DNA Methylation at CRP-Associated CpG Sites May Mediate the Pathway between Educational Attainment and Cognition.

Growing evidence has linked inflammatory processes to cognitive decline and dementia. This work examines whether an epigenetic marker of C-reactive protein (CRP), a common clinical inflammatory biomarker, may mediate the relationship between educational attainment and cognition. We first evaluated whether 53 previously-reported CRP-associated DNA methylation sites (CpGs) are associated with CRP, both individually and aggregated into a methylation risk score (MRSCRP), in 3298 participants from the Health and Retirement Study (HRS, mean age=69.7 years). Forty-nine CpGs (92%) were associated with the natural logarithm of CRP in HRS after adjusting for age, sex, smoking, BMI, genetic ancestry, and white blood cell counts (p<0.05), and each standard deviation increase in MRSCRP was associated a 0.38 unit increase in lnCRP (p=4.02E-99). In cross-sectional analysis, for each standard deviation increase in MRSCRP, total memory score and total cognitive score decreased, on average, by 0.28 words and 0.43 items, respectively (p<0.001). Further, MRSCRP mediated 6.9% of the relationship between high school education and total memory score in a model adjusting for age, sex, and genetic ancestry (p<0.05); this was attenuated to 2.4% with additional adjustment for marital status, APOE ε4 status, health behaviors, and comorbidities (p<0.05). Thus, CRP-associated methylation may partially mediate the relationship between education and cognition at older ages. Further research is warranted to determine whether DNA methylation at these sites may improve current prediction models for cognitive impairment in older adults.