Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer’s disease

Francieli Rohden, Pamela C. L. Ferreira, Bruna Bellaver, João Pedro Ferrari-Souza, Cristiano S. Aguzzoli, Carolina Soares, Sarah Abbas, Hussein Zalzale, Guilherme Povala, Firoza Z. Lussier, Douglas T. Leffa, Guilherme Bauer-Negrini, Nesrine Rahmouni, Cécile Tissot, Joseph Therriault, Stijn Servaes, Jenna Stevenson, Andrea L. Benedet, Nicholas J. Ashton, Thomas K. Karikari, Dana L. Tudorascu, Henrik Zetterberg, Kaj Blennow, Eduardo R. Zimmer, Diogo Souza, Pedro Rosa-Neto and Tharick A. Pascoal ()
Additional contact information
Francieli Rohden: University of Pittsburgh
Pamela C. L. Ferreira: University of Pittsburgh
Bruna Bellaver: University of Pittsburgh
João Pedro Ferrari-Souza: University of Pittsburgh
Cristiano S. Aguzzoli: University of Pittsburgh
Carolina Soares: University of Pittsburgh
Sarah Abbas: University of Pittsburgh
Hussein Zalzale: University of Pittsburgh
Guilherme Povala: University of Pittsburgh
Firoza Z. Lussier: University of Pittsburgh
Douglas T. Leffa: University of Pittsburgh
Guilherme Bauer-Negrini: University of Pittsburgh
Nesrine Rahmouni: Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-Montréal
Cécile Tissot: University of Pittsburgh
Joseph Therriault: Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-Montréal
Stijn Servaes: Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-Montréal
Jenna Stevenson: Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-Montréal
Andrea L. Benedet: The Sahlgrenska Academy at the University of Gothenburg
Nicholas J. Ashton: The Sahlgrenska Academy at the University of Gothenburg
Thomas K. Karikari: University of Pittsburgh
Dana L. Tudorascu: University of Pittsburgh
Henrik Zetterberg: The Sahlgrenska Academy at the University of Gothenburg
Kaj Blennow: The Sahlgrenska Academy at the University of Gothenburg
Eduardo R. Zimmer: Universidade Federal do Rio Grande do Sul
Diogo Souza: Universidade Federal do Rio Grande do Sul
Pedro Rosa-Neto: Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-Montréal
Tharick A. Pascoal: University of Pittsburgh

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60806-1

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