Abstract
BACKGROUND: While abundant evidence suggests a correlation between depression and the risk of cognitive impairments, the causal relationship, as well as the mechanisms mediating this association, remain uncertain. METHODS: We conducted an observational study within the National Health and Nutrition Examination Survey (NHANES), simultaneously employing weighted multivariable-adjusted linear regression to explore the association between them. Subsequently, Mendelian randomization analysis was employed to investigate the causal relationship between them as well as the mediating effects. RESULTS: The observational analysis of NHANES data indicates that depression is independently associated with cognitive function. Regarding MR, genetically predicted depression is causally related to cognitive function in the IVW method (OR 0.33, 95% CI 0.14-0.78, P = 0.012). Furthermore, depression leads to obesity (OR = 1.91, P = 2.53 × 10 - 3) and elevated blood pressure (OR 2.34, P = 3.62 × 10 - 3). Waist circumference (OR = 0.85, P = 3.00 × 10 - 4), BMI (OR = 0.84, P = 1.06 × 10 - 6), and hypertension (OR = 0.95, P = 4.00 × 10 - 3) all contribute to cognitive function. Additionally, there is no causal association between cognitive function and depression (OR 1.00, 95% CI 0.99-1.01, P = 0.559) in reverse Mendelian randomization. Mediation analysis indicates that BMI and hypertension mediate 9.9% and 3.6% of the cognitive function under depression conditions, respectively. CONCLUSIONS: Our study indicates that depression can lead to obesity and hypertension, which can reduce cognitive function. These findings underscore the importance of timely identification and management of depression in patients with cognitive impairments and suggest that treatments aimed at reducing weight and lowering blood pressure may help prevent cognitive impairment.