Is stroke the cause of vascular dementia? A two-sample Mendelian Randomization analysis

Abstract Background Vascular dementia, the second most common cause of dementia, is closely related to stroke. This study aimed to determine whether stroke is causally associated with vascular dementia. Methods A two-sample Mendelian randomization (MR) was performed. Genetic instruments were acquired with a genome-wide significant threshold (p < 5x10− 8) from the MRC Integrative Epidemiology Unit (IEU) open genome-wide association studies (GWAS) project. Methods including inverse variance-weighted (IVW), MR-Egger, weighted-median methods, and MR pleiotropy residual sum and outlier (MR-PRESSO) were performed to evaluate the effects and to assess heterogeneity and horizontal pleiotropy. Controversies were resolved with a meta-analysis. A leave-one-out analysis was also performed. Results A causal association was observed between total stroke and vascular dementia, with an odds ratio (OR) of 1.81 (95% CI, 1.81 to 2.34) and a P-value of 0.026 for IVW, and an OR of 1.81 (95% CI, 1.32 to 2.31) and a P-value of 0.047 for MR-PRESSO. Ischemic stroke was also causally associated with vascular dementia, with an OR of 1.87 (95% CI, 1.39 to 2.36), a P-value of 0.011 for IVW. MR-PRESSO had an OR of 1.87 (95% CI, 1.35 to 2.40) and a P-value of 0.048. Body mass index (BMI) was also associated with vascular dementia, with an OR of 1.29 (95% CI, 1.13 to 1.48) and P-value < 0.01 according to the meta-analysis. No significant association was observed between stroke subtypes, other stroke risk factors, or stroke-related medications. Discussion An estimation of two-sample MR found that stroke and BMI were the causes of vascular dementia.