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Peer-reviewedCC BYAnnals of clinical and translational neurology

The Association of Amyloid-β and Tau With Synaptic Dysfunction in Alzheimer's Disease.

  • Fausto Roveta1,2,3
  • Augusto J Mendes2,3
  • Valentina Garibotto4,5,6
  • Cecilia Boccalini5
  • Aurelien Lathuiliere2,7
  • Innocenzo Rainero1
  • Elisa Rubino1
  • Henrik Zetterberg8,9,10,11,12,13
  • Nicholas J Ashton8,14,15
  • Federica Ribaldi2,3
  • Giovanni B Frisoni2,3
  • Alzheimer's Disease Neuroimaging Initiative
15 affiliations
  1. 1Department of Neuroscience "Rita Levi-Montalcini", University of Turin, Turin, Italy.
  2. 2Geneva Memory Center, Department of Rehabilitation and Geriatrics, Geneva University Hospitals, Geneva, Switzerland.
  3. 3Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland.
  4. 4Division of Nuclear Medicine and Molecular Imaging, Diagnostic Department, Geneva University Hospitals, Geneva, Switzerland.
  5. 5Laboratory of Neuroimaging and Innovative Molecular Tracers (NIMTlab), Geneva University Neurocenter and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
  6. 6CIBM Center for Biomedical Imaging, Geneva, Switzerland.
  7. 7Laboratory for Translational Research in Neurodegeneration, University of Geneva, Geneva, Switzerland.
  8. 8Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
  9. 9Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
  10. 10Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
  11. 11Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
  12. 12Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
  13. 13UK Dementia Research Institute at UCL, London, UK.
  14. 14Banner Alzheimer's Institute and University of Arizona, Phoenix, Arizona, USA.
  15. 15Banner Sun Health Research Institute, Sun City, Arizona, USA.
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Abstract

Objective

To clarify the relative contributions of amyloid and tau to synaptic dysfunction in Alzheimer's disease (AD).Methods

We included 109 cognitively unimpaired and impaired individuals from the Geneva Memory Center with available CSF synaptic biomarkers (neurogranin, SNAP-25, GAP-43). Participants were stratified according to amyloid (A) and tau (T) status, and group comparisons and correlations between synaptic and AD biomarkers were assessed. Multiple linear regression models evaluated the independent associations of amyloid and tau with synaptic markers: Model I (n = 109) included CSF Aβ42 and p-tau181, while Model II (n = 69) included amyloid PET centiloid and CSF p-tau181. Mediation analyses were performed to further investigate these relationships. Findings were replicated in the ADNI cohort (n = 787).Results

Synaptic biomarker levels were significantly higher in A+/T+ individuals compared with A-/T- and A+/T- groups (p < 0.001). CSF p-tau181 strongly correlated with synaptic markers. In Model I, GAP43 was positively associated with both CSF Aβ42 (β = 0.31, 95% CI 0.23-0.40) and p-tau181 (β = 0.94, 95% CI 0.84-1.04; p < 0.001). In Model II, lower amyloid PET centiloid (β = -0.31, 95% CI -0.46 to -0.16) and higher p-tau181 (β = 1.02, 95% CI 0.86-1.19) predicted increased GAP43 (p < 0.001), with the same pattern of associations observed for neurogranin and SNAP-25. The association between amyloid burden and synaptic biomarkers was largely indirect, statistically mediated by CSF p-tau181. Results were replicated in ADNI.Interpretation

Tau pathology showed strong associations with synaptic biomarkers, with a potential mediating role in the association between amyloid pathology and synaptic dysfunction. These findings support a central role of tau-related processes in synaptic dysfunction in AD.

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Cite

BibTeXRIS
BibTeX
@article{roveta2026association,
  title = {{The Association of Amyloid-β and Tau With Synaptic Dysfunction in Alzheimer's Disease.}},
  author = {Fausto Roveta and Augusto J Mendes and Valentina Garibotto and Cecilia Boccalini and Aurelien Lathuiliere and Innocenzo Rainero and Elisa Rubino and Henrik Zetterberg and Nicholas J Ashton and Federica Ribaldi and Giovanni B Frisoni and Alzheimer's Disease Neuroimaging Initiative},
  journal = {Annals of clinical and translational neurology},
  year = {2026},
  month = oct,
  doi = {10.1002/acn3.70558},
  url = {https://europepmc.org/article/MED/42960521},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - The Association of Amyloid-β and Tau With Synaptic Dysfunction in Alzheimer's Disease.
AU  - Fausto Roveta
AU  - Augusto J Mendes
AU  - Valentina Garibotto
AU  - Cecilia Boccalini
AU  - Aurelien Lathuiliere
AU  - Innocenzo Rainero
AU  - Elisa Rubino
AU  - Henrik Zetterberg
AU  - Nicholas J Ashton
AU  - Federica Ribaldi
AU  - Giovanni B Frisoni
AU  - Alzheimer's Disease Neuroimaging Initiative
PY  - 2026
DA  - 2026/10/30
JO  - Annals of clinical and translational neurology
DO  - 10.1002/acn3.70558
UR  - https://europepmc.org/article/MED/42960521
AB  - Objective  To clarify the relative contributions of amyloid and tau to synaptic dysfunction in Alzheimer's disease (AD).Methods  We included 109 cognitively unimpaired and impaired individuals from the Geneva Memory Center with available CSF synaptic biomarkers (neurogranin, SNAP-25, GAP-43). Participants were stratified according to amyloid (A) and tau (T) status, and group comparisons and correlations between synaptic and AD biomarkers were assessed. Multiple linear regression models evaluated the independent associations of amyloid and tau with synaptic markers: Model I (n = 109) included CSF Aβ42 and p-tau181, while Model II (n = 69) included amyloid PET centiloid and CSF p-tau181. Mediation analyses were performed to further investigate these relationships. Findings were replicated in the ADNI cohort (n = 787).Results  Synaptic biomarker levels were significantly higher in A+/T+ individuals compared with A-/T- and A+/T- groups (p < 0.001). CSF p-tau181 strongly correlated with synaptic markers. In Model I, GAP43 was positively associated with both CSF Aβ42 (β = 0.31, 95% CI 0.23-0.40) and p-tau181 (β = 0.94, 95% CI 0.84-1.04; p < 0.001). In Model II, lower amyloid PET centiloid (β = -0.31, 95% CI -0.46 to -0.16) and higher p-tau181 (β = 1.02, 95% CI 0.86-1.19) predicted increased GAP43 (p < 0.001), with the same pattern of associations observed for neurogranin and SNAP-25. The association between amyloid burden and synaptic biomarkers was largely indirect, statistically mediated by CSF p-tau181. Results were replicated in ADNI.Interpretation  Tau pathology showed strong associations with synaptic biomarkers, with a potential mediating role in the association between amyloid pathology and synaptic dysfunction. These findings support a central role of tau-related processes in synaptic dysfunction in AD.
SN  - 2328-9503
ER  -