Summary: Chronic stress involving the hypothalamic–pituitary–adrenal (HPA) axis may contribute to the development of Alzheimer’s disease, according to researchers.
Source: Wiley
Chronic psychosocial stress—which operates through the hypothalamic–pituitary–adrenal axis (HPA axis)—may increase the risk of Alzheimer’s disease.
A comprehensive review published in Biological Reviews examines how environmental exposures and inherited genetic differences shape HPA axis function and how those differences could influence the likelihood of developing Alzheimer’s disease.
The review also outlines a potential mechanism by which genetic variation affecting the HPA axis might alter inflammatory responses in the brain, a central process in neurodegeneration.
“Chronic stress impacts many biological systems,” said senior author David Groth, PhD, of Curtin University in Australia. “There is a close interaction between prolonged stress exposure and the pathways that govern the body’s response to that stress.”
“Genetic differences in stress-response pathways can shape how the brain’s immune cells act, sometimes producing a maladaptive or exaggerated response,” Groth adds. “In the long term, this can disrupt normal brain processes and raise the risk of neurodegeneration and dementia.”
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About this research: stress, the HPA axis and Alzheimer’s disease
Source: Wiley
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Original Research: Closed access. Chronic stress and Alzheimer’s disease: the interplay between the hypothalamic–pituitary–adrenal axis, genetics and microglia by David Groth et al., Biological Reviews.
Abstract
Chronic stress and Alzheimer’s disease: the interplay between the hypothalamic–pituitary–adrenal axis, genetics and microglia
Chronic psychosocial stress is increasingly recognized as a contributing risk factor for sporadic Alzheimer’s disease (AD). The hypothalamic–pituitary–adrenal (HPA) axis is the body’s primary stress-response system and tightly controls the release of cortisol, a glucocorticoid hormone implicated in multiple physiological processes.
Many patients with Alzheimer’s disease display disturbances of HPA axis regulation and elevated cortisol levels, which are thought to play a meaningful role in disease progression. However, the precise biological mechanisms linking HPA axis dysregulation and AD remain incompletely understood.
Across the general population there are notable individual differences in sensitivity to stress and to glucocorticoids. These differences arise from a mix of environmental influences and inherited genetic variation, and they may ultimately influence an individual’s vulnerability to Alzheimer’s disease.
This review first synthesizes current evidence on how environmental factors and genetic variation shape HPA axis reactivity and function, and how those effects could modulate AD risk. Second, the authors propose a testable mechanism in which genetic factors that alter HPA axis responsiveness also influence neuroinflammatory processes—particularly the behavior of microglia, the resident immune cells of the brain.
The central hypothesis is that altered glucocorticoid signaling can “prime” microglia toward a pro-inflammatory state. Once primed, these immune cells may produce neurotoxic responses that disrupt neuronal health and promote neurodegeneration over time.
Clarifying the molecular pathways that connect chronic stress, HPA axis dysfunction, genetic susceptibility and microglial activation could help to identify individuals at higher risk for stress-related progression to neurodegeneration. Such understanding may also guide the development and evaluation of interventions focused on stress management, and inform assessments of potential risks associated with widespread clinical use of glucocorticoid medications.
By drawing together genetic, environmental and immunological perspectives, the review highlights an integrated framework for studying how life-long stress exposure and innate biological differences interact to influence Alzheimer’s disease risk, progression and potential prevention strategies.