Salivary Cortisol and Cognitive Decline and Alzheimer Disease in Older Adults.

Abstract

Alterations in hypothalamic-pituitary-adrenal axis activity have been implicated in cognitive aging, yet large, racially diverse studies using physiologically active salivary cortisol studies are limited. To determine whether diurnal salivary cortisol indices are associated with cognitive outcomes, including incident Alzheimer disease (AD), and whether distributions and associations differ by race. This prospective cohort study was conducted from 2000 to 2011, with 11 years of follow-up, as part of the Chicago Health and Aging Project, a community-based study of older adults in urban Chicago. Participants provided salivary cortisol samples across a day (waking, afternoon, and bedtime) and completed cognitive assessments. Analyses were conducted from June to October 2025. Five salivary cortisol indices capturing intraday variability (coefficient of variation [CV]), cumulative exposure (mean cortisol and area under the curve with respect to ground [AUCg]), and diurnal change (diurnal slope and AUC with respect to increase [AUCi]). Outcomes of interest were global cognition, cognitive decline, and incident AD, adjusted for demographic, health, and behavioral factors. Among 3895 participants (mean [SD] age, 76.7 [6.8] years; 2509 [64.4%] women; 2503 Black participants [64.3%] and 1392 White participants [35.7%]), all cortisol indices were cross-sectionally associated with cognitive performance. Longitudinally, compared with the first quintile (Q1), medium to high cortisol intraday variability (CV) was associated with slower decline (Q3: β = 0.02 [95% CI, 0.001 to 0.04]; P = .04; Q4: β = 0.03 [95% CI, 0.01 to 0.04]; P = .003), whereas the highest cumulative exposure was associated with faster decline (mean cortisol Q5: β = -0.02 [95% CI, -0.04 to -0.004]; P = .02; AUCg Q5: β = -0.02 [95% CI, -0.03 to 0.00]; P = .046). Diurnal change indices (slope, AUCi) were not associated with decline or incident AD. Black participants exhibited lower cortisol exposure but flatter slopes and lower intraday variability, reflecting a blunted diurnal rhythm; associations with decline were similar across races. In this cohort study of Black and White older adults, altered diurnal cortisol patterning was associated with faster cognitive decline but not short-term AD risk. These findings support salivary cortisol as a potential early biomarker of neurocognitive aging. Racial differences in cortisol patterning suggest differential biological embedding of stress, consistent with structural inequities.