Metformin Use Likely Reduces Alzheimer's Disease Risk

Madeleine Haase

April 21, 2022

The study covered in this summary was published in medRxiv.org as a preprint and has not yet been peer reviewed.

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.

Disclosures

  • The authors have disclosed no relevant financial relationships.

  • Jie Zheng is supported by the Academy of Medical Sciences Springboard Award, the Wellcome Trust, the Government Department of Business, Energy and Industrial Strategy, the British Heart Foundation and Diabetes UK.

  • Jie Zheng is funded by the Vice-Chancellor Fellowship from the University of Bristol.

This is a summary of a preprint research study, "Evaluating the Efficacy and Mechanism of Metformin Targets on Reducing Alzheimer's Disease Risk in the General Population: A Mendelian Randomization Study," written by Jie Zheng from the Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, and colleagues, published on MedRxiv.org and provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on medRxiv.org.

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