Exploring the relationship between methylation of the cortisol receptor genes and brain and cognitive outcomes in individuals with elevated amyloid-β

Chronic stress has been implicated as a risk factor for Alzheimer’s disease (AD), although the molecular pathways linking stress with AD are poorly understood. In this study, relationships between differential methylation of the cortisol receptor genes, the glucocorticoid and mineralocorticoid receptors ( NR3C1 and NR3C2 , respectively) and brain-health phenotypes (cognition, brain amyloid-b (Aβ) burden and regional brain volumes) were examined in two independent cohorts of cognitively unimpaired individuals with accumulating brain Aβ. In addition, interactions between methylation and depression/anxiety symptoms were assessed. Nominal associations between methylation and brain-health phenotypes, including cognition, brain Aβ burden, and regional brain volumes, were observed across both cohorts. Further analyses of interactions between CpG x depression/anxiety symptoms identified that the relationships between methylation and brain-health outcomes differed significantly depending on the presence of depression/anxiety symptoms. Among the observed associations, lower methylation at cg24052866 (NR3C1) was associated with faster cognitive decline, whilst lower methylation at cg07275757 (NR3C2), cg10993059 (NR3C2) , and cg25708981 (NR3C1) was associated with faster brain atrophy, specifically in those individuals with depressive symptoms. These results suggest that across the four CpG sites lower methylation is associated with worse outcomes in those with depression symptoms. This work has identified relationships between methylation of cortisol receptor genes and AD phenotypes, many of these moderated by depression symptoms. These findings, highlight the need for further investigation into methylation as biomarkers for stress-related risk in AD.