Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology
Open accessAbstract
To date, there is no validated fluid biomarker for tau pathology in Alzheimer’s disease, with contradictory results from studies evaluating the correlation between phosphorylated tau in CSF with tau PET imaging. Tau protein is subjected to proteolytic processing into fragments before being secreted to the CSF. A recent study suggested that tau cleavage after amino acid 368 by asparagine endopeptidase (AEP) is upregulated in Alzheimer’s disease. We used immunoprecipitation followed by mass spectrometric analyses to evaluate the presence of tau368 species in CSF. A novel Simoa® assay for quantification of tau368 in CSF was developed, while total tau (t-tau) was measured by ELISA and the presence of tau368 in tangles was evaluated using immunohistochemistry. The diagnostic utility of tau368 was first evaluated in a pilot study (Alzheimer’s disease = 20, control = 20), then in a second cohort where the IWG-2 biomarker criteria were applied (Alzheimer’s disease = 37, control = 45), and finally in a third cohort where the correlation with 18F-GTP1 tau PET was evaluated (Alzheimer’s disease = 38, control = 11). The tau368/t-tau ratio was significantly decreased in Alzheimer’s disease (P < 0.001) in all cohorts. Immunohistochemical staining demonstrated that tau fragments ending at 368 are present in tangles. There was a strong negative correlation between the CSF tau368/t-tau ratio and 18F-GTP1 retention. Our data suggest that tau368 is a tangle-enriched fragment and that the CSF ratio tau368/t-tau reflects tangle pathology. This novel tau biomarker could be used to improve diagnosis of Alzheimer’s disease and to facilitate the development of drug candidates targeting tau pathology. Furthermore, future longitudinal studies will increase our understanding of tau pathophysiology in Alzheimer’s disease and other tauopathies.
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Plasma total tau's weak performance may stem from assay limitations, while phosphorylated tau forms may have better clinical utility.
“These results may be related to limitations of the methodology to measure plasma t-tau, and the measurement of phosphorylated species of tau may have better clinical performance, as suggested by recent studies.44”
From Plasma Tau and Neurofilament Light in Frontotemporal Lobar Degeneration and Alzheimer Disease (2021) · cites this paper as [44]
The Introduction and CSF collection and biomarker analyses sections discuss assays for cerebrospinal-fluid tau, not plasma tau. The Discussion compares CSF tau measures with tau PET, but does not say that limitations in measuring plasma total tau explain its performance or that plasma phosphorylated tau has better clinical performance. Searches for plasma assay limitations and plasma p-tau found no passage addressing those claims; page numbers were unavailable in our copy. (LLM, conf=0.76)
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- Authors
- Blennow, K., Chen, C., Cicognola, C., Wildsmith, K. R., Manser, P. T., Bohorquez, S. M. S., Zhang, Z., Xie, B., Peng, J., Hansson, O., Kvartsberg, H., Portelius, E., Zetterberg, H., Lashley, T., Brinkmalm, G., Kerchner, G. A., Weimer, R. M., Ye, K., & Höglund, K.
- Affiliations
- Sahlgrenska University Hospital (SE)
- Emory University (US)
- University of Gothenburg (SE)
- Genentech (US)
- St. Jude Children's Research Hospital (US)
- Lund University (SE)
- UK Dementia Research Institute (GB)
- Corresponding author
- Höglund, Kina
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-12-13
- Volume
- 143
- Issue
- 2
- Pages
- 650-660
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC7009597
- OpenAlex
- W2997373980
- Cited by
- 105
- References
- 39
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 17 · 2023: 22 · 2022: 19 · 2021: 17 · 2020: 10
- FWCI
- 7.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Brain (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- BrightFocus Foundation (A2015359)
- Swedish Brain Foundation and the Wallström-Sjöblom foundation
- Swedish Alzheimer Foundation
- Swedish Brain Foundation
- Torsten Söderberg Foundation
- Swedish Research Council (# 2017-00915)
- ALF-VGR (#238961)
- NIH (R01AG047928, GN30009, NCT02640092)
- 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
- cerebrospinal fluid biomarkers, tau PET, tau tangles, Alzheimer's disease, asparaginyl endopeptidase, tau cleavage, Simoa assay, neurodegeneration
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Female, Humans, Longitudinal Studies, Male, Middle Aged, Peptide Fragments, Cohort Studies, Biomarkers, Amyloid beta-Peptides, tau Proteins
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