Association Between Ratio of Triglycerides to HDL-C and Cognitive Impairment: A Longitudinal Population-Based Analysis and Mendelian Randomization Study.
OBJECTIVES: This study aimed to explore the longitudinal association between the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and cognitive impairment in older adults and further assess potential causality using Mendelian randomization (MR). DESIGN: Longitudinal population-based analysis combined with two-sample MR. Data from Waves 6-8 (2015-2019) of the Survey of Health, Ageing, and Retirement in Europe (SHARE) were analyzed using hierarchical regression models and mixed linear effects models. MR utilized genome-wide association studies (GWAS) summary data. PARTICIPANTS: 11,444 adults aged ≥60 years from SHARE Wave 6, with longitudinal follow-up in Waves 7 (N = 2,775) and 8 (N = 5,469). MEASUREMENTS: TG/HDL-C ratio, cognitive function (orientation, immediate/delayed recall, verbal fluency, numeracy), and cognitive impairment (defined as scores >1.5 SD below age-group mean). Covariates included socio-demographics, health behaviors, comorbidities, and national-level factors. MR employed genetic variants associated with TG/HDL-C as instrumental variables. RESULTS: Higher TG/HDL-C ratios were negatively associated with total cognitive scores (β = -0.115, χ² = 15.44, df = 1, p < 0.001), immediate recall (β = -0.029, χ² = 12.34, df = 1, p < 0.001), delayed recall (β = -0.028, χ² = 7.33, df = 1, p < 0.001), verbal fluency (β = -0.038, χ² = 11.53, df = 1, p < 0.001), and numeracy (β = -0.019, χ² = 4.55, df = 1, p < 0.05) in fully adjusted models. Longitudinal analysis revealed increased cognitive impairment risk in the highest TG/HDL-C quartile (OR=1.43, 95% CI:1.01-2.03, χ² = 9.24, df = 1) over 4 years. MR supported a causal link between elevated TG/HDL-C and cognitive decline. CONCLUSIONS: Elevated TG/HDL-C ratios are longitudinally associated with cognitive decline in older adults. Managing lipid metabolism may mitigate cognitive impairment, highlighting the importance of TG/HDL-C as a modifiable risk factor in aging populations.