Summary: Chronic stress which involves the HPA axis may contribute to the development of Alzheimer’s disease, researchers report.
Chronic psychosocial stress—which involves a pathway called the hypothalamic-pituitary-adrenal axis (HPA axis)–may contribute to the development of Alzheimer’s disease.
A new review published in Biological Reviews describes how environmental and genetic factors can impact individuals’ HPA axis, and ultimately their risk of Alzheimer’s disease.
The review also proposes a mechanism by which genetic factors that influence the HPA axis may also affect inflammation, a key driver of neurodegeneration.
“What we know is that chronic stress does affect many biological pathways within our body. There is an intimate interplay between exposure to chronic stress and pathways influencing the body’s reaction to such stress,” said senior author David Groth, PhD, of Curtin University, in Australia.
“Genetic variations within these pathways can influence the way the brain’s immune system behaves leading to a dysfunctional response. In the brain, this leads to a chronic disruption of normal brain processes, increasing the risk of subsequent neurodegeneration and ultimately dementia.”
Chronic stress and Alzheimer’s disease: the interplay between the hypothalamic–pituitary–adrenal axis, genetics and microglia
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.