# Benefits of Metformin Repurposed for Alzheimer’s Disease Prevention, Evidence From Mendelian Randomization

## TL;DR

Metformin, a diabetes drug, may help prevent Alzheimer's disease by affecting mitochondrial function and biological aging, according to evidence from genetic studies.

## Contribution

The paper presents new evidence from Mendelian randomization studies suggesting metformin's protective effects against Alzheimer's beyond its glucose-lowering properties.

## Key findings

- Metformin gene expression is linked to reduced Alzheimer's disease risk in the general population.
- Metformin may protect against Alzheimer's by improving mitochondrial function and reducing mitochondrial complex 1-related gene expression.
- Metformin benefits include slowing biological aging and improving phenotypic age and telomere length.

## Abstract

Previous observational studies reported a decreased incidence of dementia in type 2 diabetic patients who take metformin compared to other hypoglycemic drugs. The possible neuroprotective effects of metformin also showed dose-dependent effects, either the daily dosage or the accumulative dosages taken. However, the Mendelian randomization (MR) study, one of the causal inference methods robust to confounders and reverse causation, poses some challenges because no specific target genes are attributable to metformin. Instead, researchers have based their MR study on a downstream biomarker such as A1c. This talk will review current evidence of MR studies on metformin exposure that look through the mechanistic effects of metformin other than glycemic control reflected by A1c in more detail. A recent study showed evidence of metformin gene expression in reducing the risk of Alzheimer’s disease (AD) in the general population. Plausible mechanisms in AD protection include mitochondrial function and decreased mitochondrial complex 1-related gene expression. Another mechanistic link might be through a reduction in biological aging, an important process underlying AD pathogenesis. The MR studies of metformin effects showed benefits on phenotypic age and leukocyte telomere length. Our future goal is to thoroughly investigate the causal inference of metformin and other repurposed drugs for AD prevention through MR studies. A large number of observational study participants enable various sensitivity analyses that can show how these protective effects differ in different population characteristics and thus help identify patients who would benefit most from metformin following the Precision Gerontology concept.