Intact circadian rhythm despite cortisol hypersecretion in Alzheimer's disease: A meta-analysis

Hypersecretion of the glucocorticoid steroid hormone cortisol by individuals with Alzheimer's disease (AD) has been suspected for several decades, during which time dozens of examinations of this phenomenon have been conducted and published. The goals of this investigation were to summarize this sizeable body of literature, test whether participant and methodological characteristics modify the magnitude of the AD-associated basal cortisol hypersecretion, and examine whether cortisol circadian rhythmicity is maintained among individuals with AD. To this end, the present meta-analysis and systematic review examined over 300 comparisons of indices of basal HPA-axis functioning between individuals with AD and cognitively normal older adults. AD was associated with basal cortisol elevations (g = 0.45) but the magnitude of the effect was not systematically impacted by any of the participant characteristics considered or the time-of-day of the cortisol sampling. Further, there was no evidence of group differences among direct indices of circadian rhythmicity such as the cortisol awakening response or the diurnal cortisol slope. These results suggest that basal hypersecretion of cortisol, but not circadian dysrhythmia, is characteristic of individuals with AD. Mechanistically, the observed hypersecretion is consistent with the theorized AD-driven deterioration of the hippocampus and subsequent reduction in hypothalamic-pituitary-adrenal axis inhibition. Further investigation is warranted to elucidate the role and timing of cortisol elevations in the progression of AD.