Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology

Research output: Contribution to journalArticle

Abstract

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.

Details

Authors
  • Kaj Blennow
  • Chun Chen
  • Claudia Cicognola
  • Kristin R. Wildsmith
  • Paul T. Manser
  • Sandra M.Sanabria Bohorquez
  • Zhentao Zhang
  • Boer Xie
  • Junmin Peng
  • Oskar Hansson
  • Hlin Kvartsberg
  • Erik Portelius
  • Henrik Zetterberg
  • Tammaryn Lashley
  • Gunnar Brinkmalm
  • Geoffrey A. Kerchner
  • Robby M. Weimer
  • Keqiang Ye
  • Kina Höglund
Organisations
External organisations
  • Sahlgrenska Academy
  • Sahlgrenska University Hospital
  • Emory University
  • Genentech, Inc
  • St Jude Children´s Research Hospital, Memphis
  • Skåne University Hospital
  • University College London
  • Karolinska Institutet
  • UK Dementia Research Institute
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Clinical Laboratory Medicine

Keywords

  • Alzheimer’s disease, biomarkers, CSF, pathology, tau
Original languageEnglish
Pages (from-to)650-660
Number of pages11
JournalBrain : a journal of neurology
Volume143
Issue number2
Publication statusPublished - 2020 Feb
Publication categoryResearch
Peer-reviewedYes