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

Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. Pathology and Laboratory Medicine, Experimental Pathology, Emory University School of Medicine, Atlanta, Georgia, USA. Research and Development, Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China. Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 39105, USA. Department of Development Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 39105, USA. St. Jude Proteomics Facility, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 39105, USA. Memory Clinic, Skåne University Hospital, Skåne, Sweden. Clinical Memory Research Unit, Lund University, Sweden. Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK. UK Dementia Research Institute at UCL, London WC1N 3BG, UK. Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Disease Research, Neurogeriatrics Division, Karolinska Institutet, Novum, Huddinge, Stockholm, Sweden.

Brain : a journal of neurology. 2020;(2):650-660
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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.