medRxiv · Mar 19, 2026
Serum autotaxin is associated with DHEAS and predicts longitudinal cognitive changes in older women: Analysis of the Arao cohort study
By Sun S, Kajitani N, Yoshiura K et al.
Abstract Aim To examine the determinants of serum autotaxin (ATX) levels in community-dwelling older adults, focusing specifically on endogenous adrenal steroids, and to investigate the cross-sectional and longitudinal associations between serum ATX levels, cognitive function, and depressive symptoms. Methods Data were obtained from community-dwelling older adults aged 65 years and older in Arao City, Japan (baseline: 1,488; follow-up: 730). Serum ATX and dehydroepiandrosterone sulfate (DHEAS) levels were measured, and cognitive function and depressive symptoms were assessed using the Mini–Mental State Examination (MMSE) and Geriatric Depression Scale (GDS). Multiple linear regression models were applied to examine any cross-sectional associations among serum ATX levels, adrenal steroids, and MMSE/GDS scores. Longitudinal analyses assessed whether baseline serum ATX levels predicted 6-year changes in MMSE and GDS scores, with additional sex-stratified analyses and propensity score matching conducted to address any potential follow-up bias. Results After adjusting for age and sex, DHEAS levels were inversely associated with ATX levels. Cross-sectional analyses identified no association between serum ATX levels and MMSE/GDS scores. However, longitudinal analyses demonstrated significant associations between baseline serum ATX levels and changes in MMSE scores, particularly among women, and remained significant after multivariate and propensity score–matched analyses. Conclusion This study provides epidemiological evidence of an inverse association between DHEAS and ATX, indicating a potential link between adrenal endocrine function and ATX regulation. In older women, baseline serum ATX levels were associated with inter-individual variability in subsequent cognitive trajectories, indicating a potential role for ATX in age-related cognitive changes.