Sex-Specific Effect of Cortisol on Cerebral Glucose Metabolism Across Alzheimer's Disease Spectrum: A Neuroimaging Study

Abdullah Alqarni^1*Essam Alkhybari¹Mohammed Alshuhri¹Manal Aljuhani¹Ibrahim Hadadi²Manal Alosaimi³Hussein Alshaari⁴Mansour M Alqahtani⁴Amr Abd-Elghany^1,5

• ¹Prince Sattam bin Abdulaziz University College of Applied Medical Sciences, Al Kharj, Saudi Arabia
• ²King Khalid University College of Applied Medical Sciences, Abha, Saudi Arabia
• ³King Saud University College of Applied Medical Sciences, Riyadh, Saudi Arabia
• ⁴Najran University Faculty of Applied Medical Science, Najran, Saudi Arabia
• ⁵Cairo University Faculty of Science, Giza, Egypt

Higher levels of cortisol can disrupt the normal patterns of cerebral glucose metabolism in the human brain. This study aims to investigate the effects of elevated cortisol levels on cerebral glucose metabolism in men and women across Alzheimer's disease spectrum. The data was derived from the publicly available Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Eight hundred and twenty-two participants across varying diagnostic cognition status were included: 469 men (mean age of 74.14 ± 7.19 years) and 353 women (mean age of 72.31 ± 7.34 years). Main effect and interaction terms were used in generalized linear models to examine the association between elevated cortisol levels and cerebral glucose metabolism as measured by Fluorodeoxyglucose positron emission tomography (FDG-PET) in men and women across Alzheimer's disease spectrum. Sex-stratified analysis was conducted a priori based on established biological differences in HPA axis function between sexes. Elevated cortisol levels were negatively associated with brain glucose consumption in women, but not in men. Women with APOE4 alleles were at greater risk of brain hypometabolism. Diastolic blood pressure in men, but not women, was negatively associated with brain glucose consumption, an indication of higher vascular vulnerability in men. Notably, while sex-stratified analyses revealed these differential patterns, the formal cortisol*sex interaction term did not reach statistical significance (p = 0.157), potentially due to limited statistical power for detecting interactions. Larger studies are warranted to confirm these sex-specific findings. These findings suggest that cortisol may represent a modifiable risk factor warranting further investigation, particularly in postmenopausal women who experience estrogen decline, a known neuroprotective mediator.