Methotrexate and the Risk of Dementia: A Two-Sample Mendelian Randomization Study
Xiao-Na Ma1,2, Wei Feng1,2, Shu-Lin Chen1,2
1State Key Laboratory of Traditional Chinese Medicine Syndrome, The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
Introduction:
Recent studies have suggested a potential association between methotrexate use and an increased risk of dementia. However, the causal relationship between methotrexate and dementia remains unclear. This study aims to investigate the potential causal effect of methotrexate use on the risk of dementia using a two-sample Mendelian randomization (TSMR) approach.
Methods:
We conducted a TSMR study using summary statistics from genome-wide association studies (GWAS) of methotrexate use and dementia. We obtained genetic instruments for methotrexate use from a large-scale GWAS meta-analysis and genetic instruments for dementia from a separate GWAS meta-analysis. We performed several statistical analyses, including inverse-variance weighted (IVW), weighted median (WM1), weighted mode (WM2), and MR-Egger regression methods, to estimate the causal effect of methotrexate on dementia risk.
Results:
Our TSMR analysis showed a significant positive association between genetic predisposition to methotrexate use and dementia risk. The IVW method estimated a causal odds ratio (OR) of 0.476 [95% confidence interval (CI) 0.362-0.626] per unit increase in the log odds ratio of methotrexate use. WM1, WM2, and MR-Egger methods provided consistent results.
Conclusion:
The findings of this mendelian randomization (MR) study suggest a potential causal effect of methotrexate use on the risk of dementia. However, further research is needed to validate these findings and explore the underlying mechanisms. Since methotrexate is widely prescribed for various autoimmune diseases, a better understanding of its potential impact on dementia risk is crucial for optimizing treatment strategies and addressing potential adverse effects.
Insights
This study used Mendelian randomization to investigate if methotrexate use causes dementia. Findings suggest a potential causal link, highlighting the need for further research into methotrexate
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Emerging evidence suggests a link between methotrexate (MTX) and increased dementia risk.
- The causal relationship between MTX use and dementia remains uncertain.
- This study investigates the potential causal effect of MTX on dementia risk.
Purpose of the Study:
- To determine if methotrexate use causally influences dementia risk.
- To employ a two-sample Mendelian randomization (TSMR) approach for causal inference.
Main Methods:
- Utilized summary statistics from large-scale genome-wide association studies (GWAS) for MTX use and dementia.
- Selected genetic instruments for MTX use and dementia.
- Applied multiple TSMR methods including IVW, weighted median, and MR-Egger regression.
Main Results:
- TSMR analysis revealed a significant positive association between genetic liability to MTX use and dementia risk.
- The inverse-variance weighted (IVW) method indicated a causal odds ratio (OR) of 0.476 (95% CI 0.362-0.626).
- Weighted median and MR-Egger methods corroborated the findings.
Conclusions:
- Mendelian randomization analysis suggests a potential causal effect of MTX use on dementia risk.
- Further research is warranted to confirm these findings and elucidate underlying mechanisms.
- Understanding MTX's impact on dementia is crucial for optimizing treatment of autoimmune diseases.
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