Abstract
Cardiovascular disease is the leading global cause of mortality, affecting the development of cognitive impairment in the elderly. Lipid-lowering drugs are commonly used to manage cardiovascular disease risk, but their effects on cognitive performance have produced conflicting results in previous research. To better guide the selective decision-making and application of lipid-lowering drugs, this study aims to determine the causal relationship between lipid-lowering drugs and cognitive performance through Mendelian randomization. We conducted a 2-sample Mendelian randomization study based on summary statistics from genome-wide association studies for lipid-lowering drugs and cognitive performance. Single-nucleotide polymorphisms significantly related to low-density lipoprotein cholesterol or triglycerides and associated with drug target genes served as proxies for statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, fibrates, etc. Genetically predicted statins (β = -0.094, 95% confidence interval -0.138 to -0.049, P < .001) and ezetimibe (β = -0.319, 95% confidence interval -0.408 to -0.231, P < .001) had adverse effects on cognitive performance, while other drugs, including PCSK9 inhibitors and fibrates, etc showed no significant impact. This study suggests that statins and ezetimibe may have adverse effects on cognition, while PCSK9 inhibitors and fibrates appear to have no such effect, which may help clinicians make more informed prescription decisions. These findings should be interpreted carefully and require further validation by long-term follow-up clinical studies.