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

Overview

Journal Neurol Ther

Publisher Springer

Specialty Neurology

Date 2024 Apr 9

PMID 38592337

Authors

Xiao-Na Ma

Wei Feng

Shu-Lin Chen

Xiao-Qin Zhong

Chang-Song Lin

Qiang Xu

Affiliations

Soon will be listed here.

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.

References

Zhu Z, Yu Q, Leng X, Han W, Li Z, Huang C . 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(1):795. PMC: 7493135. DOI: 10.1186/s13063-020-04687-3. View

Zimmerman M, Clemens D, Duryee M, Sarmiento C, Chiou A, Hunter C . Direct antioxidant properties of methotrexate: Inhibition of malondialdehyde-acetaldehyde-protein adduct formation and superoxide scavenging. Redox Biol. 2017; 13:588-593. PMC: 5552384. DOI: 10.1016/j.redox.2017.07.018. View

Zorlu M, Kiskac M, Karatoprak C, Cakirca M, Yavuz E, Cetin G . Pott's disease and hypercalcemia in a patient with rheumatoid arthritis receiving methotrexate monotherapy. Indian J Pharmacol. 2013; 45(6):631-3. PMC: 3847260. DOI: 10.4103/0253-7613.121385. View

Brown P, Pratt A, Isaacs J . Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers. Nat Rev Rheumatol. 2016; 12(12):731-742. DOI: 10.1038/nrrheum.2016.175. View

Zhu H, Li R, Da Z, Bi L, Li X, Li Y . Remission assessment of rheumatoid arthritis in daily practice in China: a cross-sectional observational study. Clin Rheumatol. 2017; 37(3):597-605. DOI: 10.1007/s10067-017-3850-z. View

Micha R, Imamura F, Wyler von Ballmoos M, Solomon D, Hernan M, Ridker P . Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol. 2011; 108(9):1362-70. PMC: 3196048. DOI: 10.1016/j.amjcard.2011.06.054. View

Zhu S, Wang Q, Jiang J, Luo Y, Sun Z . A conjugate of methotrexate and an analog of luteinizing hormone releasing hormone shows increased efficacy against prostate cancer. Sci Rep. 2016; 6:33894. PMC: 5032167. DOI: 10.1038/srep33894. View

Zhou M, Zhang X, Yang Y, Liu Z, Tian B, Jie J . Carrier-free functionalized multidrug nanorods for synergistic cancer therapy. Biomaterials. 2013; 34(35):8960-7. DOI: 10.1016/j.biomaterials.2013.07.080. View

Guevara N, Hernandez T, Rosado F, Gupta S . Pericarditis Induced by Methotrexate: A Case Report and Literature Review. Cureus. 2023; 15(6):e40257. PMC: 10335726. DOI: 10.7759/cureus.40257. View

10.

Lim A, Gaffney K, Scott D . Methotrexate-induced pancytopenia: serious and under-reported? Our experience of 25 cases in 5 years. Rheumatology (Oxford). 2005; 44(8):1051-5. DOI: 10.1093/rheumatology/keh685. View

11.

Yamamoto A, Itoh T, Nasu R, Kajiwara E, Nishida R . Sodium alginate inhibits methotrexate-induced gastrointestinal mucositis in rats. Biol Pharm Bull. 2013; 36(10):1528-34. DOI: 10.1248/bpb.b13-00154. View

12.

Zhao Q, Tan L, Wang H, Jiang T, Tan M, Tan L . The prevalence of neuropsychiatric symptoms in Alzheimer's disease: Systematic review and meta-analysis. J Affect Disord. 2015; 190:264-271. DOI: 10.1016/j.jad.2015.09.069. View

13.

Magierski R, Sobow T, Schwertner E, Religa D . Pharmacotherapy of Behavioral and Psychological Symptoms of Dementia: State of the Art and Future Progress. Front Pharmacol. 2020; 11:1168. PMC: 7413102. DOI: 10.3389/fphar.2020.01168. View

14.

Mellinger T, Forester B, Vogeli C, Donelan K, Gulla J, Vetter M . Impact of dementia care training on nurse care managers' interactions with family caregivers. BMC Geriatr. 2023; 23(1):16. PMC: 9832603. DOI: 10.1186/s12877-022-03717-w. View

15.

Rattinger G, Schwartz S, Daniel Mullins C, Corcoran C, Zuckerman I, Sanders C . Dementia severity and the longitudinal costs of informal care in the Cache County population. Alzheimers Dement. 2015; 11(8):946-54. PMC: 4506892. DOI: 10.1016/j.jalz.2014.11.004. View

16.

Zulfiqar S, Garg P, Nieweg K . Contribution of astrocytes to metabolic dysfunction in the Alzheimer's disease brain. Biol Chem. 2019; 400(9):1113-1127. DOI: 10.1515/hsz-2019-0140. View

17.

Zheng Y, Zhang J, Zhao Y, Zhang Y, Zhang X, Guan J . Curcumin protects against cognitive impairments in a rat model of chronic cerebral hypoperfusion combined with diabetes mellitus by suppressing neuroinflammation, apoptosis, and pyroptosis. Int Immunopharmacol. 2021; 93:107422. DOI: 10.1016/j.intimp.2021.107422. View

18.

Zulke A, Luppa M, Kohler S, Riedel-Heller S . [What does the population know about risk and protective factors for dementia? An international review of the current state of knowledge in various countries]. Nervenarzt. 2023; 94(5):384-391. DOI: 10.1007/s00115-023-01471-x. View

19.

Zulke A, Luppa M, van Boxtel M, Deckers K, Heger I, Kohler S . Older adults' awareness of modifiable risk and protective factors for dementia and interest in eHealth interventions for brain health: a comparison between the Netherlands and Germany. BMC Public Health. 2023; 23(1):2321. PMC: 10668348. DOI: 10.1186/s12889-023-17247-6. View

20.

Zuin M, De Giorgio R, Capatti E, Boschetti E, Zuliani G . Inflammatory bowel disease as a new risk factor for dementia. Aging Clin Exp Res. 2022; 34(7):1725-1728. DOI: 10.1007/s40520-022-02076-1. View