Exploring the role of statin interventions on cognitive function by Mendelian randomization study

Background While statin use is linked to cognitive impairment, causal relationships with specific dementia subtypes remain unclear. Objective To investigate causal effects of statin medication, genetically mimicked statin effects, and plasma lipids on various cognitive impairments using Mendelian randomization (MR). Methods Utilizing summary genome-wide association studies data, we identified genetic variants associated with statin medication, cholesterol-dependent/independent statin effects, and dementia subtypes, such as Alzheimer's disease (AD), dementia in Alzheimer's disease (ADD), late-onset Alzheimer's disease, dementia with Lewy body (DLB), dementia with Lewy body in APOE ε4 + carriers, frontotemporal dementia, Parkinson's disease dementia, and vascular dementia. Univariable MR assessed causality, primarily via inverse variance weighting (IVW). Mediation effects were evaluated using the coefficient product method. Sensitivity analyses ensured robustness. Results IVW-MR indicated statin medication significantly reduced AD risk but increased ADD and DLB risk. Elevated total cholesterol (TC) increased dementia, ADD, and DLB, while higher low density lipoprotein cholesterol decreased AD risk. Specific DHCR24 variants reduced DLB risk, while HMGCS1 variants increased it. RAC1 variants lowered AD risk, whereas RHOC mitigated ADD risk. Critically, TC mediated 93.91% (95% CI = 68.27%∼119.55%) of statins’ effect on dementia, 84.37% (95% CI = 62.21%∼106.52%) on ADD, and 61.94% (95% CI = 43.47%∼80.42%) on DLB. The genetically mimicked effect of statins does not show a mediating role. Conclusions Statin medication, plasma lipids, and their genetic proxies exhibit causal links to cognitive impairment. Crucially, TC mediates statin-associated risks for cognitive impairment.