High Cortisol and the Risk of Dementia and Alzheimer's Disease: A Review of the Literature

Abstract

Introduction: Cortisol effects on the brain are exerted through two distinct receptors, inducing complex and even opposite effects on the cerebral structures implicated in the various cognitive functions. High cortisol may also have deleterious effects on the brain structures and contribute to neurodegeneration, in particular Alzheimer's disease (AD), via different mechanisms. Objective: To examine the interrelationships between cortisol, cognitive impairment and AD. Methods: Review of the literature. Results: Clinical studies found that elevated cortisol was associated with poorer overall cognitive functioning, as well as with poorer episodic memory, executive functioning, language, spatial memory, processing speed, and social cognition; while in animals, glucocorticoid administration resulted in cognitive impairment and abnormal behavior. In cognitively healthy subjects, higher cortisol levels have been associated with an increased risk of cognitive decline and AD. Subjects with dementia and Mild Cognitive Impairment (MCI) due to AD have been found to have higher CSF cortisol levels than cognitively healthy controls. Elevated CSF cortisol may also be associated with a more rapid cognitive decline in MCI due to AD. Elevated cortisol levels have been also found in delirium. High cortisol may mediate the impact of stressful life events, high neuroticism, depression, sleep disturbances, as well as cardiovascular risk factors on cognitive performance, neurodegeneration, and cognitive decline. High cortisol may also exert neurotoxic effects on the hippocampus, and promote oxidative stress and amyloid β peptide toxicity. Further possible underlying mechanisms include the interactions of cortisol with inflammatory mediators, neurotransmitters, and growth factors. Conclusion: Elevated cortisol levels may exert detrimental effects on cognition and contribute to AD pathology. Further studies are needed to investigate cortisol-reducing and glucocorticoidreceptor modulating interventions to prevent cognitive decline.

Keywords: cognition; cortisol; dementia; executive functions; memory.

Figure 1

Dose–response relationship between the memory performance and the cortisol levels. The first part of the plot shows that memory performance increases as cortisol levels increase (due to the activation of mineralocorticoid receptors or MRs). As soon as the MRs are saturated, further increase in cortisol levels activates the glucocorticoids receptors or GRs and memory performance decreases. Adapted with permission from Lupien et al. (2007).

Figure 2

Hypothetical dose–response relationship between the executive functions performance and the cortisol levels. As the prefrontal cortex only expresses GRs, the higher the cortisol levels, the poorer the executive functions performance.

Figure 3

(A) In normal circumstances, the CRF released by the hypothalamus activates ACTH release by the pituitary gland, which stimulates the adrenal glands to secrete cortisol. Cortisol inhibits its own secretion via a negative feedback loop. The hippocampus inhibits the hypothalamo-pituitary-adrenal axis. (B) When cortisol is elevated, it can induce hippocampal atrophy, which “lifts the brake” on the hypothalamo-pituitary-adrenal axis. The resulting cortisol increase induces further hippocampal atrophy, resulting in a vicious circle. CRF, corticotropin-releasing factor; ACTH, Adrenocorticotropic hormone.