Restricted accessResearch articleFirst published online 2025-7
Double product is longitudinally associated with reduced cognitive function in type 2 diabetes with insights from cross-lagged panel analysis and mediation by leucine-rich α-2-glycoprotein 1
Elevated systolic blood pressure (SBP) and resting heart rate (RHR) contribute to pathogenesis of diabetic complications. They increase inflammation which can upregulate leucine-rich α-2-glycoprotein 1 (LRG1), an emerging biomarker of cognitive decline.
Objective
To examine association between double product (DP, derived from multiplying SBP and RHR) and cognitive function in type 2 diabetes (T2D), with possible mediation by plasma LRG1.
Methods
In this prospective cohort of 1319 patients (mean age 62.5 ± 7.3), plasma LRG1 was measured with enzyme-linked immunosorbent assay. Cognitive function was assessed using Repeatable Battery for Assessment of Neuropsychological Status (RBANS). Cross-lagged panel analysis was done to examine temporal relationship between DP and cognitive function.
Results
Baseline DP was associated with lower baseline RBANS total score (adjusted coefficient = −2.43; 95%CI −4.76, −0.10; p = 0.041). 586 patients were followed up to 8.6 years. Baseline DP was associated with follow-up RBANS total score (adjusted coefficient = −3.80; 95%CI −6.51, −1.10; p = 0.006). It was also associated with lower follow-up RBANS scores in immediate memory and delayed memory with adjusted coefficients −4.38 (95%CI −8.49, −0.28; p = 0.036) and −5.12 (95%CI −9.88, −0.35; p = 0.035) respectively. In cross-lagged panel analysis, standardized effect size of baseline DP on follow-up RBANS total score (β = −0.08; p = 0.002) was larger than that of baseline RBANS total score on follow-up DP (β = −0.04; p = 0.266). LRG1 accounted for 14.7% of the association in mediation analysis (p = 0.035).
Conclusions
DP was independently associated with cognitive function with possible mediation by LRG1. DP preceded decline in cognitive function. DP may be potential intervention and monitoring target for prevention of cognitive impairment and possibly Alzheimer's disease in T2D.
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