC (acceptedVersion, other-oa)
- Lund University Publications (Lund University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Keywords
- Alzheimer's disease, tau pathology, tau biomarkers, tau PET tracers, phosphorylated tau, cerebrospinal fluid biomarkers, blood-based biomarkers, anti-tau therapy, clinical trial participant selection, early disease detection, tau immunotherapy, tau aggregation inhibitors, dementia diagnosis, mild cognitive impairment, primary care
- MeSH terms
- Alzheimer Disease, Brain, Humans, Biomarkers, Amyloid beta-Peptides, tau Proteins, Neuroimaging, Cognitive Dysfunction
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