评估二甲双胍靶点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。
Evaluating the efficacy and mechanism of metformin targets on reducing Alzheimer's disease risk in the general population: a Mendelian randomisation study.
机构信息
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.
出版信息
Diabetologia. 2022 Oct;65(10):1664-1675. doi: 10.1007/s00125-022-05743-0. Epub 2022 Jul 29.
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 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, was associated with 4% lower odds of Alzheimer's disease (OR 0.96 [95% CI 0.95, 0.98], p=1.06×10) 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) 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) 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.
目的/假设：在观察性研究中，二甲双胍的使用与糖尿病患者痴呆发生率的降低有关。然而，在普通人群中，两者之间的因果关系尚不清楚。本研究使用孟德尔随机化（MR）来研究二甲双胍靶点对阿尔茨海默病的因果影响以及两者之间在大脑中潜在的联系机制。
方法
鉴定二甲双胍药物靶点作用的遗传替代物，方法是鉴定与 HbA 水平相关的基因（N=344182）和相应基因表达水平的基因（N≤31684）中的变异。认知结果来自包含 527138 名中年欧洲人的全基因组关联研究，其中包括 71880 名患有阿尔茨海默病或阿尔茨海默病代理。在普通人群中生成代表终生使用二甲双胍对阿尔茨海默病和认知功能的 MR 估计值。进一步估计大脑皮层中 22 个与二甲双胍相关基因的表达水平（N=6601 个供体）对阿尔茨海默病的影响。
结果
遗传上替代二甲双胍的使用，相当于 HbA 降低 6.75mmol/mol（1.09%），与非糖尿病个体中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）。一个二甲双胍靶点，线粒体复合物 1（MCI），对阿尔茨海默病有显著影响（OR 0.88，p=4.73×10），与 AMP 激活蛋白激酶无关。大脑皮层组织中表达的 MR 显示，MCI 相关基因（NDUFA2）表达降低与阿尔茨海默病风险降低相关（OR 0.95，p=4.64×10）和认知功能改善相关。
结论/解释：二甲双胍的使用可能会降低普通人群患阿尔茨海默病的风险。线粒体功能和 NDUFA2 基因可能是痴呆保护的作用机制。
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