| dc.description.abstract | Alzheimer’s disease, the most common type of dementia, is marked by memory loss, mood shifts, and personality changes, linked to the build-up of amyloid-beta and tau proteins in the brain, as well as neuroinflammation. Alzheimer’s disease cases are categorised into two forms, familial and sporadic. While autosomal dominant mutations account for 1-10% of all Alzheimer’s disease cases, most cases result from the combination between multiple genetic and environmental factors. One significant environmental risk factor is common infections, which not only increase susceptibility to Alzheimer’s disease but also exacerbate brain inflammation. Given the disease's severe symptoms and rising prevalence in an aging population, effective treatments are well sought after. The first active immune therapy for Alzheimer’s, AN1792, was designed to target amyloid-beta proteins and stimulate an adaptive immune response.
DNA methylation is an epigenetic mechanism that changes gene expression in response to environmental stimuli and disease. Many studies have aimed to characterise the DNA methylation changes underlying Alzheimer’s disease; however, few have considered the impact of peripheral infections alongside Alzheimer’s disease-induced neuroinflammation.
This thesis aimed to expand the Alzheimer’s disease research field by investigating the contributions of DNA methylation on both systemic infection and amyloid-beta immunisation in Alzheimer’s disease brain tissue. A large-scale epigenome-wide association study was performed on DNA methylation values across the genome quantified using array-based technology. A model was generated to identify if an interaction between Alzheimer’s disease diagnosis and infection status affected methylation. We identified a number of sites with altered methylation in the brain linked to infection, including a region of differential methylation within the CBS gene. To tackle the issue of cellular heterogeneity in bulk brain tissue, a nuclei sorting technique was applied to the same bulk tissue to analyse cell type-specific methylation. Utilising a similar model to the bulk tissue, we revealed noticeable differences in methylation within neurons at a site located within the SPAG16, and differences within microglia at a site located within the PINX1 gene. These sites were identified from the investigation of bulk tissue and observed to be differentially methylated. Finally, an epigenome-wide association study in limited samples obtained from subjects of the AN1792 clinical trial compared DNA methylation with AD controls. A single genome-wide significant site of differential methylation was identified within the CUGBP2 gene, and nine regions of differential methylation were further nominated.
In summary, this thesis offers a comprehensive assessments of DNA methylation in the brain related to Alzheimer’s disease, stressing the importance of considering infection in future studies. It also identifies of epigenetic associations to amyloid-beta immunisation highlighting potential new therapeutic targets and biomarkers for future study. | en_GB |
