Background. Methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133) gene polymorphisms are related to a growing risk of Alzheimer’s disease; however, whether this association applies to mild cognitive impairment (MCI) remains unclear. Objective. We conducted this meta-analysis to evaluate the contribution of MTHFR C677T (rs1801133) gene variants to the risk of MCI. Methods. PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases were searched from their inception to March 21, 2021, with language restricted to English or Chinese. We used fixed or random effects to examine the association between MTHFR C677T (rs1801133) gene variants and MCI susceptibility. Forest plots of pooled odds ratios (ORs) and 95% confidence intervals (CIs) were generated. Results. Eight articles with 2,175 participants were included in the present meta-analysis. There was no significant association between MTHFR C677T (rs1801133) gene variants and MCI susceptibility under the allelic (OR, 1.318; 95% CI, 0.964–1.801; ), dominant (OR, 1.296; 95% CI, 0.925–1.817; ), recessive (OR, 1.397; 95% CI, 0.845–2.312; ), heterozygous (OR, 1.031; 95% CI, 0.855–1.243; ), or homozygous (OR, 1.506; 95% CI, 0.850–2.667; ) models. Conclusion. The results suggest that MTHFR C677T (rs1801133) gene polymorphisms are not associated with MCI susceptibility. However, large-scale studies covering various factors are required.

Background: Alzheimer's disease (AD) is a debilitating neurodegenerative disorder. Although peripheral immune cells have been implicated in the pathology of AD, the causal relationship between peripheral blood immune cells and AD remains to be fully elucidated. Objective: To examine the association between peripheral blood immune cell phenotypes and AD, mediated by peripheral blood metabolite, a two-step Mendelian randomization (MR) analysis was performed. Methods: Summary statistics were obtained from the two largest independent cohorts. We explored bidirectional univariable MR analysis to explore causal associations and assessed the mediated proportion of peripheral blood metabolite phenotypes. Results: The proportion of IgD + CD38- B cells (Bm1) were found to increase the risk of AD in both the FinnGen database ( p  = 0.033) and the UK Biobank ( p  = 0.034). Conversely, hematopoietic stem cells were associated with a decreased risk of AD in the FinnGen database ( p  = 0.045) and the UK Biobank ( p  = 0.017). Mediation analysis revealed indirect effects of the proportion of Bm1 on AD through cysteine levels (β = 5 × 10 ⁻³ ), Acetylcarnitine (C2) to propionylcarnitine (C3) ratio (β = 4.5 × 10 ⁻³ ), and Gamma-glutamyl-alpha-lysine levels (β = 2.6 × 10 ⁻³ ), with mediated proportion of 19.4%, 16.9% and 9.6% of the total effect, respectively. Additionally, hematopoietic stem cells influenced AD through Glycolithocholate sulfate levels (β = 1.5 × 10 ⁻³ ), with a mediated proportion of 3.5%. Conclusions: Our findings demonstrate that two peripheral blood immune cell phenotypes impact the risk of AD. These immune cells may influence AD through various peripheral blood metabolite, identifying potential intervention targets for individuals at risk.