A recent mendelian randomization study depicted that incident vascular dementia may cause a decrease in circulating high-density lipoprotein cholesterol (HDL-C). The relationship between hypercholesterolemia and vascular dementia has been suggested by a growing body of observational studies, but their exact cause is still unknown.

Therefore, the goal of this study was to use univariable mendelian randomization (uvMR), multivariable MR (mvMR), and bidirectional two-sample MR methods to infer causal associations of circulating lipid-associated traits [encompassing low-density lipoprotein cholesterol (LDL-C), HDL-C, triglycerides, apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I)] with vascular dementia.

The relationship of lipid-lowering medication target genes expression (encompassing APOB, HMGCR, PCSK9, and NPC1L1) and LDL-C level mediated by these target genes were then investigated using summary-data-based MR (SMR) and two-sample MR analysis. Forward MR studies revealed that the genetically predicted concentrations of apoB, HDL-C, LDL-C,  triglycerides, and apoA-I were not substantially linked to vascular dementia risk. Notably, reverse MR analysis revealed suggestive evidence for a causal relationship between genetically predicted vascular dementia and HDL-C [odds ratio (OR), 0.997].

The MR results, on the other hand, did not reveal a connection between vascular dementia and apoB, apoA-I, LDL-C, and triglycerides. According to the SMR method's findings, there was no proof that the expression of the APOB, HMGCR, PCSK9, and NPC1L1 genes magnifies vascular dementia risk. Additionally, the outcomes of the MR study demonstrated that a reduced LDL-C level, mediated by the gene HMGCR, minimized vascular dementia risk (OR, 18.381).

For the other three genes, none of the inverse-variance weighted (IVW) methods illustrated any causal effects. This study used genetic information to show that the risk of vascular dementia may lead to a drop in HDL-C levels. Furthermore, the findings support the theory that reducing LDL-C levels with statins might be a successful strategy for reducing the risk of vascular dementia; however, clinical trials will be necessary to substantiate this conclusion in the future.