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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.
Bibliographical noteFunding Information:
JZ is supported by the Academy of Medical Sciences (AMS) Springboard Award, the Wellcome Trust, the Government Department of Business, Energy and Industrial Strategy (BEIS), the British Heart Foundation and Diabetes UK (SBF006\1117). JZ is funded by the Vice-Chancellor Fellowship from the University of Bristol. MX, WW, YB and GN are supported by the National Natural Science Foundation of China (82088102, 81970728 and 81941017) and the Shanghai Municipal Education Commission–Gaofeng Clinical Medicine Grant Support (20161307 and 20152508 Round 2). JZ, VW, GDS and TRG are supported by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/1 and MC_UU_00011/4). RK-L was supported by a Wellcome Trust PhD studentship (grant ref. 215193/Z18/Z). MVH works in a unit that receives funding from the UK Medical Research Council and is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre. TRG, JZ and GDS have received research funding from various pharmaceutical companies, involving GSK and Biogen to support the application of MR to drug target prioritisation. However, these companies were not involved in the design, collection, analysis and interpretation of data. The study sponsor/funder was not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.
This research was conducted using the UK Biobank resource under application number: 15825 (https://www.ukbiobank.ac.uk). The UK Biobank received ethical approval from the Research Ethics Committee (REC reference for the UK Biobank is 11/NW/0382). Data on outcomes were contributed by a number of studies to the IEU OpenGWAS database and were downloaded from https://gwas.mrcieu.ac.uk/. We thank the individuals who participated in the underlying studies; without them this work would not have been possible. MX, WW, YB and GN are members of the Innovative Research Team of High-level Local Universities in Shanghai. TRG, JZ and GDS have received research funding from various pharmaceutical companies to support the application of MR to drug target prioritisation. MVH has collaborated with Boehringer Ingelheim in research, and in adherence to the University of Oxford’s Clinical Trial Service Unit & Epidemiological Studies Unit (CSTU) staff policy, did not accept personal honoraria or other payments from pharmaceutical companies. This study was not funded or supported by any of the above institutes or companies. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. JZ, MX, VW, GDS, WW, YB, TRG and GN designed the study, wrote the research plan and interpreted the results. JZ undertook the phenome-wide MR and follow-up MR analyses with feedback from MX and VW. JY conducted the literature search of the meta-analyses. RK-L supported the one-sample MR. SB supported the factorial MR. SLAY and SL supported the instrument selection. JR collected the brain expression data and supported the gene expression analysis. PH conducted the literature review of existing dementia medications and wrote relevant sections. MVH supported the triangulation analysis. JZ wrote the first draft of the manuscript with critical comments and revision from all the other authors. JZ is the guarantor. All authors approved the final version to be published. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
© 2022, The Author(s).
- Bristol Population Health Science Institute
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- 1 Finished
Gaunt, L. F. & Davey Smith, G.
1/04/18 → 31/03/23