A systems approach to DNA methylation, gene expression, and cognitive dysfunction in Alzheimer's disease

? DESCRIPTION: This is a training grant that will give me the resources to develop into an academic physician-scientist. My long- term goal is to do research that focuses on Alzheimer's disease (AD) and neurodegenerative diseases of the aging brain, and integrate this with my clinical role as a neuropathologist (with at least 75% of my time dedicated to research). This grant has a scientific proposal component as well as a training component. The scientific proposal component will ask three questions. First, I will ask if there are differences in gene methylation between AD patients and cognitively normal patients with a similar cortical ß-amyloid load (pathological controls). AD patients have been shown to have abnormalities in DNA methylation, and ß- amyloid has also been shown to cause alterations in DNA methylation. However, pathologic controls have elevated ß-amyloid levels but are not demented. Since pathologic controls have elevated ß-amyloid levels, and ß-amyloid has been shown to cause altered DNA methylation, pathologic controls may have some DNA methylation abnormalities normally associated with AD that do not directly cause dementia. By comparing AD brain tissue to pathological control tissue, I hope to tease out changes in gene methylation that correlate strongest with the presence of dementia. Second, I will ask whether there are changes in DNA methylation that are predictive of worsening cognitive status in the setting of AD pathology, using a patient population that is being shunted for hydrocephalus. Finally, I will explore whether learning-related changes in DNA methylation are impaired in a mouse model of AD that approximates some of the methylation abnormalities seen in human AD patients. In all, these experiments will help to tease out the association of abnormal DNA methylation with impaired cognition in AD. My PhD thesis was in a computational neuroscience lab (i.e. dry-lab work). I have spent the last several years after my clinical training becoming proficient in experimental neuroscience (i.e. wet-lab work). This training grant will take advantage of this background and train me in computational techniques of analyzing genomic and genome expression data, with a focus on applying these techniques to neurodegeneration and the aging brain. I will accomplish three training goals during the course of this grant; 1) Acquire the skills to perform computational analysis of genomic and genome expression data, 2) Deepen my knowledge of the molecular biology of aging, and 3) Deepen my knowledge of the cognitive sequelae of aging and neurodegeneration. In summary, this training grant, through the scientific proposal and the training plan, will give me the resources to flourish as a scientist and make a contribution to Alzheimer's disease research.