Evaluating the efficacy and mechanism of metformin targets on reducing Alzheimer’s disease risk in the general population: a Mendelian randomization study
Abstract
Abstract Aims/hypothesis Metformin 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. 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 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. Results Genetically proxied metformin use equivalent to a 6.75 mmol/mol (1.09%) reduction of HbA 1c 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 ,…
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