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

Abstract

Low-level chronic inflammation increases with age and is associated with cognitive decline. DNA methylation (DNAm) levels may provide more stable reflections of cumulative inflammatory burden than traditional serum approaches. Using structural and diffusion MRI data from 521 individuals aged 73, we demonstrate that a DNAm proxy of C-Reactive Protein (CRP) shows significantly (on average 6.4-fold) stronger associations with brain structural outcomes than serum CRP. We additionally find that DNAm CRP has an inverse association with global and domain-specific (speed, visuospatial and memory) cognitive functioning, and that brain structure partially mediates this CRP-cognitive association (up to 29.4%), dependent on lifestyle and health factors. These data support the hypothesis that chronic systemic inflammation may contribute to neurodegenerative brain changes which underlie differences in cognitive ability in later life. DNA methylation-based predictors could be used as proxies for chronic inflammatory status.

Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health

“…2; Supplementary Note 1) suggests that the epigenome may reflect an inflammatory component of brain health. Our results support previous work suggesting that sustained peripheral inflammation is related to mood disorders 44,45 , influences general brain health 4647 and accelerates cognitive decline 8,20,34,48 .…”

“…The copyright holder for this preprint this version posted September 6, 2021. ; https://doi.org/10.1101/2021.09.03.21263066 doi: medRxiv preprint of neurological outcomes 20,21 and brain health is also thought to be influenced by peripheral factors 12,22 . Brain morphology alterations and disease pathogenesis can occur many years prior to overt neurological, cognitive and behavioural symptom presentation.…”

“…However, proteome-wide assessment of pQTMs has not been tested against a comprehensive spectrum of neurological phenotypes. Bloodbased methylation is unlikely to correlate highly with brain methylation in all cases 19 ; however, proteomic and epigenetic signatures from the blood have been shown to be informative as predictors of neurological outcomes 20,21 and brain health is also thought to be influenced by peripheral factors 12,22 . Brain morphology alterations and disease pathogenesis can occur many years prior to overt neurological, cognitive and behavioural symptom presentation.…”

Epigenetic scores for the circulating proteome as tools for disease prediction

“…A range of C5-targetting therapeutic approaches are currently in development [44][45][46][47][48][49] . EpiScores for acute inflammatory markers have been shown to offer stable longitudinal measurements of the inflammatory state of an individual, which is likely due to DNA methylation reflecting a more consistent profile of stress in the body than protein measurements 23,25 .…”

“…However, focusing on measurements of individual proteins, instead of composite measures may offer greater insights into specific DNAm-protein pathways pertinent in the earliest stages of disease pathogenesis. DNAm scores for Interleukin-6 and C-Reactive protein associate with a range of phenotypes independently of measured protein levels, show more stable longitudinal trajectories than repeated protein measurements, and, in some cases, outperform blood-based proteomic associations with brain morphology 23,25 .…”