From vessels to cognition: The mediating role of biological aging in the cognitive trajectory of diabetic patients

BACKGROUND: Estimated Pulse Wave Velocity (ePWV) is an emerging biological marker for vascular stiffness, which has been linked to cognitive function. However, few prospective studies have evaluated the relationship between ePWV and longitudinal cognitive trajectories specifically within diabetic populations, nor have potential mediating pathways-such as biological aging-been sufficiently examined. METHODS: We analyzed diabetic patients from two large-scale cohorts: the China Health and Retirement Longitudinal Study (CHARLS, 2011-2012, n = 1106) and the National Health and Nutrition Examination Survey (NHANES, 2011-2014, n = 709). In the cross-sectional phase, multivariate linear regression and restricted cubic spline (RCS) analyses examined the association between ePWV and baseline cognition. The NHANES data were utilized for cross-sectional validation. For the longitudinal phase (CHARLS, 2011-2020, n = 1076), group-based trajectory modeling (GBTM) identified distinct cognitive trajectory patterns over nine years. Multinomial logistic regression was used to assess the association between baseline ePWV and longitudinal cognitive trajectory. Mediation analysis was performed to quantify the contribution of biological age. RESULTS: In both cohorts, higher baseline ePWV was significantly associated with poorer cognitive function (CHARLS T3: β = -0.98, 95% CI: -1.63 to -0.33, P = 0.003; NHANES T3: β = -0.44, 95% CI: -0.86 to -0.03, P = 0.038). During a mean follow-up period of 7.45 years, we identified two distinct cognitive patterns: a "persistently high" and a "persistently low" trajectory. Elevated ePWV was significantly associated with an increased risk of membership in the "persistently low" trajectory group for global cognition (OR = 3.05, 95% CI: 1.84-5.04, P < 0.001), mental intactness (OR = 2.41, 95% CI: 1.44-4.04, P < 0.001), and episodic memory (OR = 3.77, 95% CI: 2.26-6.31, P < 0.001). Mediation analysis suggested that biological age mediated a substantial proportion of these associations (79.61% for global cognition, P < 0.001). CONCLUSIONS: In diabetic patients, elevated baseline ePWV is an independent predictor of a persistently low cognitive trajectory over a 9-year period. This association appears to be partially mediated by accelerated biological aging, suggesting that vascular stiffness may act as a systemic driver of cognitive compromise.