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2012 Grants - Sharp
DNA Methylation Profiling of Alzheimer's Disease Brains
Andrew Sharp, Ph.D.
Mount Sinai School of Medicine
New York, New York
2012 New Investigator Research Grant
Recent studies of twins suggest that late-onset Alzheimer's disease—the most common form of the disorder—is strongly inheritable. Yet genetic research has so far found limited evidence of the gene mutations involved in late-onset Alzheimer's. During recent years, some investigators have observed that a natural process for modifying one's DNA (or genetic material) may become altered in people at risk of dementia. This process is called DNA methylation, or the addition of methyl compounds to DNA. Methylation is used to turn genes "on" or "off" during different phases of the body's development, and it helps regulate proper gene functioning. But the process may become altered in Alzheimer's and other dementias. Because DNA methylation can be inherited from one generation to the next, altered methylation may be largely responsible for the hereditary nature of late-onset Alzheimer's disease.
For their proposed study, Andrew Sharp, Ph.D., and colleagues will assess the links between DNA methylation problems and Alzheimer's risk. One factor that may induce these problems is the level of folic acid in the body. Studies have found that diets high in folic acid can reduce the risk of dementia. Moreover, folic acid helps make methyl compounds available to DNA, and it is required for proper methylation to take place. Inadequate folic activity may hinder DNA methylation and lead to the dysfunction of numerous genes in Alzheimer's. Such genes include the one for amyloid precursor protein, the "parent" molecule of a protein fragment called beta-amyloid, which is implicated in brain changes associated with Alzheimer's disease.
For their proposed study, Dr. Sharp and colleagues plan to compare DNA methylation in brain samples from healthy people and people with Alzheimer's disease. They hope to identify specific genes and genetic regions that are abnormally methylated in Alzheimer's. The team's results could shed new light on how late-onset Alzheimer's disease can be inherited. They may also lead to novel genetic approaches for dementia therapy.