Genetic insights of lipid metabolism and lipid-lowering drugs with Lewy body dementia risk: Evidence from Mendelian randomization

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY Progress in Neuro-Psychopharmacology & Biological Psychiatry Pub Date : 2025-02-08 DOI:10.1016/j.pnpbp.2025.111282

Hanyu Zhang , Zengyuan Zhou , Jie Gu , Yingnan Lin , Yunyun Yan , Xiaonan Chen , Meixiang Fan , Yanyan Huang

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Abstract

Background

Lewy body dementia (LBD) is the second common dementia, with unclear mechanisms and limited treatment options. Dyslipidemia has been implicated in LBD, but the role of lipid-lowering drugs remains underexplored. This study aims to investigate the association between lipid traits, drug targets, and LBD risk using Mendelian Randomization (MR) analysis.

Methods

We performed univariable and multivariable MR analyses to evaluate the causal effects of lipid traits on the risk of LBD. Then, drug-target MR analysis and subtype analysis were conducted to evaluate the effects of lipid-lowering therapies on LBD.

Results

In univariable MR, genetically predicted low-density lipoprotein cholesterol (LDL-C) and remnant cholesterol (RC) levels were associated with an increased risk of LBD. Mediation analysis suggested a potential interaction between LDL-C and RC in influencing LBD risk. Drug-target MR analysis identified significant associations between genetically proxied inhibition of ANGPTL3, CETP, and HMGCR and LBD risk.

Conclusion

This MR analysis provided evidence that elevated LDL-C and RC may increase the risk of LBD. Additionally, targeting ANGPTL3, CETP, and HMGCR may represent potential therapeutic strategies for the prevention or treatment of LBD.

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脂质代谢和降脂药物与路易体痴呆风险的遗传洞察：来自孟德尔随机化的证据

背景：路易体痴呆（LBD）是第二种常见的痴呆，机制不清楚，治疗方案有限。血脂异常与LBD有关，但降脂药物的作用仍未得到充分探讨。本研究旨在利用孟德尔随机化（MR）分析探讨脂质特征、药物靶点和LBD风险之间的关系。方法采用单变量和多变量MR分析，评价脂质性状与LBD风险的因果关系。然后进行药物靶向MR分析和亚型分析，评价降脂治疗对LBD的影响。结果在单变量MR中，遗传预测的低密度脂蛋白胆固醇（LDL-C）和残余胆固醇（RC）水平与LBD风险增加相关。中介分析提示LDL-C和RC在影响LBD风险方面存在潜在的相互作用。药物靶MR分析发现，基因代理抑制ANGPTL3、CETP和HMGCR与LBD风险之间存在显著关联。结论本MR分析提供了LDL-C和RC升高可能增加LBD风险的证据。此外，靶向ANGPTL3、CETP和HMGCR可能是预防或治疗LBD的潜在治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Progress in Neuro-Psychopharmacology & Biological Psychiatry 医学-精神病学

CiteScore

12.00

自引率

1.80%

发文量

153

审稿时长

56 days

期刊介绍： Progress in Neuro-Psychopharmacology & Biological Psychiatry is an international and multidisciplinary journal which aims to ensure the rapid publication of authoritative reviews and research papers dealing with experimental and clinical aspects of neuro-psychopharmacology and biological psychiatry. Issues of the journal are regularly devoted wholly in or in part to a topical subject. Progress in Neuro-Psychopharmacology & Biological Psychiatry does not publish work on the actions of biological extracts unless the pharmacological active molecular substrate and/or specific receptor binding properties of the extract compounds are elucidated.