
==== Front
Res Sq
ResearchSquare
Research Square
2693-5015
American Journal Experts

39184102
10.21203/rs.3.rs-4782732/v1
10.21203/rs.3.rs-4782732
preprint
1
Article
Glial reactivity is linked to synaptic dysfunction across the aging and Alzheimer’s disease spectrum
Pascoal Tharick https://orcid.org/0000-0001-9057-8014

Rohden Francieli
Ferreira Pamela https://orcid.org/0000-0003-2134-9829

Bellaver Bruna https://orcid.org/0000-0002-2212-3373

Ferrari-Souza João Pedro
Aguzzoli Cristiano
Soares Carolina https://orcid.org/0000-0002-2338-4495

Abbas Sarah
Zalzale Hussein
Povala Guilherme https://orcid.org/0000-0002-2023-6569

Lussier Firoza
Leffa Douglas
Bauer-Negrini Guilherme
Rahmouni Nesrine
Tissot Cécile
Therriault Joseph Therriault
Servaes Stijn
Stevenson Jenna
Benedet Andrea
Ashton Nicholas
Karikari Thomas
Tudorascu Dana
Zetterberg Henrik https://orcid.org/0000-0003-3930-4354

Blennow Kaj https://orcid.org/0000-0002-1890-4193

Zimmer Eduardo
Souza Diogo
Rosa-Neto Pedro https://orcid.org/0000-0001-9116-1376

12 8 2024
rs.3.rs-4782732https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
https://www.researchsquare.com/article/rs-4782732/v1
nihpp-rs4782732v1.pdf
Abstract

Previous studies have shown that glial and neuronal changes may trigger synaptic dysfunction in Alzheimer’s disease(AD). However, the link between glial and neuronal markers and synaptic abnormalities in the living brain is poorly understood. Here, we investigated the association between biomarkers of astrocyte and microglial reactivity and synaptic dysfunction in 478 individuals across the aging and AD spectrum from two cohorts with available CSF measures of amyloid-β(Aβ), phosphorylated tau(pTau181), astrocyte reactivity(GFAP), microglial activation(sTREM2), and synaptic biomarkers(GAP43 and neurogranin). Elevated CSF GFAP levels were linked to presynaptic and postsynaptic dysfunction, regardless of cognitive status or Aβ presence. CSF sTREM2 levels were associated with presynaptic biomarkers in cognitively unimpaired and impaired Aβ + individuals and postsynaptic biomarkers in cognitively impaired Aβ + individuals. Notably, CSF pTau181 levels mediated all associations between GFAP or sTREM2 levels and synaptic dysfunction biomarkers. These results suggest that neuronal-related synaptic biomarkers could be used in clinical trials targeting glial reactivity in AD.
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