Evaluating the efficacy and mechanism of metformin targets on reducing Alzheimer’s disease risk in the general population: a Mendelian randomization study
Authors: Zheng Jie , Xu Min , Walker Venexia , Yuan Jinqiu , Korologou-Linden Roxanna , Robinson Jamie , Huang Peiyuan , Burgess Stephen , Au Yeung Shiu Lun , Luo Shan , Holmes Michael V. , Smith George Davey , Ning Guang , Wang Weiqing , Gaunt Tom R. , Bi Yufang 
Published: April 2022

AbstractAims/hypothesisMetformin use has been associated with reduced incident dementia in diabetic patients in observational studies. However, the causality between the two in the general population is unclear. This study uses Mendelian randomization (MR) to investigate the causal effect of metformin targets on Alzheimer’s disease (AD) 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 of 527,138 middle-aged Europeans, including 71,880 AD or AD-by-proxy patients. MR estimates representing lifelong metformin use on AD and cognitive function in the general population were generated. Effect of expression level of 22 metformin-related genes in brain cortex (N=6,601 donors) on AD was further estimated.ResultsGenetically proxied metformin use equivalent to a 6.75 mmol/mol (1.09%) reduction of HbA1c was associated with 4% lower odds of AD (odds ratio [OR]=0.964, 95%CI=0.982∼0.946, P=1.06×10−4) in non-diabetic individuals. One metformin target, mitochondrial complex 1 (MCI), showed a robust effect on AD (OR=0.88, P=4.73×10−4) that was independent of AMPK. MR of expression in brain cortex tissue showed that decreased MCI-related gene, NDUFA2, expression was associated with reduced AD risk (OR=0.95, P=4.64×10−4) and less cognitive decline.Conclusion/interpretationMetformin use is likely to cause reduced AD risk in the general population. Mitochondrial function and the NDUFA2 gene are likely mechanisms of action in dementia protection.Research in contextWhat is already known about this subjectMetformin is an anti-diabetic drug with repurposing potential for dementia prevention.In a search of PubMed, Embase and clinicaltrials.gov, a few observational studies suggested the association of metformin use with reduced dementia incidence in diabetic patientsWhat is the key question?What is the effect of genetically proxied metformin use on Alzheimer’s disease (AD) and cognitive function in the general population, especially for those without diabetes? Is the causal role between the two at least partly influenced by mechanisms in the brain?What are the new findings?In a Mendelian randomization analysis of over 527,138 individuals (71,880 AD or AD-by-proxy cases), genetically proxied metformin use equivalent to a 6.75 mmol/mol (1.09%) reduction of HbA1c was associated with 14% lower odds of AD (odds ratio=0.86), where mitochondrial complex I is a key effect modifier.Expression level of a mitochondrial complex I related gene, NDUFA2, showed an effect on reducing AD risk and less cognitive decline in brain.How might this impact on clinical practice in the foreseeable future?Our study predicts the efficacy of metformin on reducing AD risk and reducing cognitive decline in the general population, especially for those without diabetes.Mitochondrial function and a mitochondrial related gene, NDUFA2, could be considered as a novel drug target for dementia prevention.Graphical abstractTweet Effect of metformin targets reduced 4% of Alzheimer’s disease risk in non-diabetic individuals. @oldz84 @tomgaunt @mendel_random @mrc_ieu