Chronic stress and Alzheimer's disease: The interplay between the hypothalamic–pituitary–adrenal axis, genetics and microglia
Authors/Creators
Ayeisha Milligan Armstrong
Tenielle Porter, Edith Cowan UniversityFollow
Hazel Quek
Anthony White
John Haynes
Connie Jackaman
Victor Villemagne, Edith Cowan UniversityFollow
Kylie Munyard
Simon M. Laws, Edith Cowan UniversityFollow
Giuseppe Verdile, Edith Cowan UniversityFollow
David Groth
Abstract
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.
RAS ID
36629
Document Type
Journal Article
Date of Publication
2021
Volume
96
Issue
5
School
School of Medical and Health Sciences / Centre for Precision Health
Copyright
subscription content
Publisher
Wiley
Comments
Milligan Armstrong, A., Porter, T., Quek, H., White, A., Haynes, J., Jackaman, C., . . . Groth, D. (2021). Chronic stress and A lzheimer's disease: The interplay between the hypothalamic–pituitary–adrenal axis, genetics and microglia. Biological Reviews, 96(5), 2209-2228. https://doi.org/10.1111/brv.12750