Abstract
OBJECTIVE: Cognitive impairment has become a critical public health challenge in China's aging population, with growing evidence linking its progression to dysregulated glycolipid metabolism. The hemoglobin A1c to high-density lipoprotein cholesterol (HbA1c/HDL-C) ratio, a novel composite biomarker reflecting integrated glycolipid homeostasis, has recently demonstrated prognostic value in metabolic disorders. Based on these insights, this population-based study leverages longitudinal data from the China Health and Retirement Longitudinal Study (CHARLS) to investigate the association between the HbA1c/HDL-C ratio and cognitive decline in older Chinese adults. METHOD: We included 813 community-dwelling adults aged ≥ 60 years from the China Health and Retirement Longitudinal Study (CHARLS) cohort, who had complete data on glycated hemoglobin (HbA1c), high-density lipoprotein cholesterol (HDL-C), and cognitive function at baseline. The HbA1c/HDL-C ratio was calculated as the ratio of HbA1c (%) to HDL-C (mmol/L). Cognitive decline was defined as a decrease in the global cognitive score over time, assessed using a validated cognitive battery. Cox proportional hazards models were used to estimate the association between the HbA1c/HDL-C ratio and incident cognitive decline. Sensitivity analyses included generalized linear mixed models (GLMM) and restricted cubic spline (RCS) regression to explore potential non-linear relationships. Subgroup and RCS analyses were also performed on HDL-C levels to further investigate underlying mechanisms. RESULTS: After adjusting for various risk factors, our analysis revealed a significant association between the HbA1c/HDL-C ratio and an increased risk of cognitive decline in individuals aged 60 and older. Compared to the Q1 group, the highest hazard ratio (HR) was observed in the Q2 group (HR = 1.53, 95% CI: 1.16-2.02, P = 0.002). The HR was 1.36 (95% CI: 1.03-1.81, P = 0.029) for the Q3 group versus Q1, and 1.40 (95% CI: 1.05-1.88, P = 0.024) for the Q4 group versus Q1. Results from the Generalized Linear Mixed Model (GLMM) were consistent with those from the Cox regression, supporting the primary findings.Furthermore, Restricted Cubic Spline (RCS) regression analysis indicated a non-linear relationship between the HbA1c/HDL-C ratio and cognitive decline, with an inflection point at a ratio of 2.06. Specifically, ratios below this threshold were associated with an increased risk of cognitive decline (HR: 2.31, 95% CI 1.32-4.04, P = 0.003), whereas the predictive ability was attenuated when the ratio exceeded this value (P = 0.269). Additional analysis suggested that this non-linearity may originate from a non-linear association between HDL-C and cognitive decline. CONCLUSION: Our findings indicate a significant yet nonlinear relationship between the HbA1c/HDL-C ratio and the incidence of cognitive decline in individuals aged 60 and above. This nonlinearity may stem from a nonlinear relationship between HDL-C and cognitive decline.