Circulating Stress Hormones, Brain Health, and Cognition in Healthy Older Adults: Cross-Sectional Findings and Sex Differences in Age-Well

Abstract

Background: Increased stress is a proposed risk factor for Alzheimer’s disease (AD). We examined cross-sectional associations between circulating stress biomarkers and multimodal measures of brain health and cognition susceptible to AD in older adults and sex-specific subgroups. Methods: Baseline data from 132 cognitively unimpaired participants without depression (age, mean ± SD = 74.0 ± 4.0 years, women: n = 80) in the Age-Well trial (NCT02977819) were included. Stress hormone levels were measured in overnight fasting blood serum (cortisol, dehydroepiandrosterone sulfate) and blood plasma (epinephrine, norepinephrine) samples. AD-sensitive measures of brain health, including glucose metabolism (n = 89), cerebral perfusion, gray matter volume, amyloid deposition in a priori regions of interest, and cognitive markers were evaluated. Models were adjusted for age, sex, education, trait anxiety, and depressive symptoms. Results: Higher epinephrine levels were associated (false discovery rate–corrected p < .05) with lower glucose metabolism in the anterior cingulate cortex (β = −0.26, p = .008), posterior cingulate cortex (β = −0.32, p = .006), and precuneus (β = −0.27, p = .021) and lower perfusion in the posterior cingulate cortex (β = −0.23, p = .013). Interactions between stress hormones and sex showed (false discovery rate–corrected p < .05) that in women only, higher epinephrine was associated with larger anterior cingulate cortex volume (interaction: β = 0.32, p = .016), whereas in men only, higher cortisol was associated with lower episodic memory performance (interaction: β = 0.98, p = .012). Conclusions: The current study demonstrates the involvement of circulating stress hormones, particularly epinephrine and cortisol, in greater resilience or vulnerability of brain health and cognitive indicators of susceptibility to AD in older adults. The identification of sex-specific patterns in these associations may inform the development of more effective and tailored interventions.

Keywords

• Aging
• Alzheimer’s disease
• Hypothalamic-pituitary-adrenal (HPA)
• Prevention
• Stress
• Sympathetic-adrenal-medullary (SAM)