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

Jie Zheng; Min Xu; Venexia Walker; Jinqiu Yuan; Roxanna Korologou-Linden; Jamie Robinson; Peiyuan Huang; Stephen Burgess; Shiu Lun Au Yeung; Shan Luo; Michael V Holmes; George Davey Smith; Guang Ning; Weiqing Wang; Tom R Gaunt; Yufang Bi

doi:10.1007/s00125-022-05743-0

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

Diabetologia. 2022 Oct;65(10):1664-1675. doi: 10.1007/s00125-022-05743-0. Epub 2022 Jul 29.

Authors

Jie Zheng^{1

2

3}, Min Xu^{4

5}, Venexia Walker⁶, Jinqiu Yuan^{7

8

9

10}, Roxanna Korologou-Linden⁶, Jamie Robinson⁶, Peiyuan Huang⁶, Stephen Burgess^{11

12}, Shiu Lun Au Yeung¹³, Shan Luo¹³, Michael V Holmes^{6

14

15

16}, George Davey Smith^{6

17}, Guang Ning^{18

19}, Weiqing Wang^{18

19}, Tom R Gaunt^{20

21}, Yufang Bi^{22

23}

Affiliations

¹ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Jie.Zheng@bristol.ac.uk.
² 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. Jie.Zheng@bristol.ac.uk.
³ MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK. Jie.Zheng@bristol.ac.uk.
⁴ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. della.xumin@163.com.
⁵ 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. della.xumin@163.com.
⁶ MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK.
⁷ Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
⁸ Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
⁹ Guangzhou Women and Children Medical Center, Guangzhou, Guangdong, China.
¹⁰ Division of Epidemiology, the JC School of Public Health & Primary Care, the Chinese University of Hong Kong, Hong Kong, Hong Kong.
¹¹ MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK.
¹² Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹³ School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, SAR, China.
¹⁴ Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK.
¹⁵ Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
¹⁶ National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK.
¹⁷ NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK.
¹⁸ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
¹⁹ 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.
²⁰ MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK. tom.gaunt@bristol.ac.uk.
²¹ NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK. tom.gaunt@bristol.ac.uk.
²² Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. byf10784@rjh.com.cn.
²³ 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. byf10784@rjh.com.cn.

Abstract

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.

Keywords: Alzheimer’s disease; Brain expression; Cognitive function; Dementia; Mendelian randomisation; Metformin targets; Mitochondrial function.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / genetics
Alzheimer Disease* / drug therapy
Alzheimer Disease* / epidemiology
Alzheimer Disease* / genetics
Brain
Genome-Wide Association Study
Humans
Mendelian Randomization Analysis
Metformin* / therapeutic use
Middle Aged

Substances

Metformin
AMP-Activated Protein Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding