DNA Methylation and Protein Markers of Chronic Inflammation and Their Associations With Brain and Cognitive Aging

Abstract

Objective:To investigate chronic inflammation in relation cognitive ageing by comparison of an epigenetic and serum biomarker of C-Reactive Protein and their associations with neuroimaging and cognitive outcomes.Methods:At baseline, participants (N = 521) were cognitively normal, around 73 years of age (M = 72.4, SD = 0.716), and had inflammation, vascular risk (cardiovascular disease history, hypertension, diabetes, smoking, alcohol consumption and BMI) and neuroimaging (structural and diffusion MRI) data available. Baseline inflammatory status was quantified by a traditional measure of peripheral inflammation – serum C-Reactive Protein (serum CRP) – and an epigenetic measure (DNA methylation signature of CRP; DNAm CRP). Linear models were used to examine the inflammation-brain health associations; mediation analyses were performed to interrogate the relationship between chronic inflammation, brain structure and cognitive functioning.Results:We demonstrate that DNAm CRP shows significantly (on average 6.4-fold) stronger associations with brain health outcomes than serum CRP. DNAm CRP is associated with total brain volume (β = -0.197, 95% CI [-0.28, -0.12], pFDR = 8.42 x 10-6), grey matter volume (β = -0.200, 95% CI [-0.28, -0.12], pFDR = 1.66 x 10-5) and white matter volume (β = -0.150, 95% CI [-0.23, -0.07], pFDR = 0.001) and regional brain atrophy. 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 29.7%), dependent on lifestyle and health factors.Conclusions:These results support the hypothesis that chronic inflammation may contribute to neurodegenerative brain changes which underlie differences in cognitive ability in later life and highlight the potential of DNA methylation proxies for indexing chronic inflammatory status.Classification of Evidence:This study provides Class II evidence that a DNA methylation signature of CRP levels is more strongly associated with brain health outcomes than serum CRP levels.

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

“…Many of the 191 proteins identified in the protein PheWAS were part of inflammatory clusters with shared functions in acute phase response, complement cascade activity, innate immune activity and cytokine pathways. Tissue expression analyses suggested that a large proportion of the 191 protein markers were not expressed in the brain; this supports work suggesting that sustained peripheral inflammation influences general brain health 31 , 32 and accelerates cognitive decline 17 , 33 – 35 . However, a subset of proteins were expressed in the central nervous system.…”

“…Additionally, DNAm accounts for inter-individual variability in circulating protein levels [14][15][16] . Recently, through integration of DNAm and protein data, we have shown that epigenetic scores for plasma protein levels-known as EpiScores-associate with brain morphology and cognitive ageing markers 17 and predict the onset of neurological diseases 18 . These studies highlight that while datasets that allow for integration of proteomic, epigenetic and phenotypic information are rarely-available, they hold potential to advance risk stratification.…”

Early-life inflammatory markers and subsequent episodes of depression and psychotic experiences in the ALSPAC birth cohort

“…CRP DNAm scores associated with more brain regions and with larger effect sizes than serum CRP, in the context of depression (36). Further, CRP DNAm scores were also better predictors of cognition than serum measures of CRP (35). Here, we found weak associations between CRP DNAm scores derived at birth and total number of PEs.…”

“…We therefore investigated novel epigenetic and genetic biomarkers of inflammation, which reflect a longer-term, more stable inflammatory exposure. Other studies, including our own investigating adult population cohorts, have highlighted the importance of researching DNAm markers of inflammation over serum-based markers (12, 35, 36). CRP DNAm scores associated with more brain regions and with larger effect sizes than serum CRP, in the context of depression (36).…”

Association between inflammation and cognition: triangulation of evidence using a population-based cohort and Mendelian randomization analyses

“…There is some evidence that systemic inflammatory markers such as C-reactive protein (CRP) are associated with poorer cognitive functioning in older adults and in people with physical or mental health conditions (Misiak et al, 2018; Morrens et al, 2022; Sartori et al, 2012). Observational studies in the general population have also reported associations between inflammatory markers, such as CRP, Interleukin-6 (IL-6) and Glycoprotein acetyls (GlycA), and poorer general and domain-specific cognition (Conole et al, 2021; Kokosi et al, 2021; Mac Giollabhui et al, 2021; Shields et al, 2021; van der Lee et al, 2018); although improved cognition has also been reported (Milton et al, 2021). Regarding the human experimental literature, the effect of acute inflammatory challenges (endotoxin and vaccines) on hot (e.g., emotion recognition) and cold (e.g., attention, memory) cognitive domains have yielded inconsistent findings (Balter et al, 2018; Bollen et al, 2017; Brydon et al, 2008; Handke et al, 2020; Harrison et al, 2014).…”