CSF total tau as a proxy of synaptic degeneration
Cerebrospinal fluid (CSF) total tau (t-tau) is considered a biomarker of neuronal degeneration alongside brain atrophy and fluid neurofilament light chain protein (NfL) in biomarker models of Alzheimer's disease (AD). However, previous studies show that CSF t-tau correlates strongly with synaptic dysfunction/degeneration biomarkers like neurogranin (Ng) and synaptosomal-associated protein 25 (SNAP25). Here, we compare the association between CSF t-tau and synaptic degeneration and axonal/neuronal degeneration biomarkers in cognitively unimpaired and impaired groups from two independent cohorts. We observe a stronger correlation between CSF t-tau and synaptic biomarkers than neurodegeneration biomarkers in both groups. Synaptic biomarkers explain a greater proportion of variance in CSF t-tau levels compared to neurodegeneration biomarkers. Notably, CSF t-tau levels are elevated in individuals with abnormalities only in synaptic biomarkers, but not in individuals with abnormalities only in neurodegeneration biomarkers. Our findings suggest that CSF t-tau is a closer proxy for synaptic degeneration than for axonal/neuronal degeneration.
Authors
- Dana Tudorascu (ORCID: https://orcid.org/0000-0003-4675-3692)
- Tharick Ali Pascoal (ORCID: https://orcid.org/0000-0001-9057-8014)
- João Pedro Ferrari‐Souza (ORCID: https://orcid.org/0000-0003-2183-1551)
- Tobey J. Betthauser (ORCID: https://orcid.org/0000-0001-8856-1352)
- Guilherme Povala (ORCID: https://orcid.org/0000-0002-2023-6569)
- Douglas Teixeira Leffa (ORCID: https://orcid.org/0000-0002-4890-8451)
- Eduardo Rigon Zimmer (ORCID: https://orcid.org/0000-0002-5349-0053)
- Kaj Blennow (ORCID: https://orcid.org/0000-0002-1890-4193)
- Carolina Soares (ORCID: https://orcid.org/0000-0002-2338-4495)
- Rachael E. Wilson (ORCID: https://orcid.org/0000-0003-4197-7777)
- Guilherme Bauer‐Negrini (ORCID: https://orcid.org/0000-0003-0956-557X)
- Pâmela C.L. Ferreira (ORCID: https://orcid.org/0000-0003-2134-9829)
- Andréa Lessa Benedet (ORCID: https://orcid.org/0000-0001-8219-1741)
- Thomas K. Karikari (ORCID: https://orcid.org/0000-0003-1422-4358)
- Bruna Bellaver (ORCID: https://orcid.org/0000-0002-2212-3373)
- Sarah Abbas
- Firoza Zubeida Lussier (ORCID: https://orcid.org/0000-0002-6877-4825)
- Cristiano Schaffer Aguzzoli (ORCID: https://orcid.org/0000-0002-7378-3830)
- Hussein Zalzale
- Henrik Zetterberg (ORCID: https://orcid.org/0000-0003-3930-4354)
- Francieli Rohden (ORCID: https://orcid.org/0000-0002-9232-7371)
- Sterling C. Johnson (ORCID: https://orcid.org/0000-0002-8501-545X)
- Pedro Rosa‐Neto (ORCID: https://orcid.org/0000-0001-9116-1376)
- Bradley T. Christian (ORCID: https://orcid.org/0000-0002-9653-559X)
- Rebecca Langhough
Institutions
- Montreal Neurological Institute and Hospital (CA)
- Universidade Federal do Rio Grande do Sul (BR)
- University of Wisconsin–Madison (US)
- University of Pittsburgh (US)
- University of California, San Francisco (US)
- Sahlgrenska University Hospital (SE)
- Instituto do Cérebro (BR)
- Hospital Moinhos de Vento (BR)
- UPMC Health System (US)
- UK Dementia Research Institute (GB)
- University of Pittsburgh Medical Center (US)
- Centre Intégré Universitaire de Santé et de Services Sociaux du Centre-Sud-de-l'Île-de-Montréal (CA)
- National Hospital for Neurology and Neurosurgery (GB)
- Global Brain Health Institute (US)
- University College London (GB)
- McGill University (CA)
- University of Gothenburg (SE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1038/s41467-025-63545-5
- Citations
- 2
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 2.33
Funders
- Alzheimer's Association
- Alzheimer's Drug Discovery Foundation
- Familjen Erling-Perssons Stiftelse
- University of Pittsburgh
- Stiftelsen för Gamla Tjänarinnor
- Weston Brain Institute
- EU Joint Programme – Neurodegenerative Disease Research
- Global Brain Health Institute
- Consortium canadien en neurodégénérescence associée au vieillissement
- Alzheimer's Society
- European Commission
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Hjärnfonden
- Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul
- Alzheimerfonden
- Instituto Serrapilheira
- UK Dementia Research Institute
- National Institutes of Health
- HORIZON EUROPE Framework Programme
- Canadian Institutes of Health Research
- Fonds de Recherche du Québec - Santé
- National Institute on Aging
- National Institute of Mental Health
- National Institute of Neurological Disorders and Stroke