Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jun;13(3):715-725.
doi: 10.1007/s40120-024-00609-6. Epub 2024 Apr 9.

Methotrexate and the Risk of Dementia: A Two-Sample Mendelian Randomization Study

Xiao-Na Ma  1   2 , Wei Feng  1   2 , Shu-Lin Chen  1   2 , Xiao-Qin Zhong  1   2 , Chang-Song Lin  3   4 , Qiang Xu  5   6
Affiliations

Methotrexate and the Risk of Dementia: A Two-Sample Mendelian Randomization Study

Xiao-Na Ma et al. Neurol Ther. 2024 Jun.

Abstract

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.

Keywords: Causal inference; Dementia; Genome-wide association studies; Mendelian randomization; Methotrexate.

PubMed Disclaimer

Conflict of interest statement

The authors declare that there is no conflict of interest in the research process.

Figures

Fig. 1
Fig. 1
Study flowchart
Fig. 2
Fig. 2
Scatterplot (results of MR analysis). MR Mendelian randomization, SNP single-nucleotide polymorphism
Fig. 3
Fig. 3
Forest plot (methotrexate and dementia). MR Mendelian randomization
Fig. 4
Fig. 4
Sensitivity analysis (methotrexate and dementia). MR Mendelian randomization
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Zhu Z, Yu Q, Leng X, et al. Can low-dose methotrexate reduce effusion-synovitis and symptoms in patients with mid- to late-stage knee osteoarthritis? Study protocol for a randomised, double-blind, and placebo-controlled trial. Trials. 2020;21:795. doi: 10.1186/s13063-020-04687-3. - DOI - PMC - PubMed
    1. Zimmerman MC, Clemens DL, Duryee MJ, et al. Direct antioxidant properties of methotrexate: inhibition of malondialdehyde-acetaldehyde-protein adduct formation and superoxide scavenging. Redox Biol. 2017;13:588–593. doi: 10.1016/j.redox.2017.07.018. - DOI - PMC - PubMed
    1. Zorlu M, Kiskac M, Karatoprak C, et al. Pott’s disease and hypercalcemia in a patient with rheumatoid arthritis receiving methotrexate monotherapy. Indian J Pharmacol. 2013;45:631–633. doi: 10.4103/0253-7613.121385. - DOI - PMC - PubMed
    1. Brown PM, Pratt AG, Isaacs JD. Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers. Nat Rev Rheumatol. 2016;12:731–742. doi: 10.1038/nrrheum.2016.175. - DOI - PubMed
    1. Zhu H, Li R, Da Z, et al. Remission assessment of rheumatoid arthritis in daily practice in China: a cross-sectional observational study. Clin Rheumatol. 2018;37:597–605. doi: 10.1007/s10067-017-3850-z. - DOI - PubMed

LinkOut - more resources