- October 10, 2025
- Pedro-Rosa Neto, et al., McGill University
Topic/Product:
CNS Disease Panel 120, Neurology
Disease Area:
Alzheimer's Disease
Sample Type:
CSF
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.
Authors & Affiliations
Marcel S. Woo¹⁵⁶, Joseph Therriault¹²⁴, Seyyed Ali Hosseini¹²⁴, Yi-Ting Wang¹²⁴, Arthur C. Macedo¹²⁴, Nesrine Rahmouni¹²⁴, Étienne Aumont¹²⁴, Stijn Servaes¹²⁴, Cécile Tissot¹⁷, Jaime Fernandez-Arias¹²⁴, Lydia Trudel¹²⁴, Brandon Hall¹²⁴, Gleb Bezgin¹²⁴, Kely Quispialaya-Socualaya¹²⁴, Marina Goncalves¹²⁴, Tevy Chan¹²⁴, Jenna Stevenson¹²⁴, Yansheng Zheng¹²⁴, Stuart Mitchell¹²⁴, Robert Hopewell¹²⁴, Paolo Vitali¹²⁴, Serge Gauthier¹²⁴, Gassan Massarweh⁴, Jean-Paul Soucy⁴, Ilaria Pola³, Kubra Tan³, Guglielmo Di Molfetta³, Nicholas J. Ashton³⁸⁹¹⁰, Kaj Blennow³¹¹, Henrik Zetterberg³¹¹¹²¹³¹⁴, Firoza Z. Lussier¹⁵¹⁶, Tharick A. Pascoal¹⁵¹⁶, Andréa L. Benedet³, and Pedro Rosa-Neto¹²⁴¹⁷.
¹ Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, McConnell Brain Imaging Centre, Montreal Neurological Institute, Montréal, QC, Canada
² Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada
³ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
⁴ Montreal Neurological Institute, Montréal, QC, Canada
⁵ Translational Neurodegeneration Laboratory, Department of Neurology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
⁶ Institute of Neuroimmunology and Multiple Sclerosis, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
⁷ Lawrence Berkeley National Laboratory, Berkeley, CA, USA
⁸ Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
⁹ Banner Alzheimer’s Institute and University of Arizona, Phoenix, AZ, USA
¹⁰ Banner Sun Health Research Institute, Sun City, AZ, USA
¹¹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
¹² Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK
¹³ UK Dementia Research Institute at UCL, London, UK
¹⁴ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China
¹⁵ Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
¹⁶ Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
¹⁷ Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA