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Alzheimer’s Disease (ad) / Alzheimer Disease / Rna Sequencing · Journal article
Neurobiology of Aging · June 26, 2026
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This post-mortem transcriptomic study found that concurrent respiratory infection at death alters cortical gene expression patterns in AD, with infection-specific alterations in vascular, immune, and host-pathogen pathways. The work identifies molecular associations but provides no evidence of functional consequences, clinical relevance, or causal mechanisms, and is limited by the cross-sectional design and surrogate endpoint.
Cross-sectional post-mortem transcriptomic observational study. Post-mortem brain donors: 113 with Alzheimer's disease and 89 cognitively normal controls; tissue collected from prefrontal cortex. Donors were stratified by presence of respiratory infection at time of death.. Compared with: Comparison of AD versus controls, cross-stratified by respiratory infection status at death.. n = 202.
763 differentially expressed genes (DEGs) identified between AD and controls without infection, enriched for oxidative phosphorylation and neurodegenerative pathways 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 Three co-expression modules identified: one strongly associated with AD enriched for aging and signal transduction; one linked to both AD and infection highlighting cytoskeletal remodeling; one specific to infection enriched in astrocytes, pericytes, and endothelial cells
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These findings raise mechanistic hypotheses about how systemic infection modulates brain transcriptional programs in AD, but the post-mortem cross-sectional design, lack of clinical endpoints, and absence of functional validation limit direct clinical applicability. Further work is needed to establish whether these transcriptional changes contribute to symptom progression or cognitive decline in living patients.
Post-mortem observational study with transcriptomic analysis identifies associations between infection status and gene expression patterns in AD brain tissue, but lacks experimental validation, longitudinal data, or causal evidence to support clinical intervention.
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These findings raise mechanistic hypotheses about how systemic infection modulates brain transcriptional programs in AD, but the post-mortem cross-sectional design, lack of clinical endpoints, and absence of functional validation limit direct clinical applicability. Further work is needed to establish whether these transcriptional changes contribute to symptom progression or cognitive decline in living patients.
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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.
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