Urinary Steroid Metabolome Signature is Associated With Cognitive Function in Older Adults

Abstract

\n Background: Elevated urine cortisol (<1% of urinary steroid metabolome) was reported to predict future development of dementia. Our objective was to determine the association of urine steroid metabolome and its diurnal variation with cognitive function in men and women. Methods: Cross-sectional study of community-dwelling adults ≥ 50 years. Participants with adrenal disorders, end-stage renal or liver disease, on exogenous steroids or drugs affecting steroid metabolism were excluded. All participants completed day and night separate urine collection. A series of seven IPad-based tests using the National Institute of Health Toolbox Cognition Battery were administered to evaluate five key domains; performance was reported using fully corrected T-scores for age, sex, education, and race with a national normative mean of 50. T-scores were generated for the two summary measures: 1) fluid cognition (includes executive function, episodic memory, working memory, and processing speed), and 2) total composite (composite of fluid and language score). Urine samples were analyzed with the liquid-chromatography, high-resolution, accurate-mass mass spectrometry for 25 urine steroid metabolites. Results: Of 109 participants, 56 (51%) were women, and age and educational status were similar in men and women. On cognitive assessment, men and women had similar median composite cognition (T-score of 53 vs 54, p=0.74) and fluid cognition (T-score of 53 vs 51, p-value 0.96). Urine steroid metabolome analysis demonstrated 21/25 steroids were higher in men vs women. In both women and men, the ratio of total cortisol metabolites/total androgen metabolites (TCM/TAM) was associated with lower fluid cognition (women: ρ= -0.34, p=0.01, men: ρ= -0.43, p=0.001) and composite cognition (women: ρ= -0.27, p=0.04, men: ρ= -0.39, p=0.004). Higher ratio of day to night TCM were associated with a better fluid cognition in men (ρ= 0.35, p=0.01), but not in women (ρ= -0.11, p=0.41). Steroid ratios suggesting a relative enzymatic deficiency of 5α-Reductase type 2 was associated with lower fluid cognition in women (ρ= -0.29, p=0.03). In men, the fluid composite score was associated with a relative deficiency in 21-Hydroxylase (ρ= 0.42, p=0.002), 3β-Hydroxysteroid dehydrogenase (ρ= 0.43, p=0.001), and P450oxidoreductase (ρ= -0.35, p=0.01). Conclusion: We showed that a higher glucocorticoid to androgen ratio and a flattened circadian steroid variation were associated with lower global and fluid cognition score. Steroid ratios reflecting steroidogenesis enzymatic activity demonstrated sex differences in relation to cognition. Additional studies should examine whether the steroid fingerprint associated with lower cognition is predictive of a future dementia onset.