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Background  Chronic 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.    Methods  We 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).    Results  We 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).    Conclusions  An 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.

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