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Nature communications
Published

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

Authors

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, Tharick A Pascoal

Abstract

Nat Commun. 2025 Jul 1;16(1):5653. doi: 10.1038/s41467-025-60806-1.

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.

PMID:40593718 | DOI:10.1038/s41467-025-60806-1

UK DRI Authors

Profile picture of Henrik Zetterberg

Prof Henrik Zetterberg

Group Leader

Pioneering the development of fluid biomarkers for dementia

Prof Henrik Zetterberg