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.
Highlights
Most genetic research on late-onset Alzheimer’s disease (LOAD) has focused on genome-wide association studies (GWAS) that have provided low effect size results in general, with the exception of apolipoprotein E (ApoE) [1,2]
This review focuses on DNA methylation dynamics and other epigenetic changes, including the role of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and its metabolic pathways in aging and LOAD pathology [11]
We review polymorphisms of the cystathionine-gamma(γ)-lyase (CTH) gene [12], the enzyme that converts cystathionine to cysteine in the transsulfuration pathway and is responsible for plasma elevation of total homocysteine
Summary
Most genetic research on late-onset Alzheimer’s disease (LOAD) has focused on genome-wide association studies (GWAS) that have provided low effect size results in general, with the exception of apolipoprotein E (ApoE) [1,2]. Studies of monozygotic twins with Alzheimer’s disease (AD) showed discordance in onset and progression indicating a role for nongenetic factors in disease pathogenesis [3]. For these reasons, genetic research turned to epigenetic modifications using epigenome-wide association studies (EWAS) in the last few years [4,5]. Epigenetic refers to potentially heritable and nonheritable modifications in gene expression induced by environmental factors without changes in DNA base sequences [1]. This review focuses on DNA methylation dynamics and other epigenetic changes, including the role of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and its metabolic pathways in aging and LOAD pathology [11]. Experimental antiaging epigenetic interventions attempt to reverse age-related changes in DNA methylation [10]
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