MTHFR C677T and A1298C polymorphisms in dementia susceptibility: evidence from a meta-analytic investigation with disease-specific and ethnicity-stratified analyses
Background Alzheimer’s disease (AD) and vascular dementia (VaD) have become significant global health challenges. Recent research evidence indicates a close comorbidity between AD and cerebral small vessel disease. The C677T (rs1801133, also known as c.665C > T) and A1298C (rs1801131) polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene have been associated with both conditions, though conclusions vary across studies. Methods We conducted a systematic search of PubMed, Embase, Web of Science and the Cochrane Library, covering the period from the inception of these databases to January 2026. Studies reporting the distribution of MTHFR C677T and/or A1298C genotypes were included. A fixed-effects model was used to calculate the pooled odds ratio (OR) and its 95% confidence interval (CI). Sensitivity analyses using random-effects models were also performed to test the robustness of the findings. Subgroup analyses were performed according to type of dementia and ethnicity. Results A total of 26 C677T studies and 8 A1298C studies were included. In the allele contrast model (T vs. C), C677T was significantly associated with dementia (OR = 1.40, 95% CI 1.05–1.87, p = 0.021) and AD (OR = 1.40, 95% CI 1.01–1.93, p = 0.043), but no statistically significant association was observed for VaD (OR = 1.42, 95% CI 0.76–2.66, p = 0.266). C677T showed no significant association under homozygous, heterozygous, dominant, or recessive inheritance models. No significant heterogeneity in association was observed across racial subgroups. A1298C showed no significant association with dementia under any genetic model. Conclusion This meta-analysis showed that the MTHFR C677T T allele is associated with the risk of AD in an allele-dependent model, with a similar but non-significant trend for VaD. The A1298C polymorphism shows no association with either type of dementia. These findings suggest that C677T genotyping may aid AD risk stratification in research, but it requires prospective validation and gene-environment studies before clinical use.