Background: B vitamins in the one-carbon metabolism pathway (folate, vitamin B₆, and vitamin B₁₂) have been implicated in DNA methylation, and their deficiency may contribute to cognitive decline through increased homocysteine (Hcy) levels and subsequent oxidative damage. The aim of this study was to investigate whether B vitamin deficiency and increased Hcy could interact with DNA methylation of oxidative-related genes and exacerbate cognitive impairment.Methods: Participants were selected from a large cohort study entitled the Effects and Mechanism Investigation of Cholesterol and Oxysterol on Alzheimer’s disease (EMCOA) study. We included 2533 participants who completed a selection of comprehensive cognitive tests and a semiquantitative food frequency questionnaire (FFQ) and were followed for an average of 2.3 years. The longitudinal effects of B vitamin intake on cognitive decline were examined using linear mixed-effect models. Seven mild cognitive impairment (MCI) patients, in the predementia stage of Alzheimer’s disease (AD), and fivev healthy controls were selected for the discovery of genome-wide differentially methylated CpG sites. Candidate oxidative stress-related genes significantly correlated with serum levels of B vitamins were selected for validation in 102 MCI patients and 68 controls. The correlations between DNA methylation levels and serum concentrations of B vitamins and oxidative biomarkers were analyzed with Spearman’s correlation. The interactive effects of DNA methylation and B vitamins on cognitive performance were further evaluated by multiple linear regression.Results: In the prospective analysis, inadequate dietary intake of vitamin B₁₂was significantly associated with accelerated cognitive decline, whereas adequate folate, vitamin B₆, and vitamin B₁₂intakes were significantly associated with better cognitive reserve. In the case-control analysis, the DNA methylation levels of NUDT15 and TXNRD1 were examined, and significantly hypermethylated sites were identified in MCI patients. Significant correlations of hypermethylated sites with serum levels of folate, homocysteine (Hcy), and oxidative biomarkers were observed, and interactive effects of B vitamins and hypermethylated sites were significantly associated with cognitive performance.Conclusion: Adequate dietary folate at baseline predicted a better cognitive reserve, while decreased serum levels of B vitamins may contribute to cognitive impairment by affecting methylation levels of specific redox-related genes.Trial registration: EMCOA, ChiCTR-OOC-17011882, Registered 5th, July 2017-Retrospectively registered,http://www.medresman.org/uc/project/projectedit.aspx?proj=2610Graphical

To investigate the relationship between oxysterols and mild cognitive impairment (MCI) in a matched case–control study. The plasma levels of four oxysterols, 27–hydroxycholesterol (27–OHC), 24S–hydroxycholesterol (24S–OHC), 7α–hydroxycholesterol (7α–OHC) and 7β–hydroxycholesterol (7β–OHC), were analyzed by High Performance Liquid Chromatography–Mass Spectrometry (HPLC–MS) and compared between 70 MCI patients and 140 matched controls with normal cognition. The odds ratio (OR) was calculated using logistic analyses to assess the association between oxysterols and MCI. Compared with controls with normal cognition, plasma level of 27–OHC was significantly higher in MCI patients. Logistic analyses suggested high plasma level of 27–OHC was significantly associated with MCI even after multivariate adjustment (OR = 2.86, 95 % CI: 1.52 ~ 5.37). Our findings suggested that the increased plasma level of 27-OHC was associated with MCI, suggesting high plasma levels of 27-OHC may pay an important role in the development of MCI.

The principal aim of this study was to demonstrate the gender-specific cognitive patterns among middle-aged and elderly Chinese adults, investigate the risk factors on global and domain-specific cognitive performance in men and women, respectively, and report demographically adjusted norms for cognitive tests. The Effects and Mechanism of Cholesterol and Oxysterol on Alzheimer’s disease (EMCOA) study enrolled 4573 participants aged 50–70 years in three Chinese cities. All participants underwent an extensive neuropsychological test battery. Composite scores for specific domains were derived from principal component analysis (PCA). Multivariate linear regression models were used to determine gender-specific risk factors and demographically adjusted normative data. Three cognitive domains of verbal memory, attention/processing speed/executive function, and cognitive flexibility were extracted. A female advantage in verbal memory was observed regardless of age, whereas men tended to outperform women in global cognition and attention/processing speed/executive function. The effects of education on women were more substantial than men for general cognition and attention/processing speed/executive function. For all the cognitive tests, regression-based and demographically adjusted normative data were calculated. There is a need for gender-specific intervention strategies for operationalizing cognitive impairment. EMCOA, ChiCTR-OOC-17011882 . Retrospectively registered on 5 July 2017.