| Title: | Evaluating the efficacy and mechanism of metformin targets on reducing Alzheimer's disease risk in the general population: a Mendelian randomisation study |
| Journal: | Diabetologia |
| Published: | 29 Jul 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35902387/ |
| DOI: | https://doi.org/10.1007/s00125-022-05743-0 |
| URL: | https://link.springer.com/content/pdf/10.1007/s00125-022-05743-0.pdf |
Publication 10382
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Abstract
Aims/hypothesisMetformin 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.MethodsGenetic proxies for the effects of metformin drug targets were identified as variants in the gene for the corresponding target that associated with HbA1c 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.ResultsGenetically proxied metformin use, equivalent to a 6.75 mmol/mol (1.09%) reduction on HbA1c, 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/interpretationMetformin 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</p>
16 Authors
- 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
1 Application
| Application ID | Title |
|---|---|
| 15825 | MR-Base: an online resource for Mendelian randomization using summary data |
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