Abstract
BackgroundB 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.MethodsParticipants 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.ResultsIn the prospective analysis, inadequate dietary intake of vitamin B12 was significantly associated with accelerated cognitive decline, whereas adequate folate, vitamin B6, and vitamin B12 intakes 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.ConclusionAdequate 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 registrationEMCOA, ChiCTR-OOC-17011882, Registered 5th, July 2017-Retrospectively registered, http://www.medresman.org/uc/project/projectedit.aspx?proj=2610Graphical
Highlights
B vitamins in the one-carbon metabolism pathway have been implicated in DNA methylation, and their deficiency may contribute to cognitive decline through increased homocysteine (Hcy) levels and subsequent oxidative damage
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
The 4th quartile of vitamin B6 was negatively associated with the Montreal Cognitive Assessment (MoCA) and digit span forwards (DSF) scores, suggesting that vitamin B6 intake much higher than the RNI may have adverse effects on global cognition and attention
Summary
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. As a leading chronic disease contributing to disability and dependence, AD is characterized by progressive cognitive decline and growing functional impairment, beginning with mild difficulties with instrumental activities of daily living (ADL), such as using a telephone and managing medication, and ending with the loss of basic ADL, such as bathing, eating, and dressing [2]. Dementia refers to severe brain disorders associated with largely generalized cognitive dysfunction, behavioral disturbances, loss of basic ADL, disability and dependency associated with personal, social, and economic burden [4]. Such concomitant cognitive and functional difficulties increase dependence to negatively affect quality of life (QOL), which is a multidimensional construct integrating cognitive function, physical function, social interactions, mental well-being, and mood [5]. The exploration of strategies to prevent or delay the onset of AD, including identification of risk factors of MCI, has become a major priority of global public health
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