Network-based analyses identify GFAP as a cross-domain hub linking synaptic, neuronal, and inflammatory CSF markers in Alzheimer’s disease
Alzheimer’s disease (AD) is characterized by complex alterations in synaptic, glial, neuronal and inflammatory markers. Given its emerging role at the interface of synaptic dysfunction and inflammation, the astrocytic marker GFAP may represent a cross-domain hub linking synaptic, neuronal and inflammatory alterations. Using multivariate and network-based analyses we examined the relationships among cerebrospinal fluid (CSF) biomarkers of astrocytic activation and synaptic failure, inflammation, and neurodegeneration in biologically confirmed AD patients and healthy controls (HC). We studied 60 AD patients and 40 HC. CSF concentrations of neurogranin, SNAP-25, CAP2, NfL, GFAP, IL-1α, IL-1β, IL-8, MCP-1, TNF-α were measured. Associations were assessed using Spearman correlations, LASSO regression, and network analysis to characterize multivariate dependency structures. Compared with controls, AD patients showed significantly higher CSF levels of neurogranin, SNAP-25, CAP2, NfL, GFAP, IL-1β, TNF-α. In AD, synaptic biomarkers were strongly intercorrelated and associated with astroglial activation, inflammatory markers, and tau-related pathology. Network analysis identified GFAP as a cross-domain hub linking synaptic, inflammatory, and neurodegenerative domains in AD. In controls, GFAP was mainly associated with neuronal injury markers. Network-based modelling revealed a disease-related reorganization of biomarker connectivity in AD, with GFAP occupying a central cross-domain position, supporting a systems-level view of AD pathophysiology.
Authors
- Elena Marcello (ORCID: https://orcid.org/0000-0003-0452-762X)
- Ramona Stringhi (ORCID: https://orcid.org/0009-0002-7797-5378)
- Andrea Pilotto (ORCID: https://orcid.org/0000-0003-2029-6606)
- Chiara Tolassi (ORCID: https://orcid.org/0009-0006-8741-1313)
- Monica Moroni (ORCID: https://orcid.org/0000-0003-1852-7217)
- Andréa Lessa Benedet (ORCID: https://orcid.org/0000-0001-8219-1741)
- Stefano Bovo (ORCID: https://orcid.org/0000-0002-0278-6786)
- Flavio Ragni (ORCID: https://orcid.org/0000-0001-7767-7288)
- Silvia Pelucchi (ORCID: https://orcid.org/0000-0002-5994-487X)
- Salvatore Caratozzolo (ORCID: https://orcid.org/0000-0001-5579-9081)
- Alessandro Padovani (ORCID: https://orcid.org/0000-0002-0119-3639)
- Giuseppe Jurman (ORCID: https://orcid.org/0000-0002-2705-5728)
- Caterina Martinuzzo
- Chiara Trasciatti
- Irene Girotto
- Laura D’Andrea
- Nicholas J. Ashton
- Monica Di Luca
- Henrik Zetterberg
- Ilaria Pola
Institutions
- Humanitas University (IT)
- Fondazione Bruno Kessler (IT)
- Banner Health (US)
- Karolinska Institutet (SE)
- Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT)
- Ospedale San Paolo (IT)
- Banner Sun Health Research Institute (US)
- Indian Institute of Science Bangalore (IN)
- University of Brescia (IT)
- University of Gothenburg (SE)
Publication Details
- Journal
- Scientific Reports
- Published
- 2026-08-25
- DOI
- https://doi.org/10.1038/s41598-026-67701-9
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Michael J. Fox Foundation for Parkinson's Research
- Alzheimer's Association
- Giovanni Armenise-Harvard Foundation
- Familjen Erling-Perssons Stiftelse
- Cure Alzheimer's Fund
- Stiftelsen för Gamla Tjänarinnor
- EU Joint Programme – Neurodegenerative Disease Research
- European Partnership on Metrology
- National Institute for Health and Care Research
- European Commission
- Ministero della Salute
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Vetenskapsrådet
- UK Dementia Research Institute
- Associazione Italiana Ricerca Alzheimer
- Olav Thon Stiftelsen
- Horizon 2020 Framework Programme
- H2020 Marie Skłodowska-Curie Actions
- NextGenerationEU