An integrated systems‐level analysis of the molecular changes resulting from systemic infections in Alzheimer’s disease

Abstract Background To fully understand the molecular consequences of neuroinflammation and systemic infection in Alzheimer’s disease (AD), it is important to scrutinise molecular changes occurring in the brain in individuals with AD after they have had a systemic infection. Recently, several epigenome‐wide association studies (EWAS) have identified robust and reproducible alterations in AD brain samples compared to controls. In the current study we have performed an EWAS comparing bulk brain tissue in individuals with AD and non‐demented controls with or without a systemic infection. Method DNA methylation arrays were employed for quantification of DNA methylation in extracted DNA from 276 prefrontal cortex brain tissue samples (controls, n = 72; AD‐diagnosed, n = 86; cognitively normal with infection, n = 48; AD‐diagnosed with infection, n = 70). Methylation values were quality checked and normalised before Analysis of Variance was performed to identify sites of significant differential methylation across all groups. Probes that were significant to AD‐only patients and infection‐only patients, when compared to controls, were removed, leaving only probes that were specifically differentially methylated in infection‐AD cases. Results Overall, more significant changes in methylation across the genome can be observed in AD patients who also suffered from systemic infection compared to AD‐only patients and infection‐only patients. By removing probes that are significantly associated with either systemic infections or AD, the remaining significant probes are therefore more likely to be associated with the consequences of infections, specifically within AD patients. Identified genes include AUTS2 , a gene implicated in developmental disorders, and ADAR , a protein‐coding gene involved in the control of the innate immune response and controlling the function of certain neurotransmitters. Conclusion The exact pathways affected by systemic infection are yet to be scrutinised, however this initial data provides evidence that unique changes to the methylome occur in AD‐diagnosed patients who additionally suffer from a systemic infection. The next steps of this project include isolating microglia to observe methylation changes specific to these cells, as well as incorporating more sample data sets to improve power.