Investigating the relationship between inflammation, DNA methylation and cognitive ability
Stevenson, Anna Jane
Maintenance of cognitive function in older age is becoming increasingly relevant due to the ageing population and the personal and socioeconomic consequences associated with cognitive decline and dementia. Identification of the determinants of cognitive impairment in older age is thus critical. The role of inflammation has become a key focus in the field of cognitive ageing. Whereas inflammatory dysregulation may be evident in age-related cognitive decline, the extent, directionality, and progression of the association is still not clear. Additional approaches are needed to delineate the relationship. Alongside inflammation, there is increasing interest in the role of the epigenetic mechanism of DNA methylation in cognitive ageing. The aim of this thesis is to investigate the associations between inflammatory markers (C-reactive protein [CRP] and interleukin-6 [IL-6]), DNA methylation, and cognitive ability. A variety of approaches are utilised to examine these interrelationships in two large cohort datasets ± the Lothian Birth Cohort 1936 (LBC1936; n=1,091) and Generation Scotland (GS; n=7,028). Following introductory chapters presenting overviews of cognitive ability, inflammation and DNA methylation, and summarising the two population cohorts, the empirical work of the thesis is presented in Chapters 5 to 9. Chapters 5 and 6 focus on investigating the association between DNA methylation-based biomarkers of ageing ('epigenetic clocks') ZiWh boWh inflammaWion and cognitive ability, respectively. In Chapter 5, the dynamics of CRP and IL-6 are investigated over the eighth decade, and two epigenetic clocks ± labelled Hannum and Horvath - are used to investigate the relationship between the two inflammatory markers and accelerated epigenetic ageing. The results indicate divergent longitudinal trajectories of the inflammatory markers, but a consistent positive association between both CRP and IL-6 with the Hannum measure of age acceleration (EEAA). In Chapter 6, a phenome-wide association study of a novel epigenetic clock incorporating inflammatory and immune markers ± DNA methylation PhenoAge ± is conducted, primarily in relation to cognitive outcomes, but also to a range of other health phenotypes. Here, the epigenetic biomarker displayed cross-sectional associations with various cognitive outcomes at the age of ~70 years in LBC1936. However, adjusting for early life cognitive ability attenuated the associations, indicative of a reverse causation whereby those with higher childhood intelligence were more likely to have higher intelligence and lower epigenetic age acceleration in later life. Chapters 7 and 8 focus on DNA methylation predictors of CRP and IL-6 and establishing their associations with cognitive ability. The results from Chapter 7 suggest that a DNA methylation proxy for CRP may provide a more stable index of chronic inflammation compared to serum levels of the inflammatory protein. Additionally, the effect sizes of the association between the methylation proxy and cognitive ability were slightly larger than that of the serum measure, indicating it may better capture the relationship between inflammation and cognitive performance. Chapter 8 revealed similar results, with a DNA methylation proxy for IL-6 showing associations with previously established correlates of IL-6, and with general cognitive ability in the Generation Scotland cohort. These results highlight the utility of DNA methylation proxies of inflammatory mediators to gain additional insight into the relationship between inflammation and cognitive function. The final empirical chapter - Chapter 9 - coalesces the work of the thesis by assessing the aforementioned epigenetic clock and inflammation-related DNA methylation signatures that were previously investigated in blood, in post-mortem brain tissue in 14 of the LBC1936 participants. This chapter additionally examines how the DNA methylation patterns relate to burdens of the primary tissue-resident immune cell of the central nervous system - microglia. The results of this chapter provide preliminary evidence that the hippocampus may be particularly susceptible to epigenetic ageing and indicate a tentative link between a higher DNA methylation PhenoAge in the brain and increased microglial burdens. However, given the small sample size of this work, these initial patterns need further confirmation. Overall, the work presented in this thesis establishes evidence for a relationship between inflammation, DNA methylation and cognitive ability. Increased inflammation and lower cognitive ability was found to associate with accelerated biological ageing. Furthermore, novel inflammation-associated methylation patterns were developed and related to cognitive performance in order to improve our understanding of the interplay between inflammation and age-related health outcomes.