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Few studies have assessed the association of educational attainment on dementia and cognitive impairment through DNA methylation age acceleration, while accommodating exposure-mediator interaction effects. We evaluated the mediation role of six epigenetic clocks with dementia, cognitive impairment non-dementia, and normal cognition, while accommodating exposure-mediator interaction effects. To understand the joint association of low education (≤12 years) and DNA methylation age acceleration (yes/no) in relation to cognitive impairment, we used weighted logistic regression, adjusting for chronological age, sex, race/ethnicity, and cell type composition. We performed four-way mediation and interaction decomposition analysis. Analyses were conducted on 2016 venous blood study participants from the Health and Retirement Study (N= 3724). Both GrimAge acceleration (OR = 1.6 95%CI 1.3–2.1) and low educational attainment (OR = 2.4 95%CI 1.9–3.0) were associated with higher odds of cognitive impairment in a mutually adjusted logistic model. We found additive interaction associations between low education and GrimAge acceleration on dementia. We observed that 6–8% of the association of education on dementia was mediated through GrimAge acceleration. While mediation effects were small, the portion of the association of education on dementia due to additive interaction with GrimAge acceleration was between 23.6 and 29.2%. These results support the interplay of social disadvantage and biological aging processes on impaired cognition.

ABSTRACTThe prevalence and severity of many diseases differs by sex, potentially due to sex-specific patterns in DNA methylation. Autosomal sex-specific differences in DNA methylation have been observed in cord blood and placental tissue but are not well studied in saliva or in diverse populations. We sought to characterize sex-specific DNA methylation on autosomal chromosomes in saliva samples from children in the Future of Families and Child Wellbeing Study, a multi-ethnic prospective birth cohort containing an oversampling of Black, Hispanic and low-income families. DNA methylation from saliva samples was analysed on 796 children (50.6% male) at both ages 9 and 15 with DNA methylation measured using the Illumina HumanMethylation 450k array. An epigenome-wide association analysis of the age 9 samples identified 8,430 sex-differentiated autosomal DNA methylation sites (P < 2.4 × 10−7), of which 76.2% had higher DNA methylation in female children. The strongest sex-difference was in the cg26921482 probe, in the AMDHD2gene, with 30.6% higher DNA methylation in female compared to male children (P < 1 × 10−300). Treating the age 15 samples as an internal replication set, we observed highly consistent results between the ages 9 and 15 measurements, indicating stable and replicable sex-differentiation. Further, we directly compared our results to previously published DNA methylation sex differences in both cord blood and saliva and again found strong consistency. Our findings support widespread and robust sex-differential DNA methylation across age, human tissues, and populations. These findings help inform our understanding of potential biological processes contributing to sex differences in human physiology and disease.