Impact of menopause associated adrenal aging on cognitive function and Alzheimer dementia neuroimaging biomarkers

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PROJECT SUMMARY Aging is associated with both physical and cognitive decline. Endocrine-wise, impairment in the hypothalamic- pituitary-adrenal axis has been reported, including elevated diurnal cortisol concentrations, abnormal suppression of cortisol following dexamethasone administration, and increased salivary cortisol. Previous studies reported association between higher cortisol concentrations and poor overall cognitive performance and structural changes in the brain, with cortical and hippocampal atrophy, as well as Alzheimer Disease (AD) development. However, these studies used suboptimal assessment of adrenal steroid metabolome, mainly concentrating on cortisol (only 1% of steroid metabolome). As we show in our preliminary data, steroid metabolome (as assessed by a novel steroid profiling assay) changes with age, differentially in women versus men, with decreased androgens and increased glucocorticoid metabolites, increasing with age glucocorticoid/androgen ratio, and steroid ratio changes suggestive of increased tissue exposure of cortisol. Previous studies reported that menopause accelerates epigenetic aging of blood, and that later age of natural menopause is associated with decreased mortality. Women undergoing bilateral salpingo-oophorectomy (BSO) prior to the age of natural menopause experience a higher degree of accelerated aging with increased rates of multiple morbidities, most notably cardiovascular disease, cognitive decline, and increased mortality. As shown in our preliminary data, most significant change in steroid metabolome occurs in women after menopause. We further show that abnormal steroid metabolome in menopausal women is associated with decline in executive function, processing speed, and working memory. In our proposed research, our hypothesis is that adrenal aging (as measured by the 24h urine steroid metabolome) is accelerated with menopause; BSO accelerates adrenal aging which, in turn, impacts cognitive function and brain structures. In our proposed research, we will take advantage of the ongoing study in the Mayo Clinic Specialized Center of Research Excellence (SCORE) on sex differences to assess how abrupt loss of ovarian hormones caused by BSO affects adrenal aging (Aim 1). In addition, through a machine learning analysis, we propose to determine whether abnormal steroid metabolome is associated with cognitive decline and AD structural changes on brain imaging (Aim 2). This project will deliver the insight into BSO-related changes in steroid metabolome and will estimate the impact of adrenal aging on cognitive changes and structural changes of AD on brain imaging. A specific steroid signature will be identified to potentially serve as biomarker of aging and cognitive decline.