Abstract
BackgroundChronic systemic inflammation has been associated with incident dementia, but its association with age-related cognitive decline is less clear. The acute responses of many inflammatory biomarkers mean they may provide an unreliable picture of the chronicity of inflammation. Recently, a large-scale epigenome-wide association study identified DNA methylation correlates of C-reactive protein (CRP)—a widely used acute-phase inflammatory biomarker. DNA methylation is thought to be relatively stable in the short term, marking it as a potentially useful signature of exposure.MethodsWe utilise a DNA methylation-based score for CRP and investigate its trajectories with age, and associations with cognitive ability in comparison with serum CRP and a genetic CRP score in a longitudinal study of older adults (n = 889) and a large, cross-sectional cohort (n = 7028).ResultsWe identified no homogeneous trajectories of serum CRP with age across the cohorts, whereas the epigenetic CRP score was consistently found to increase with age (standardised β = 0.07 and 0.01) and to do so more rapidly in males compared to females. Additionally, the epigenetic CRP score had higher test-retest reliability compared to serum CRP, indicating its enhanced temporal stability. Higher serum CRP was not found to be associated with poorer cognitive ability (standardised β = − 0.08 and − 0.05); however, a consistent negative association was identified between cognitive ability and the epigenetic CRP score in both cohorts (standardised β = − 0.15 and − 0.08).ConclusionsAn epigenetic proxy of CRP may provide a more reliable signature of chronic inflammation, allowing for more accurate stratification of individuals, and thus clearer inference of associations with incident health outcomes.
Highlights
Chronic systemic inflammation has been associated with incident dementia, but its association with age-related cognitive decline is less clear
Correlation between serum C-reactive protein (CRP), DNA methylation (DNAm) CRP score, and genetic score In both cohorts, the Pearson correlations between the DNAm CRP score and serum log(CRP) were moderate (LBC1936: r = 0.34, 95% CI [0.28, 0.4]; Generation Scotland (GS): r = 0.28 [0.19, 0.36]), with the DNAm CRP score showing a stronger correlation with serum CRP than any one of its composite CpGs in both cohorts
The correlation between the DNAm CRP score and the genetic score was low in Lothian Birth Cohort 1936 (LBC1936) (r = 0.07 [0.06, 0.14]) and not significantly different to zero in GS (r = − 0.01 [− 0.03, 0.016])
Summary
Chronic systemic inflammation has been associated with incident dementia, but its association with age-related cognitive decline is less clear. A large-scale epigenome-wide association study identified DNA methylation correlates of C-reactive protein (CRP)—a widely used acute-phase inflammatory biomarker. Epidemiological studies have associated ageing with a progressive shift to a chronic inflammatory state This low-grade, typically sub-acute, elevation of peripheral pro-inflammatory mediators in the absence of overt infection is strongly associated with the susceptibility to, and progression of, many age-associated diseases and is a key risk factor for mortality [4,5,6]. Accumulating evidence has implicated chronic inflammation with incident dementia, but the association with pre-morbid cognitive function is less firmly defined and has generated considerable debate [7]. Evidence from large, prospective cohort and cross-sectional studies has been largely mixed, with positive, negative, and null associations identified between serum inflammatory biomarker levels and cognitive ability [8,9,10,11,12]
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