ArticleNature communications2025
Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer's disease.
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Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22citing papers in PubMed
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Who cites it
22 citing papers in PubMed.
- Genetic Deletion of Adenosine AGlia · 2026Article
- Structure-Guided Optimization of CHI3L1 Modulators Reveals G721-0377 as a Lead Compound for Restoring Astrocyte Function in Alzheimer's Disease.ACS bio & med chem Au · 2026Article
- Retinal proteome changes mirror brain pathology and reveal synaptic and cytoskeletal dysfunction in Alzheimer's disease.Acta neuropathologica · 2026Article
- Sex-specific associations between astrocytic reactivity and cognitive decline in unimpaired elderly.bioRxiv : the preprint server for biology · 2026Article
- Advancing MSC-EV Therapies: Harnessing Preconditioning and Mito-EVs to Tackle Neuroinflammation and Neurodegeneration.Pharmaceutics · 2026Review
- Contributions of the Alzheimer's Disease Neuroimaging Initiative to advancing AD research: a targeted review of recent publications.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Review
- Hippocampal GFAP in aging: Associations with AD and LATE-NC pathologies and cognitive decline in older adults.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- The Perioperative Neurocognitive Disorder Prediction Based on AI-Assisted EEG Dynamic Features in Anesthetized Mice.Diagnostics (Basel, Switzerland) · 2026Article
- Elucidating the Neurobiological Underpinnings of Mild Behavioral Impairment in Tauopathies: Clinical and Molecular Insights.International journal of molecular sciences · 2026Review
- Advances in hiPSC-Derived Brain Organoids as a Model to Study Neuroinflammation in Alzheimer's Disease.Journal of neurochemistry · 2026Review
- Neurotransmitter Systems in Alzheimer's Disease.Current issues in molecular biology · 2026Review
- Dysfunctional astrocytes regulate excitatory neurons via cell adhesion and vascular lesions in patients with Alzheimer's disease.Journal of translational medicine · 2026Article
- Associations of plasma p-tau231 with serial position recall performance in free-of-dementia individuals.Journal of neuropsychology · 2026Article
- Review
- From Neuron-Centric to Glia-Centric: How Aging Glial Networks Drive Neurodegenerative Disease.Journal of neurochemistry · 2026Review
- Treadmill training induces sex-dependent changes in hippocampal epigenetic patterns and plaque-associated microglial morphology in aged TgF344 rats.Frontiers in neuroscience · 2026Article
- Synergistic effects of cerebral small vessel disease burden and plasma phosphorylated tau 181 on white matter microstructure and cognition in a Chinese cohort.Brain communications · 2026Article
- Brain Synapses: Neurons, Astrocytes, and Extracellular Vesicles in Health and Diseases.International journal of molecular sciences · 2025Review
- Neuronal PARIS-STAT3 axis drives tau pathology and glial activation in Alzheimer's disease.bioRxiv : the preprint server for biology · 2025Article
- Increased levels of GFAP and purinergic P2X7 receptor in Alzheimer's disease brain are associated with Aβ, tau pathologies and synaptic loss.Alzheimer's research & therapy · 2025Article
Corrections and comments
- Update of
Authors and funding
27 authors.
Francieli RohdenDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Pamela C L FerreiraDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.ORCID http://orcid.org/0000-0003-2134-9829
Bruna BellaverDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.ORCID http://orcid.org/0000-0002-2212-3373
João Pedro Ferrari-SouzaDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.ORCID http://orcid.org/0000-0003-2183-1551
Cristiano S AguzzoliDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.ORCID http://orcid.org/0000-0002-7378-3830
Carolina SoaresDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.ORCID http://orcid.org/0000-0002-2338-4495
Sarah AbbasDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Hussein ZalzaleDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Guilherme PovalaDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.ORCID http://orcid.org/0000-0002-2023-6569
Firoza Z LussierDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Douglas T LeffaDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Guilherme Bauer-NegriniDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Nesrine RahmouniTranslational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Hospital Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Montréal, QC, Canada.
Cécile TissotDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.ORCID http://orcid.org/0000-0003-2711-3833
Joseph TherriaultTranslational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Hospital Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Montréal, QC, Canada.
Stijn ServaesTranslational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Hospital Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Montréal, QC, Canada.
Jenna StevensonTranslational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Hospital Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Montréal, QC, Canada.
Andrea L BenedetDepartment of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Nicholas J AshtonDepartment of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Thomas K KarikariDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.ORCID http://orcid.org/0000-0003-1422-4358
Dana L TudorascuDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Henrik ZetterbergDepartment of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.ORCID http://orcid.org/0000-0003-3930-4354
Kaj BlennowDepartment of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.ORCID http://orcid.org/0000-0002-1890-4193
Eduardo R ZimmerGraduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.ORCID http://orcid.org/0000-0002-5349-0053
Diogo SouzaGraduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
Pedro Rosa-NetoTranslational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer's Disease Research Unit, Douglas Hospital Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Montréal, QC, Canada.ORCID http://orcid.org/0000-0001-9116-1376
Tharick A PascoalDepartment of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. pascoalt@upmc.edu.ORCID http://orcid.org/0000-0001-9057-8014
Funding
Vascular Moderators of the Impact of Alzheimer's Pathology in the Young-OldP01AG025204 · NIA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI HOWARD J AIZENSTEIN, Ann D. Cohen · 2005 to 2026
$56.5MLongitudinal multicenter head-to-head harmonization of tau PET tracersR01AG073267 · NIA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI BAKER, SUZANNE L, PASCOAL, THARICK · 2021 to 2025
$41.1MPlasma brain-derived tau: a novel Alzheimer’s disease-type neurodegeneration biomarker with potential to complete the AT(N) scheme in bloodR01AG083874 · NIA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Thomas K Karikari · 2023 to 2026
$14.5MAlzheimer Diagnosis in older Adults with Chronic Conditions ADACC NetworkU24AG082930 · NIA · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI Nicole R. Fowler, Thomas K Karikari · 2023 to 2026
$7.3MHead-to-head comparisons of high-performance plasma phospho-tau epitopes for the detection of Alzheimer's diseaseR01AG075336 · NIA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Tharick Pascoal · 2022 to 2026
$3.7MThe effects of iron on oxidative stress and Alzheimer's biomarkers in amyloid-positive and negative elderly normalR01AG068398 · NIA · WEILL MEDICAL COLL OF CORNELL UNIV · PI CHIANG, GLORIA CHIA-YI · 2020 to 2024
$2.8MNIA NIH HHS P01 AG025204NIA NIH HHS R01 AG068398NIA NIH HHS R01 AG073267NIA NIH HHS R01 AG075336NIA NIH HHS R01 AG083874NIA NIH HHS U24 AG082930
Abstract
Previous studies suggest glial and neuronal changes may trigger synaptic dysfunction in Alzheimer's disease (AD), but the link between their markers and synaptic abnormalities in the living brain remains unclear. We investigated the association between glial reactivity and synaptic dysfunction biomarkers in cerebrospinal fluid (CSF) from 478 individuals in cognitively unimpaired (CU) and cognitively impaired (CI) individuals. We measured amyloid-β (Aβ), phosphorylated tau (pTau181), astrocyte reactivity (GFAP), microglial activation (sTREM2), and synaptic markers (GAP43, neurogranin). CSF GFAP levels were associated with presynaptic and postsynaptic dysfunction, independent of cognitive status or Aβ presence. CSF sTREM2 levels were related to presynaptic markers in cognitively unimpaired and impaired Aβ+ individuals, and to postsynaptic markers in cognitively impaired Aβ+ individuals. Notably, CSF pTau mediated the relationships between GFAP or sTREM2 and synaptic dysfunction. Our findings, validated in two independent cohorts (TRIAD and ADNI), reveal a distinct pattern of glial contribution to synaptic degeneration.
Indexed as
AgingAlzheimer DiseaseNeurogliaSynapsesAgedAged, 80 and overAmyloid beta-PeptidesAstrocytesBiomarkersBrainCognitive DysfunctionFemaleGlial Fibrillary Acidic ProteinHumansMaleMembrane GlycoproteinsAmyloid beta-PeptidesBiomarkersGFAP protein, humanGlial Fibrillary Acidic ProteinMembrane GlycoproteinsNeurograninReceptors, Immunologictau ProteinsTREM2 protein, human
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.