期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 87, 期 1, 页码 463-477出版社
IOS PRESS
DOI: 10.3233/JAD-220050
关键词
Alzheimer's disease; cholesterol; mendelian randomization; metabolite
资金
- National Natural Science Foundation of China [82071201, 81971032]
- Shanghai Municipal Science and Technology Major Project [2018SHZ DZX01]
- Research Start-up Fund of Huashan Hospital [2022QD002]
- Excellence 2025Talent Cultivation Program at Fudan University [3030277001]
- ZHANGJIANG LAB
- Tianqiao and Chrissy Chen Institute
- State Key Laboratory of Neurobiology and Frontiers Center for Brain Science of Ministry of Education, Fudan University
- French National Foundation
- LABEX DISTALZ grant, Inserm, Institut Pasteur de Lille, Universite de Lille 2
- Lille University Hospital
- Medical Research Council [503480]
- Alzheimer's Research UK [503176]
- Wellcome Trust [082604/2/07/Z]
- German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) [01GI0102, 01GI0711, 01GI0420]
- NIH/NIA [R01 AG033193, U01 AG032984, U24AG021886, U01AG016976]
- NIA [AG081220]
- AGES [N01-AG-12100]
- NHLBI [R01 HL105756]
- Icelandic Heart Association
- Erasmus Medical Center
- Erasmus University
- Alzheimer's Association grant [ADGC-10-196728]
Using a two-sample Mendelian randomization approach, this study found a causal association between circulating glycoprotein acetyls, ApoB, LDL cholesterol, and serum total cholesterol levels and a higher risk of Alzheimer's disease (AD), while increased levels of glutamine were associated with a lower risk of AD.
Background: Metabolomics is a promising approach that can be used to understand pathophysiological pathways of Alzheimer's disease (AD). However, the causal relationships between metabolism and AD are poorly understood. Objective: We aimed to investigate the causal association between circulating metabolites and risk of AD through two-sample Mendelian randomization (MR) approach. Methods: Genetic associations with 123 circulating metabolic traits were utilized as exposures. Summary statistics data from International Genomics of Alzheimer's Project was used in primary analysis, including 21,982 AD cases and 41,944 controls. Validation was performed using family history of AD data from UK Biobank (27,696 cases of maternal AD, 14,338 cases of paternal AD, and 272,244 controls). We utilized inverse-variance weighted method as primary method. Results: We found significantly increased risks of developing AD per standard deviation increase in the levels of circulating ApoB (odd ratio[OR] = 3.18; 95% confidence interval [CI]: 1.52-6.66, p= 0.0022), glycoprotein acetyls (OR = 1.21; 95%CI: 1.05-1.39, p= 0.0093), total cholesterol (OR = 2.73; 95%CI: 1.41-5.30, p= 0.0030), and low-density lipoprotein (LDL) cholesterol (OR = 2.34; 95%CI: 1.53-3.57, p = 0.0001). Whereas glutamine (OR = 0.81; 95%CI: 0.71-0.92, p = 0.0011) were significantly associated with lower risk of AD. We also detected causal effects of several different composition of LDL fractions on increased AD risk, which has been verified in validation. However, we found no association between circulating high-density lipoprotein cholesterol and AD. Conclusion: Our findings suggest causal effects of circulating glycoprotein acetyls, ApoB, LDL cholesterol, and serum total cholesterol on higher risk of AD, whereas glutamine showed the protective effect.
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