Even mild, clinically silent cortisol excess can be associated with subtle cognitive alterations, impaired sleep, and early functional connectivity changes, despite preserved brain morphology.
Patients with MACS exhibited slightly lower Mini-Mental State Examination (MMSE) scores compared with patients with non-functioning adrenal tumors (NFAT).
Patients with MACS demonstrated poorer delayed verbal recall compared to NFAT patients, negatively correlated with serum cortisol levels.
Patients with MACS showed significantly poorer sleep quality compared to NFAT patients, as measured by the Pittsburgh Sleep Quality Index (PSQI).
No group differences in depressive symptoms were observed between MACS and NFAT patients.
Resting-state fMRI revealed altered hippocampal connectivity in MACS patients, with reduced connectivity with the caudate nucleus and increased connectivity with mesial occipital regions.
Voxel-based morphometry showed no structural brain differences between MACS and NFAT groups.
This research suggests that people with mild autonomous cortisol secretion (MACS) — a condition where the adrenal glands produce slightly too much of the stress hormone cortisol without causing obvious symptoms — show subtle but measurable effects on the brain. Compared to people with non-functioning adrenal tumors (which do not produce excess hormones), those with MACS performed slightly worse on tests of general mental function and memory, slept more poorly, and showed different patterns of brain activity on functional MRI scans. Importantly, higher cortisol levels were directly linked to worse memory and cognitive scores, suggesting a dose-response relationship. Despite these functional and cognitive differences, brain scans looking at the physical structure of the brain found no differences between the two groups — meaning the brain's architecture appears intact even when its activity patterns have already changed. The changes in connectivity were centered on the hippocampus, a brain region critical for memory and known to be sensitive to cortisol. Mood (depression) did not differ between groups, suggesting that emotional symptoms may appear later or may require higher cortisol levels to emerge. This research matters because MACS is commonly discovered incidentally during imaging for unrelated reasons, and it has traditionally been considered clinically benign. These findings suggest that even without obvious symptoms of Cushing's syndrome, low-level excess cortisol may already be affecting brain function, memory, and sleep. The authors call for longitudinal studies to determine whether these changes worsen over time and whether treating the cortisol excess can reverse them.
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Upload Your LabsZiccardi L, Romano A, Moltoni G, De Carolis A, Aloini M, Cavallari M, et al.. (2026). Mild autonomous cortisol secretion and brain function: cognitive, structural, and functional correlates.. Frontiers in endocrinology. https://doi.org/10.3389/fendo.2026.1913085