胆固醇酯转移蛋白 (CETP) 活性降低与痴呆症风险:孟德尔随机分析。

IF 7.9 1区 医学 Q1 CLINICAL NEUROLOGY Alzheimer's Research & Therapy Pub Date : 2024-10-16 DOI:10.1186/s13195-024-01594-6
Amand F Schmidt, Michael H Davidson, Marc Ditmarsch, John J Kastelein, Chris Finan
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引用次数: 0

摘要

背景:低密度脂蛋白胆固醇(LDL-C)浓度升高与痴呆症风险有关,相反,高密度脂蛋白胆固醇(HDL-C)和载脂蛋白-A1(Apo-A1)血浆浓度升高与痴呆症风险降低有关。抑制胆固醇酯转移蛋白(CETP)会对这些血脂的浓度产生有意义的影响,因此可能为治疗痴呆症提供机会:方法:采用药物靶向孟德尔随机化(MR)方法预测降低CETP浓度(μg/mL)对血浆脂质、心血管疾病结局、尸检证实的路易体痴呆(LBD)以及帕金森氏痴呆的靶向效应:CETP浓度降低的磁共振分析再现了CETP抑制剂临床试验中观察到的血脂效应,以及对冠心病(几率比(OR)0.92,95%置信区间(CI)0.89;0.96)、心力衰竭、腹主动脉瘤、任何中风、缺血性中风和小血管中风(0.90,95%CI 0.85;0.96)的保护作用。对痴呆症相关特征的考虑表明,较低的 CETP 浓度与较高的总脑容量(每标准差 0.04,95%CI 0.02;0.06)、较低的枸杞多糖症风险(OR 0.81,95%CI 0.74;0.89)和帕金森氏痴呆症风险(OR 0.26,95%CI 0.14;0.48)相关。APOE4分层分析表明,与APOE-ε4-(OR 0.89 95%CI 0.79; 1.01)相比,APOE-ε4 +参与者的枸杞多糖效应最明显(OR 0.61 95%CI 0.51; 0.73);交互作用P值为5.81 × 10- 4.结论:这些结果表明,抑制 CETP 可能是治疗痴呆症的一种可行策略,预计对 APOE-ε4 携带者的效果更明显。
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Lower activity of cholesteryl ester transfer protein (CETP) and the risk of dementia: a Mendelian randomization analysis.

Background: Elevated concentrations of low-density lipoprotein cholesterol (LDL-C) are linked to dementia risk, and conversely, increased plasma concentrations of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein-A1 (Apo-A1) associate with decreased dementia risk. Inhibition of cholesteryl ester transfer protein (CETP) meaningfully affects the concentrations of these blood lipids and may therefore provide an opportunity to treat dementia.

Methods: Drug target Mendelian randomization (MR) was employed to anticipate the on-target effects of lower CETP concentration (μg/mL) on plasma lipids, cardiovascular disease outcomes, autopsy confirmed Lewy body dementia (LBD), as well as Parkinson's dementia.

Results: MR analysis of lower CETP concentration recapitulated the blood lipid effects observed in clinical trials of CETP-inhibitors, as well as protective effects on coronary heart disease (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.89; 0.96), heart failure, abdominal aortic aneurysm, any stroke, ischemic stroke, and small vessel stroke (0.90, 95%CI 0.85; 0.96). Consideration of dementia related traits indicated that lower CETP concentrations were associated higher total brain volume (0.04 per standard deviation, 95%CI 0.02; 0.06), lower risk of LBD (OR 0.81, 95%CI 0.74; 0.89) and Parkinson's dementia risk (OR 0.26, 95%CI 0.14; 0.48). APOE4 stratified analyses suggested the LBD effect was most pronounced in APOE-ε4 + participants (OR 0.61 95%CI 0.51; 0.73), compared to APOE-ε4- (OR 0.89 95%CI 0.79; 1.01); interaction p-value 5.81 × 10- 4.

Conclusions: These results suggest that inhibition of CETP may be a viable strategy to treat dementia, with a more pronounced effect expected in APOE-ε4 carriers.

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来源期刊
Alzheimer's Research & Therapy
Alzheimer's Research & Therapy 医学-神经病学
CiteScore
13.10
自引率
3.30%
发文量
172
审稿时长
>12 weeks
期刊介绍: Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.
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