One-carbon metabolism and Alzheimer's disease: focus on epigenetics

Alzheimer's disease (AD) represents the most common form of dementia in the elderly, characterized by progressive loss of memory and cognitive capacity severe enough to interfere with daily functioning and the quality of life. Rare, fully penetrant mutations in three genes (APP, PSEN1 and PSEN2) are responsible for familial forms of the disease. However, more than 90% of AD is sporadic, likely resulting from complex interactions between genetic and environmental factors. Increasing evidence supports a role for epigenetic modifications in AD pathogenesis. Folate metabolism, also known as one-carbon metabolism, is required for the production of S-adenosylmethionine (SAM), which is the major DNA methylating agent. AD individuals are characterized by decreased plasma folate values, as well as increased plasma homocysteine (Hcy) levels, and there is indication of impaired SAM levels in AD brains. Polymorphisms of genes participating in one-carbon metabolism have been associated with AD risk and/or with increased Hcy levels in AD individuals. Studies in rodents suggest that early life exposure to neurotoxicants or dietary restriction of folate and other B vitamins result in epigenetic modifications of AD related genes in the animal brains. Similarly, studies performed on human neuronal cell cultures revealed that folate and other B vitamins deprivation from the media resulted in epigenetic modification of the PSEN1 gene. There is also evidence of epigenetic modifications in the DNA extracted from blood and brains of AD subjects. Here I review one-carbon metabolism in AD, with emphasis on possible epigenetic consequences.