Remnant Cholesterol and Incident Depression in Aging: A 14-Year Prospective Cohort Study and Mendelian Randomization Analysis

BACKGROUND: Long-term cohort data combined with Mendelian randomization (MR) were used to investigate whether elevated remnant cholesterol (RC) causally contributes to depression risk. METHODS: A total of 4,422 adults aged ≥50 years from Wave 2 (2004-2005) of the ELSA were followed up to 14 years through Wave 9 (2019). Incident depression was defined as CES-D ≥4 during follow-up. Associations were assessed using Cox proportional hazards models, restricted cubic splines (RCS), and subgroup analyses. Two-sample MR used 134 RC SNPs and depression GWAS data, with Bayesian weighted MR (BWMR) to reduce pleiotropy and support causality. RESULTS: Over 14 years, 1,048 incident depression cases occurred (23.7%); each 1 mmol/L higher RC was associated with a 1.2% increased risk (hazard ratio [HR]: 1.01, 95% confidence intervals [CI]: 1.001-1.022, P = 0.030). Compared to Q1, participants in Q4 had a 24.8% increased risk (HR: 1.248, 95% CI: 1.005-1.550, P = 0.045). RCS revealed a significant positive linear association between RC and depression risk after multivariable adjustment (P for overall = 0.025; P for nonlinearity = 0.057). Subgroup analyses showed consistent effects across age, sex, BMI, diabetes, and lifestyle (all interaction P > 0.05). MR analyses confirmed that genetically elevated RC was associated with major depressive disorder and ICD-10 depressive episodes (primary outcomes, P < 0.05), with anxiety-related traits as secondary supportive evidence (P < 0.05). BWMR results validated IVW findings. CONCLUSIONS: Elevated RC is independently and causally linked to higher depression risk in middle-aged and older adults, with BWMR supporting its role as a modifiable biomarker for integrated cardiometabolic and psychiatric prevention.