A transcriptome‐wide analysis of Alzheimer’s disease brain during systemic inflammation
Giulia Pegoraro, Rebecca G. Smith, Lachlan Ford MacBean, Adam R. Smith, Delphine Boche, Ehsan Pishva, Katie Lunnon- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
The onset and progression of Alzheimer’s disease (AD) has been widely linked with inflammation both in the periphery and within the brain. Indeed, many AD sufferers ultimately die with a systemic infection, and infections during life can increase the risk of developing dementia and the rate of cognitive decline in AD patients. One of the aims of this study is to investigate the molecular mechanisms involved in the CNS response to systemic infections in AD through the analysis of gene expression changes.
Method
The cohort of patients selected for the study is composed of 238 post‐mortem prefrontal cortex brain samples. The cohort is divided as follows: 68 samples affected by AD and 55 controls, all of whom died with an infection, and 62 AD patients and 53 controls who did not have an infection at the time of the death. The infections included in the analysis consists of respiratory infections (i.e. pneumonia), urinary and chest infections. Following RNA sequencing, a weighted gene correlation network analysis (WGCNA) and pathway enrichment analysis were performed.
Result
The results from WGCNA show a module of particular interest with a correlation with both AD and respiratory infections, which represent most of the cases of infection. The pathway enrichment analysis performed on the genes composing this module identified several relevant biological pathways. Among the ten most significant pathways, part of them is involved in immune responses, such as “leukocyte activation involved in immune response” and “cell activation involved in immune response”.
Conclusion
This analysis laid the foundations for further investigations into gene expression changes associated with AD and infection. Future work will include repeating the analysis focusing on respiratory infections only, to examine if this source of heterogeneity is limiting our findings. Ultimately this data will be combined with miRNA sequencing and DNA methylation data from the same individuals, the work for which is ongoing.