Evaluating the efficacy and mechanism of metformin targets on reducing Alzheimer’s disease risk in the general population: a Mendelian randomisation study,Diabetologia

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Evaluating the efficacy and mechanism of metformin targets on reducing Alzheimer’s disease risk in the general population: a Mendelian randomisation study
Diabetologia ( IF 8.2 ) Pub Date : 2022-07-29 , DOI: 10.1007/s00125-022-05743-0
Jie Zheng _{1,

2,

3} , Min Xu _{1,

2} , Venexia Walker ₃ , Jinqiu Yuan _{4,

5,

6,

7} , Roxanna Korologou-Linden ₃ , Jamie Robinson ₃ , Peiyuan Huang ₃ , Stephen Burgess _{8,

9} , Shiu Lun Au Yeung ₁₀ , Shan Luo ₁₀ , Michael V Holmes _{3,

11,

12,

13} , George Davey Smith _{3,

14} , Guang Ning _{1,

2} , Weiqing Wang _{1,

2} , Tom R Gaunt _{3,

14} , Yufang Bi _{1,

2}

Affiliation

Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK.
Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
Guangzhou Women and Children Medical Center, Guangzhou, Guangdong, China.
Division of Epidemiology, the JC School of Public Health & Primary Care, the Chinese University of Hong Kong, Hong Kong, Hong Kong.
MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK.
Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China.
Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK.
Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK.
NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK.

Aims/hypothesis

Metformin use has been associated with reduced incidence of dementia in diabetic individuals in observational studies. However, the causality between the two in the general population is unclear. This study uses Mendelian randomisation (MR) to investigate the causal effect of metformin targets on Alzheimer’s disease and potential causal mechanisms in the brain linking the two.

Methods

Genetic proxies for the effects of metformin drug targets were identified as variants in the gene for the corresponding target that associated with HbA_1c level (N=344,182) and expression level of the corresponding gene (N≤31,684). The cognitive outcomes were derived from genome-wide association studies comprising 527,138 middle-aged Europeans, including 71,880 with Alzheimer’s disease or Alzheimer’s disease-by-proxy. MR estimates representing lifelong metformin use on Alzheimer’s disease and cognitive function in the general population were generated. Effect of expression level of 22 metformin-related genes in brain cortex (N=6601 donors) on Alzheimer’s disease was further estimated.

Results

Genetically proxied metformin use, equivalent to a 6.75 mmol/mol (1.09%) reduction on HbA_1c, was associated with 4% lower odds of Alzheimer’s disease (OR 0.96 [95% CI 0.95, 0.98], p=1.06×10⁻⁴) in non-diabetic individuals. One metformin target, mitochondrial complex 1 (MCI), showed a robust effect on Alzheimer’s disease (OR 0.88, p=4.73×10⁻⁴) that was independent of AMP-activated protein kinase. MR of expression in brain cortex tissue showed that decreased MCI-related gene (NDUFA2) expression was associated with lower Alzheimer’s disease risk (OR 0.95, p=4.64×10⁻⁴) and favourable cognitive function.

Conclusions/interpretation

Metformin use may cause reduced Alzheimer’s disease risk in the general population. Mitochondrial function and the NDUFA2 gene are plausible mechanisms of action in dementia protection.

Graphical abstract

中文翻译：

评估二甲双胍降低普通人群阿尔茨海默病风险的疗效和机制：一项孟德尔随机研究

目标/假设

在观察性研究中，二甲双胍的使用与糖尿病患者痴呆症的发病率降低有关。然而，两者在一般人群中的因果关系尚不清楚。本研究使用孟德尔随机化 (MR) 来研究二甲双胍靶标对阿尔茨海默氏病的因果效应以及将两者联系起来的大脑中潜在的因果机制。

方法

_{二甲双胍药物靶点作用的遗传代理被确定为与 HbA 1c}水平 ( N =344,182) 和相应基因的表达水平 ( N ≤31,684)相关的相应靶点的基因变异。认知结果来自全基因组关联研究，该研究包括 527,138 名中年欧洲人，其中 71,880 名患有阿尔茨海默氏病或阿尔茨海默氏病代理人。生成了代表终生使用二甲双胍对阿尔茨海默氏病和普通人群认知功能的 MR 估计值。进一步评估了22个二甲双胍相关基因在脑皮质（N =6601个供体）中表达水平对阿尔茨海默病的影响。

结果

遗传替代二甲双胍的使用，相当于 HbA _1c降低 6.75 mmol/mol (1.09%) ，与阿尔茨海默病的几率降低 4% 相关（OR 0.96 [95% CI 0.95, 0.98]，p =1.06×10 ^-4 ) 在非糖尿病个体中。一种二甲双胍靶标线粒体复合物 1 (MCI) 显示出对阿尔茨海默病的强大影响（OR 0.88，p =4.73×10 ^-4），这与 AMP 活化蛋白激酶无关。大脑皮层组织中表达的 MR 显示，降低的 MCI 相关基因 ( NDUFA2 ) 表达与较低的阿尔茨海默病风险 (OR 0.95，p =4.64×10 ^-4 ) 和良好的认知功能相关。