Porter Tenielle, Armstrong Ayeisha Milligan, Milicic Lidija, Vacher Michael, Fernandez Shane, O'Brien Eleanor, Doré Vincent, Bourgeat Pierrick, Shishegar Rosita, Xia Ying, Rowe Christopher, Villemagne Victor, Maruff Paul, Masters Colin, Verdile Giuseppe, Laws Simon, Groth David
Res Sq. 2025 Sep 10:rs.3.rs-7540786. doi: 10.21203/rs.3.rs-7540786/v1.
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 ( and , 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 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 was associated with faster cognitive decline, whilst lower methylation at , and 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.
慢性应激已被认为是阿尔茨海默病（AD）的一个风险因素，尽管将应激与AD联系起来的分子途径仍知之甚少。在本研究中，我们在两个独立队列的认知未受损但脑内β淀粉样蛋白（Aβ）不断累积的个体中，研究了皮质醇受体基因、糖皮质激素受体和盐皮质激素受体（分别为 和 ）的差异甲基化与脑健康表型（认知、脑Aβ负荷和脑区体积）之间的关系。此外，还评估了甲基化与抑郁/焦虑症状之间的相互作用。在两个队列中均观察到甲基化与脑健康表型之间的名义关联，包括认知、脑Aβ负荷和脑区体积。对 之间相互作用的进一步分析发现，甲基化与脑健康结果之间的关系因抑郁/焦虑症状的存在而有显著差异。在观察到的关联中， 处较低的甲基化与更快的认知衰退相关，而 、 处较低的甲基化与更快的脑萎缩相关，特别是在有抑郁症状的个体中。这些结果表明，在这四个CpG位点上，较低的甲基化与有抑郁症状个体的较差结果相关。这项研究确定了皮质醇受体基因甲基化与AD表型之间的关系，其中许多关系受抑郁症状的调节。这些发现凸显了进一步研究甲基化作为AD中与应激相关风险的生物标志物的必要性。
