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Lookup NU author(s): Debbie LettORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2026 The Authors.Alzheimer’s disease (AD) is characterized by neuroinflammation, yet the impact of concurrent systemic infections on the AD brain remains poorly understood. We investigated the molecular mechanisms underlying the central nervous system response to systemic infections in AD by analyzing RNA sequencing data generated in the prefrontal cortex from 202 post-mortem donors (113 AD, 89 controls), where we stratified by the presence of a respiratory infection at the time of death. We identified 763 significant differentially expressed genes (DEGs) between AD and controls without infection, which were enriched for oxidative phosphorylation and neurodegenerative pathways. In contrast, 122 DEGs distinguished AD from controls during infection, with 57 genes uniquely altered in AD in the presence of infection, including MAPK4 , VAV3 , and POU3F4 , implicating infection-dependent mechanisms of vascular and immune regulation. Pathway activity analysis revealed that infection in AD suppresses some immune and vascular pathways, while enhancing transcriptional and developmental programs. Weighted gene co-expression network analysis uncovered three key modules: one module strongly associated with AD, enriched for aging and signal transduction; one module linked to both AD and infection, highlighting cytoskeletal remodeling and host–pathogen interactions; and one module specific to infection, enriched in astrocytes, pericytes, and endothelial cells, implicating blood–brain barrier dysfunction. These findings suggest that systemic respiratory infections reshape transcriptional programs in the AD brain, dampening immune effector pathways and engaging vascular and host–pathogen processes in blood–brain-barrier–associated cell types. Our results highlight the complex interplay between systemic infection, neuroinflammation, and vascular responses in AD.
Author(s): Pegoraro G, MacBean LF, Smith AR, Soanes DM, Smith RG, Imm J, Harvey J, Kouhsar M, Laroche V, Weymouth L, Castanho I, Hide W, Palmer L, Lett DJ, Robinson AC, Woodman N, McDade K, Boche D, Pishva E, Lunnon K
Publication type: Article
Publication status: Published
Journal: Neurobiology of Aging
Year: 2026
Volume: 167
Pages: 155-167
Print publication date: 08/07/2026
Online publication date: 26/06/2026
Acceptance date: 24/06/2026
Date deposited: 04/08/2026
ISSN (print): 0197-4580
ISSN (electronic): 1558-1497
Publisher: Elsevier Inc.
URL: https://doi.org/10.1016/j.neurobiolaging.2026.06.010
DOI: 10.1016/j.neurobiolaging.2026.06.010
PubMed id: 42419155
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