Increased glucocorticoid production and altered cortisol metabolism in women with mild to moderate Alzheimer’s disease

Abstract

Background: Abnormalities at several levels of the hypothalamic–pituitary–adrenal axis, which may promote glucocorticoid dependent neurodegeneration, have been reported in patients with Alzheimer’s disease. In this study we have explored the possibility that peripheral cortisol metabolism is enhanced and glucocorticoid production is increased compensatory in patients with mild to moderate Alzheimer’s disease. Methods: Urinary excretion of cortisol and its principal conjugated metabolites was studied in ten women with mild to moderate Alzheimer’s disease, seven healthy elderly women and seven young women. Results: There was an age-related fall in glucocorticoid production (median, 2009 [range 1828–4201] vs. 9315 [range 3613–16,244] μg/24 hours in elderly vs. young control subjects). A-ring metabolism (i.e., the irreversible inactivation of cortisol by 5α- and 5β-reductases) was reduced in old age. However, patients with Alzheimer’s disease showed persistence of cortisol metabolite excretion. Glucocorticoid production was significantly increased in patients with Alzheimer’s disease versus healthy elderly control subjects (median, 7269 [range 6005–15,335] vs. 2009 [range 1828–4201] μg/24 hours), and patients with Alzheimer’s disease had increased A-ring reduction of cortisol. Conclusions: An increased glucocorticoid production is an early feature of Alzheimer’s disease and may be secondary to enhanced metabolic clearance of cortisol by A-ring reduction.