{ "abstract": "Objective\n\nTo clarify the relative contributions of amyloid and tau to synaptic dysfunction in Alzheimer's disease (AD).Methods\n\nWe 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\n\nSynaptic 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\n\nTau 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.", "abstract_shown": true, "affiliations": [ "Department of Neuroscience \"Rita Levi-Montalcini\", University of Turin, Turin, Italy.", "Geneva Memory Center, Department of Rehabilitation and Geriatrics, Geneva University Hospitals, Geneva, Switzerland.", "Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland.", "Division of Nuclear Medicine and Molecular Imaging, Diagnostic Department, Geneva University Hospitals, Geneva, Switzerland.", "Laboratory of Neuroimaging and Innovative Molecular Tracers (NIMTlab), Geneva University Neurocenter and Faculty of Medicine, University of Geneva, Geneva, Switzerland.", "CIBM Center for Biomedical Imaging, Geneva, Switzerland.", "Laboratory for Translational Research in Neurodegeneration, University of Geneva, Geneva, Switzerland.", "Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.", "Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.", "Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.", "Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.", "Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.", "UK Dementia Research Institute at UCL, London, UK.", "Banner Alzheimer's Institute and University of Arizona, Phoenix, Arizona, USA.", "Banner Sun Health Research Institute, Sun City, Arizona, USA." ], "article_type": "research article", "arxiv": null, "author_total": 12, "authors": [ { "affs": [ 0, 1, 2 ], "name": "Fausto Roveta", "orcid": "0000-0001-7230-7819" }, { "affs": [ 1, 2 ], "name": "Augusto J Mendes" }, { "affs": [ 3, 4, 5 ], "name": "Valentina Garibotto" }, { "affs": [ 4 ], "name": "Cecilia Boccalini" }, { "affs": [ 1, 6 ], "name": "Aurelien Lathuiliere" }, { "affs": [ 0 ], "name": "Innocenzo Rainero" }, { "affs": [ 0 ], "name": "Elisa Rubino" }, { "affs": [ 7, 8, 9, 10, 11, 12 ], "name": "Henrik Zetterberg" }, { "affs": [ 7, 13, 14 ], "name": "Nicholas J Ashton" }, { "affs": [ 1, 2 ], "name": "Federica Ribaldi", "orcid": "0000-0001-9208-4472" }, { "affs": [ 1, 2 ], "name": "Giovanni B Frisoni" }, { "name": "Alzheimer's Disease Neuroimaging Initiative" } ], "bibtex": "https://research.draconitic.com/paper/atzvhq9jpe4k6.bib", "cited_by": 0, "doi": "10.1002/acn3.70558", "fulltext_url": "https://europepmc.org/articles/PMC13720864", "id": "atzvhq9jpe4k6", "issns": [ "2328-9503" ], "landing_url": "https://europepmc.org/article/MED/42960521", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "Research Article" ] ], "openalex": null, "pdf_url": "https://europepmc.org/articles/PMC13720864?pdf=render", "pmcid": "PMC13720864", "pmid": "42960521", "published": "2026-10-30", "publisher": "Wiley", "ris": "https://research.draconitic.com/paper/atzvhq9jpe4k6.ris", "sources": [ { "first_seen": "2026-10-31T12:21:46Z", "native_id": "MED:42960521", "source": "europepmc", "url": "https://europepmc.org/article/MED/42960521" }, { "first_seen": "2026-11-03T12:21:40Z", "native_id": "PMC13720864", "source": "pmc", "url": "https://doi.org/10.1002/acn3.70558" } ], "subjects": [ { "field": "medicine", "origin": "journal-openalex:F27", "subfield": "general" } ], "title": "The Association of Amyloid-β and Tau With Synaptic Dysfunction in Alzheimer's Disease.", "title_text": "The Association of Amyloid-β and Tau With Synaptic Dysfunction in Alzheimer's Disease.", "type": "peer-reviewed", "updated_at": "2026-11-03T12:21:40Z", "url": "https://research.draconitic.com/paper/atzvhq9jpe4k6", "venue": "Annals of clinical and translational neurology", "versions": [] }