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).

Figure 1

Flow diagram. The flow diagram shows the inclusion process from the baseline dataset of the Age-Well trial. DHEA, dehydroepiandrosterone; MRI, magnetic resonance imaging.

Figure 2

Associations between plasma epinephrine and brain health. Scatter plots show the association between epinephrine and cerebral glucose metabolism in the anterior cingulate cortex (ACC) (A), posterior cingulate cortex (PCC) (B), and precuneus (C) as well as between epinephrine and cerebral perfusion in the PCC (D) for the total sample and stratified by sex. Higher epinephrine levels were associated (false discovery rate–corrected p < .05) with lower glucose metabolism and lower cerebral perfusion in these brain regions independent of sex. Black lines indicate regression lines with shaded areas showing the 95% CI for the total sample, red dots and lines indicate data points and regression lines for the subgroup with women, blue dots and lines indicate data points and regression lines for the subgroup with men. SUV, standardized uptake value.

Figure 3

Interactions between sex and stress biomarkers on brain health and cognition. (A) The scatter plot shows the interaction (false discovery rate–corrected p < .05) between sex and plasma epinephrine on anterior cingulate cortex (ACC) brain volume. In women, but not in men, higher epinephrine was associated with greater ACC volume. (B) Interaction (false discovery rate–corrected p < .05) between serum cortisol and sex on verbal episodic memory. In men, but not in women, higher cortisol levels were associated with lower memory performance. Black lines indicate regression slopes for the total sample; red dots and lines indicate data points and regression lines, with shaded areas showing the 95% CI for the subgroup with women; blue dots and lines indicate data points and regression lines, with shaded areas showing the 95% CI for the subgroup with men.