Chronic psychosocial stress is increasingly being recognised as a risk factor for sporadic Alzheimer's disease (AD). The hypothalamic–pituitary–adrenal axis (HPA axis) is the major stress response pathway in the body and tightly regulates the production of cortisol, a glucocorticoid hormone. Dysregulation of the HPA axis and increased levels of cortisol are commonly found in AD patients and make a major contribution to the disease process. The underlying mechanisms remain poorly understood. In addition, within the general population there are interindividual differences in sensitivities to glucocorticoid and stress responses, which are thought to be due to a combination of genetic and environmental factors. These differences could ultimately impact an individuals’ risk of AD. The purpose of this review is first to summarise the literature describing environmental and genetic factors that can impact an individual's HPA axis reactivity and function and ultimately AD risk. Secondly, we propose a mechanism by which genetic factors that influence HPA axis reactivity may also impact inflammation, a key driver of neurodegeneration. We hypothesize that these factors can mediate glucocorticoid priming of the immune cells of the brain, microglia, to become pro-inflammatory and promote a neurotoxic environment resulting in neurodegeneration. Understanding the underlying molecular mechanisms and identifying these genetic factors has implications for evaluating stress-related risk/progression to neurodegeneration, informing the success of interventions based on stress management and potential risks associated with the common use of glucocorticoids.

中文翻译：

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慢性压力和阿尔茨海默病：下丘脑-垂体-肾上腺轴、遗传和小胶质细胞之间的相互作用

慢性社会心理压力越来越被认为是散发性阿尔茨海默病 (AD) 的危险因素。下丘脑-垂体-肾上腺轴（HPA 轴）是体内主要的应激反应通​​路，并严格调节皮质醇（一种糖皮质激素）的产生。HPA 轴失调和皮质醇水平升高在 AD 患者中很常见，并且对疾病过程做出了重大贡献。其潜在机制仍然知之甚少。此外，在一般人群中，个体对糖皮质激素和应激反应的敏感性存在差异，这被认为是由于遗传和环境因素的共同作用所致。这些差异最终会影响个人患 AD 的风险。本综述的目的是首先总结描述环境和遗传因素的文献，这些因素会影响个体的 HPA 轴反应性和功能，并最终影响 AD 风险。其次，我们提出了一种机制，通过该机制，影响 HPA 轴反应性的遗传因素也可能影响炎症，这是神经变性的关键驱动因素。我们假设这些因素可以介导大脑免疫细胞小胶质细胞的糖皮质激素启动，使其促炎并促进导致神经变性的神经毒性环境。了解潜在的分子机制并确定这些遗传因素对评估与压力相关的风险/神经退行性疾病的进展具有影响，