Glia inflammation and cell death pathways drive disease progression in preclinical and early AD

Accumulation of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) are followed by the activation of glia cells and infiltration of peripheral immune cells that collectively accelerate neurodegeneration in preclinical AD models. Yet, the role of neuroinflammation for neuronal injury and disease progression in preclinical and early symptomatic AD remains elusive. Here, we combined multiplexed immunoassays and SomaScan proteomics of the cerebrospinal fluid (CSF) with MRI and PET brain imaging of people across the AD continuum to identify pathways that are associated with AD progression. Unbiased clustering revealed that glia-mediated inflammation, activation of cell death pathways (CDPs) and synaptic pathologies were among the earliest Aβ-induced changes, and were associated with disease progression in preclinical AD. Mediation analysis revealed that activation of CDPs were decisive drivers of inflammation in early symptomatic AD. The cycle of glia-mediated neuroinflammation and neuronal injury characterizes preclinical AD and has implications for novel treatment approaches.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2025-10-10
DOI
https://doi.org/10.1038/s44321-025-00316-1
Citations
1
Primary Topic
Neuroinflammation and Neurodegeneration Mechanisms
Type
article
Field-Weighted Citation Impact
0.84
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article

Glia inflammation and cell death pathways drive disease progression in preclinical and early AD

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EMBO Molecular Medicine
Neuroinflammation and Neurodegeneration Mechanisms
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article

Glia inflammation and cell death pathways drive disease progression in preclinical and early AD

Serge Gauthier, Tharick Ali Pascoal, Guglielmo Di Molfetta, Joseph Therriault, Nicholas James Ashton, Kaj Blennow, Marcel S. Woo, Gassan Massarweh, Jaime Fernandez‐Arias, Nesrine Rahmouni, Andréa Lessa Benedet, Kely Quispialaya-Socualaya, Arthur C. Macedo, Stijn Servaes, Tevy Chan, Brandon J. Hall, Stuart Mitchell, Seyyed Ali Hosseini, Firoza Zubeida Lussier, Cécile Tissot, Robert Hopewell, Henrik Zetterberg, Yansheng Zheng, Étienne Aumont, Jean‐Paul Soucy, Gleb Bezgin, Pedro Rosa‐Neto, Yi-Ting Wang, Marina Gonçalves, Paolo Vitali, Jenna Stevenson, Kübra Tan, Lydia Trudel, Ilaria Pola
article en
1 citations

Abstract

Accumulation of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) are followed by the activation of glia cells and infiltration of peripheral immune cells that collectively accelerate neurodegeneration in preclinical AD models. Yet, the role of neuroinflammation for neuronal injury and disease progression in preclinical and early symptomatic AD remains elusive. Here, we combined multiplexed immunoassays and SomaScan proteomics of the cerebrospinal fluid (CSF) with MRI and PET brain imaging of people across the AD continuum to identify pathways that are associated with AD progression. Unbiased clustering revealed that glia-mediated inflammation, activation of cell death pathways (CDPs) and synaptic pathologies were among the earliest Aβ-induced changes, and were associated with disease progression in preclinical AD. Mediation analysis revealed that activation of CDPs were decisive drivers of inflammation in early symptomatic AD. The cycle of glia-mediated neuroinflammation and neuronal injury characterizes preclinical AD and has implications for novel treatment approaches.

EMBO Molecular MedicineVol. 17(11)
Montreal Neurological Institute and Hospital (CA), University of Wisconsin–Madison (US), University of Arizona (US), Lawrence Berkeley National Laboratory (US), Universität Hamburg (DE), University of Pittsburgh (US), King's College London (GB), Sahlgrenska University Hospital (SE), McGill University Health Centre (CA), Southwestern Medical Center (US), University Medical Center Hamburg-Eppendorf (DE), UK Dementia Research Institute (GB), Institute of Neuroimmunology of the Slovak Academy of Sciences (SK), Banner Sun Health Research Institute (US), National Hospital for Neurology and Neurosurgery (GB), University College London (GB), McGill University (CA), The University of Texas Southwestern Medical Center (US), University of Gothenburg (SE)
Openalex Percentile: Top 21%
Neuroinflammation and Neurodegeneration Mechanisms
0.84
DOIOpen Access PDFOpenAlex
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