Cholesterol-lowering drug targets reduce risk of dementia: Mendelian randomization and meta-analyses of 1 million individuals

IF 11.1 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-10-08 DOI:10.1002/alz.70638

Liv Tybjærg Nordestgaard, Aimee Hanson, Eleanor Sanderson, Emma Anderson, Venexia Walker, Anne Tybjærg-Hansen, George Davey Smith, Børge G. Nordestgaard

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引用次数: 0

Abstract

INTRODUCTION

We tested whether genetically proxied non-high-density lipoprotein cholesterol (non-HDL-C)–lowering drug targets reduce risk of all-cause dementia.

METHODS

We included 1,091,775 individuals from three prospective general population cohorts with individual-level data and two consortia with summary-level data. We selected genetic variants within HMGCR, NPC1L1, PCSK9, ANGPTL4, LPL, and CETP associated with non-HDL-C. These variants were used as exposures in Cox regression and one- and two-sample Mendelian randomization. Results were meta-analyzed.

RESULTS

Meta-analysis of one-sample Mendelian randomization odds ratios per 1 mmol/L (39 mg/dL) lower non-HDL-C was 0.24 (0.18–0.31) for HMGCR, 0.18 (0.12–0.25) for NPC1L1, 0.97 (0.70–1.35) for PCSK9, 1.66 (0.52–5.36) for ANGPTL4, 1.41 (0.63–3.16) for LPL, and 0.30 (0.26–0.34) for CETP. Cox regression and two-sample Mendelian randomization results were mostly directionally consistent.

DISCUSSION

Genetic lowering of non-HDL cholesterol via HMGCR, NPC1L1, and CETP reduces the risk of dementia. This reflects the effect of lifelong differences in non-HDL cholesterol on risk of dementia.

Highlights

Variants in HMGCR, NPC1L1, and CETP reduce the risk of dementia via non-high-density lipoprotein cholesterol (non-HDL-C).
An effect of PCSK9, ANGPTL4, and LPL variants on dementia risk cannot be excluded.
This reflects the effect of lifelong lower non-HDL-C on risk of dementia.

Abstract Image

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降胆固醇药物靶点降低痴呆风险：100万人的孟德尔随机化和荟萃分析

我们测试了基因替代的非高密度脂蛋白胆固醇（non - HDL - C）降低药物靶点是否能降低全因痴呆的风险。方法我们纳入了1091775名个体，分别来自三个具有个体水平数据的前瞻性普通人群队列和两个具有汇总水平数据的联合体。我们选择了HMGCR、NPC1L1、PCSK9、ANGPTL4、LPL和CETP中与非HDL - C相关的遗传变异。这些变异被用作Cox回归和单样本和双样本孟德尔随机化的暴露。结果进行meta分析。结果meta分析显示，每1 mmol/L （39 mg/dL）低非HDL - C的单样本孟德尔随机化优势比HMGCR为0.24 (0.18 - 0.31)，NPC1L1为0.18 (0.12-0.25)，PCSK9为0.97 (0.70-1.35)，ANGPTL4为1.66 (0.52-5.36)，LPL为1.41 (0.63-3.16)，CETP为0.30（0.26-0.34）。Cox回归和两样本孟德尔随机化结果在方向性上基本一致。通过HMGCR、NPC1L1和CETP基因降低非高密度脂蛋白胆固醇可降低痴呆风险。这反映了非高密度脂蛋白胆固醇的终生差异对痴呆风险的影响。HMGCR、NPC1L1和CETP的变异通过非高密度脂蛋白胆固醇（non -高密度脂蛋白C）降低痴呆的风险。不能排除PCSK9、ANGPTL4和LPL变异对痴呆风险的影响。这反映了终生较低的非HDL - C对痴呆风险的影响。

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

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.