Characterisation of an inflammation-related epigenetic score and its association with cognitive ability

Abstract

Results from large cohort studies investigating the association between inflammation and cognition have been mixed, possibly due to methodological disparities. However, a key issue in research utilising inflammatory biomarkers is their typically phasic responses. C-reactive protein (CRP) is widely used to investigate the association between chronic inflammation and cognition, but its plasma concentrations can markedly deviate in response to acute infection. Recently a large-scale epigenome-wide association study identified DNA methylation correlates of CRP. DNA methylation is thought to be relatively stable in the short term, marking it as a potentially useful signature of exposure. Here, we generate an epigenetic CRP score and investigate its trajectories with age, and associations with cognitive ability, in comparison to serum CRP in two cohorts: a longitudinal study of older adults (the Lothian Birth Cohort 1936, n=889) and a large, cross-sectional cohort (Generation Scotland, n=7,028).We identified differing trajectories of serum CRP across the cohorts, with no homogeneous trends seen with age. Conversely, the epigenetic score was consistently found to increase with age, and to do so more rapidly in males compared to females. Higher levels of serum CRP were found to associate with poorer cognition in Lothian Birth Cohort 1936, but not in Generation Scotland. However, a consistent negative association was identified between cognition and the epigenetic score in both cohorts. Furthermore, the epigenetic score accounted for a greater proportion of variance in cognitive ability.Our results suggest that epigenetic signatures of acute inflammatory markers may provide an enhanced signature of chronic inflammation, allowing for more reliable stratification of individuals, and thus clearer inference of associations with incident health outcomes.

An epigenetic proxy of chronic inflammation outperforms serum levels as a biomarker of brain ageing

“…In addition, while DNAm levels are dynamic, their short term variability is relatively stable 39 , and they may reflect longer-term immune function 40 . In the same cohort as in the present study, a DNAm proxy of CRP exhibited greater longitudinal stability and stronger associations with a single global measure of cognitive functioning than blood based CRP levels 21,41 . Given this temporal stability, a DNAm signature of inflammation could represent a cumulative, aggregate measure of chronic inflammation analogous to the HbA1c test used to index average blood sugar levels for diabetics 21 .…”

“…As higher DNAm CRP levels were associated with lower cognitive performance both here (Supplementary Table 2) and previously 21 , we quantified the degree to which brain structural differences contribute to the inflammation-cognition association, and which facets show the strongest unique contributions to this relationship. We used a structural equation modelling (SEM) framework to simultaneously characterise the associations among CRP, brain and cognitive metrics, and also specifically test the hypothesis that brain structure partially and significantly mediates associations between measures of CRP and cognitive ability.…”

“…Studies using serum inflammatory measures in non-clinical groups show mixed positive, negative and null associations with respect to cognitive outcomes 2,[15][16][17][18][19][20][21] , and have not yet clarified the magnitude and regional extent of brain structural associations [3][4][5][6]22,23 . Limitations of previous studies include disparity in methodology (different imaging metrics and cognitive measures), small sample sizes (typically, n <100, although a recent study looked at chronic inflammation in association with cognitive and neuroimaging measures in over 2,000 participants 23 ) and a lack of screening for acutely elevated inflammation levels suggestive of infection 24 .…”

“…( a ) Schematic demonstrating how chronic inflammation increases with age (left panel) and can be indexed by inflammatory proteins taken from a blood sample (right panel), such as serum levels and DNA methylation (DNAm) proxies of C-Reactive Protein. Graphs below reflect trajectories of respective inflammation scores over age, as outlined in 21 . ( b ) Life-span curves for cognitive ability, demonstrating that there is considerable inter-individual heterogeneity in rate and timing of cognitive decline, with some people on more accelerated cognitive ageing trajectories than others 9 .…”

“…Recent advances in the use of epigenetics to investigate long-term health outcomes 21,28,29 may present a solution to the challenge of reliably recording average inflammation levels. DNA methylation (DNAm) is an epigenetic mechanism where the addition of a methyl group to a cytosine-phosphate-guanine (CpG) nucleotide base pairing regulates gene activity 30 .…”