Key Takeaways :
Use of Metformin likely reduces the risk for Alzheimer’s disease (AD) in the general population.
Expression of a mitochondrial complex I–related gene, NDUFA2, reduced AD risk and was associated with less cognitive decline in the brain.
Mitochondrial function and the NDUFA2 gene are likely mechanisms of action in dementia protection.
Why This Matters?
Dementia has been associated with treatment status of diabetes.
Metformin is an antidiabetic drug that shows potential in preventing dementia.
Study Design
Genetic proxies for the effects of metformin drug targets were identified as variants in the gene for the corresponding target that is associated with A1c level (N = 344,182) and expression level of the corresponding gene (N ≤ 31,684).
The cognitive outcomes were derived from genome-wide association studies of 527,138 middle-aged Europeans, including 71,880 AD or AD-by-proxy patients.
Mendelian randomization 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 = 6601 donors) on AD was further estimated.
Key Results
Genetically proxied metformin use equivalent to a 6.75 mmol/mol (1.09%) reduction of A1c was associated with 4% lower odds of AD (P = 1.06 × 10-4) in individuals who did not have diabetes.
One metformin target, mitochondrial complex 1 (MCI), showed a robust effect on AD (P = 4.73 × 10-4) that was independent of AMP–activated protein kinase.
Mendelian randomization of expression in brain cortex tissue showed that decreased expression of the MCI-related gene NDUFA2 was associated with reduced AD risk (P = 4.64 × 10-4) and less cognitive decline.
Limitations
By the nature of Mendelian randomization, this study’s estimates represent the average linear causal effects across the general population.
The Mendelian randomization analysis of molecular phenotypes uses a small number of genetic predictors that can lead to weak instrument bias.
The biology of metformin is only partly understood. There is a possibility that this study missed targets and genes that are still under investigation or are difficult to target using existing genetic tools.
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