Han Lijun, Su Chang, Lian Ruonan, Han Junming, Fan Xiude, Gao Ling
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China.
Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong Province, China.
Medicine (Baltimore). 2025 Sep 5;104(36):e44260. doi: 10.1097/MD.0000000000044260.
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.
心血管疾病是全球主要的死亡原因，影响老年人认知障碍的发展。降脂药物常用于管理心血管疾病风险，但它们对认知表现的影响在先前的研究中产生了相互矛盾的结果。为了更好地指导降脂药物的选择性决策和应用，本研究旨在通过孟德尔随机化确定降脂药物与认知表现之间的因果关系。我们基于降脂药物和认知表现的全基因组关联研究的汇总统计数据进行了一项两样本孟德尔随机化研究。与低密度脂蛋白胆固醇或甘油三酯显著相关且与药物靶基因相关的单核苷酸多态性用作他汀类药物、依泽替米贝、前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）抑制剂、贝特类药物等的替代指标。基因预测的他汀类药物（β = -0.094，95%置信区间-0.138至-0.049，P <.001）和依泽替米贝（β = -0.319，95%置信区间-0.408至-0.231，P <.001）对认知表现有不良影响，而其他药物，包括PCSK9抑制剂和贝特类药物等则未显示出显著影响。本研究表明，他汀类药物和依泽替米贝可能对认知有不良影响，而PCSK9抑制剂和贝特类药物似乎没有这种影响，这可能有助于临床医生做出更明智的处方决策。这些发现应谨慎解释，需要长期随访临床研究进一步验证。
