Perturbations in lipid metabolism mediate the relationship between cholecystectomy and dementia: A mediation Mendelian randomization study

Background The relationship between surgical approaches and postoperative cognitive dysfunction remains controversial. Objective To investigate the causal effect of cholecystectomy on dementia and its subtypes, and the mediating role of circulating lipid metabolites. Methods Using large-scale genome-wide association studies (GWAS), the causal effect of genetically proxied cholecystectomy (18,319 cases and 444,614 controls) on dementia (20,667 cases and 428,053 controls), dementia due to Parkinson's disease (643 cases and 199, 772 controls), dementia in Alzheimer's disease (6741 cases and 428,053 controls), frontotemporal dementia (145 cases and 432,207 controls), vascular dementia (3116 cases and 433,066 controls), and dementia with Lewy bodies (2591 cases and 4027 controls) were explored by two-sample Mendelian randomization (TSMR). Mediating lipid metabolites were identified by TSMR. GWAS data used for analysis were obtained from the IEU Open GWAS Project and the FinnGen Consortium. Results Cholecystectomy patients had an increased risk of dementia and dementia in Alzheimer's disease, with odds ratios (OR) of 2.33 (95% CI = 1.074–5.068, p = 0.032) and 3.43 (95% CI = 1.029–11.411, p = 0.045) respectively. Phospholipids in small high-density lipoprotein (HDL) partially mediated the causal effect between cholecystectomy and dementia, with a mediating effect of 9.06%. Conclusions This mediation MR study revealed a causal relationship between cholecystectomy and dementia, especially dementia in Alzheimer's disease, and revealed a partial mediating role of circulating phospholipids in small HDL. However, further studies are needed to verify whether phospholipids in small HDL can be a new biomarker for predicting, preventing or even treating dementia in cholecystectomy patients.