Epigenetic Factors in Late-Onset Alzheimer’s Disease: MTHFR and CTH Gene Polymorphisms, Metabolic Transsulfuration and Methylation Pathways, and B Vitamins

Abstract

DNA methylation and other epigenetic factors are important in the pathogenesis of late-onset Alzheimer’s disease (LOAD). Methylenetetrahydrofolate reductase (MTHFR) gene mutations occur in most elderly patients with memory loss. MTHFR is critical for production of S-adenosyl-l-methionine (SAM), the principal methyl donor. A common mutation (1364T/T) of the cystathionine-γ-lyase (CTH) gene affects the enzyme that converts cystathionine to cysteine in the transsulfuration pathway causing plasma elevation of total homocysteine (tHcy) or hyperhomocysteinemia—a strong and independent risk factor for cognitive loss and AD. Other causes of hyperhomocysteinemia include aging, nutritional factors, and deficiencies of B vitamins. We emphasize the importance of supplementing vitamin B12 (methylcobalamin), vitamin B9 (folic acid), vitamin B6 (pyridoxine), and SAM to patients in early stages of LOAD.

Helicobacter pylori, Vascular Risk Factors and Cognition in U.S. Older Adults

“…It has been shown in vitamin B 12 absorption studies that H. pylori infection is associated with food-cobalamin malabsorption [3], which can be reversed after H. pylori eradication [4]. Low levels of B 12 and high Hcy have been found to be associated in the U.S. population; elevated Hcy is an independent risk factor for dementia [31,32] and vitamin B 12 deficiency is a well-recognized cause of dementia [5,29,30].…”

“…H. pylori infection causes gastritis, peptic ulcer disease, non-cardia adenocarcinoma, and lymphoma of the stomach [2], as well as malabsorption of cobalamin (vitamin B 12 ) due to reduced stomach acidity from H. pylori infection that blocks release of cobalamin from dietary protein; moreover, chronic inflammation with bacterial overgrowth increases consumption of cobalamin resulting in low serum levels [3,4]. Accumulation of homocysteine (Hcy)-an independent vascular risk factor-resulting from decreases of cobalamin and folate is associated with late-onset Alzheimer's disease (LOAD) [5]. A number of studies have previously raised the possibility that H. pylori could be a risk factor for stroke and coronary artery disease [6][7][8][9][10][11][12][13][14].…”

Differential Methylation in APOE Genes (Chr19; exon four; from 44,909,188 to 44,909,373) and Increased Apolipoprotein E Plasmatic Levels in Subjects with Mild Cognitive Impairment”

“…The current findings might have implications for clinical practice as these genetic phenotypes, detected from peripheral blood samples, can potentially be used as early biomarkers to MCI. Moreover, if a high-risk profile for vascular cognitive impairment is identified, [14] clinical intervention strategies to treat and control modifiable risk factors [16] associated with MCI progression can be intensively implemented in order to prevent or delay the development of dementia. [14,16] Further studies are needed to confirm these findings and to clarify the risk-association of DNA methylation from different tissues with MCI and to determine whether the clinical intervention of controlling modifiable risk factors found in dementia can modify the DNA methylation pattern and reduce the risk for MCI progression.…”

“…This could be attributed to the fact that LA regions, as part of developing countries, fail to diagnose individuals with MCI and/or to identify individuals at high risk for dementia. Additionally, Hispanics have higher rates of a number of vascular risk factors associated with both MCI and dementia, such as hypertension, diabetes mellitus, smoking, sedentary lifestyle, hyperhomocysteinemia, obesity and dyslipidemia [12][13][14][15][16].…”

DNA methylation in the pathology of Alzheimer's disease: from gene to cognition

“…A mutation in MTHFR and low dietary intake of vitamins B9 and B12 may delay the clearance of HCY and eventually results in elevated levels of HCY in the plasma. 53 The above dietary deficiency was also found to lower the activity of DNMTs, while at the same time, enhancing the activity of DNA demethylase, which may exert a large-scale effect on genomic regulation. 54 Clinically, a reduced level of SAM was detected in the cerebrospinal fluid of AD patients, 55 further strengthening the significance of the methionine cycle on AD pathology.…”