Evaluating the efficacy and mechanism of metformin targets on reducing Alzheimer's disease risk in the general population: a Mendelian randomisation study

Abstract

Aims/hypothesis: Metformin use has been associated with reduced incidence of dementia in diabetic individuals in observational studies. However, the causality between the two in the general population is unclear. This study uses Mendelian randomisation (MR) to investigate the causal effect of metformin targets on Alzheimer's disease 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 527,138 middle-aged Europeans, including 71,880 with Alzheimer's disease or Alzheimer's disease-by-proxy. MR estimates representing lifelong metformin use on Alzheimer's disease 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 Alzheimer's disease was further estimated.

Results: Genetically proxied metformin use, equivalent to a 6.75 mmol/mol (1.09%) reduction on HbA_1c, was associated with 4% lower odds of Alzheimer's disease (OR 0.96 [95% CI 0.95, 0.98], p=1.06×10^-4) in non-diabetic individuals. One metformin target, mitochondrial complex 1 (MCI), showed a robust effect on Alzheimer's disease (OR 0.88, p=4.73×10^-4) that was independent of AMP-activated protein kinase. MR of expression in brain cortex tissue showed that decreased MCI-related gene (NDUFA2) expression was associated with lower Alzheimer's disease risk (OR 0.95, p=4.64×10^-4) and favourable cognitive function.

Conclusions/interpretation: Metformin use may cause reduced Alzheimer's disease risk in the general population. Mitochondrial function and the NDUFA2 gene are plausible mechanisms of action in dementia protection.

Keywords: Alzheimer’s disease; Brain expression; Cognitive function; Dementia; Mendelian randomisation; Metformin targets; Mitochondrial function.

Fig. 1

Diagram of the study design. This MR study aims to identify the causal relationships between metformin (drug), five metformin-related targets (drug targets), general metformin effects (exposure), expression of 22 metformin-related genes (exposures), and Alzheimer’s disease/cognitive function (outcomes). Three levels of evidence were used to construct the causal atlas, including literature and biological and genetic evidence. AD, Alzheimer’s disease; CF, cognitive function

Fig. 2

MR analysis of metformin’s effects on Alzheimer’s disease and cognitive function. The OR (a) and the SD unit change (b) are shown for the five metformin-related targets. Purple squares represent the effects of the five targets on the two outcomes; blue diamonds represent the fixed-effect and random-effect meta-analyses estimating the general effect across the five targets. One SD unit lowering of HbA_1c refers to 6.75 mmol/mol (1.09%) reduction in HbA_1c

Fig. 3

MR effects of NDUFA2 expression in brain cortex on Alzheimer’s disease and cognitive function. (a) MR estimates, presented as log(OR) of outcome per unit change in expression of NDUFA2. Bars show the 95% CI of the effect estimates. (b) Regional plot of NDUFA2 expression in the cis-acting NDUFA2 region. (c) Regional plot of Alzheimer’s disease in the NDUFA2 region. Result of other genes are listed in ESM Table 13. One unit refers to 1 SD of the expression level change of NDUFA2

Fig. 4

Triangulation of observational estimate from meta-analysis, one-sample MR evidence and two-sample MR evidence for metformin effect on cognitive function. Data are presented as SD unit increase of cognitive function per 6.75 mmol/mol (1.09%) reduction of HbA_1c via metformin use. One unit refers to 1 SD change in cognitive function. Bars show the 95% CI of the effect estimates