Genome-Wide Exploration of DNA Methylation in the Aging Brain and Its Relation to Alzheimer's Disease (P05.070)

Abstract

Objective: To explore the role of chromatin conformation in the decline of cognition that accompanies aging and aging-related neurodegenerative diseases such as Alzheimer9s disease (AD). Background The plasticity of the epigenome suggests that it may be one medium through which life experiences throughout the life course could effect stable changes in gene expression that could ultimately influence the risk of dementia. Design/Methods: We base this investigation on a unique bank of frozen brains from subjects with longitudinal cognitive data collected in two studies of aging: the Memory and Aging Project and the Religious Order Study. A sample of dorsolateral prefrontal cortex was obtained from each of 759 subjects and using the Illumina Humanmet450K platform; this generated data on the extent of DNA methylation at 486,428 CpG sites distributed throughout the genome. Results: These data are remarkably similar across individuals, with over 98% pairwise correlation between any two subjects. However, using principal component (PC) analysis, we do find strong correlations with age (PC7) and sex (PC9) methylome-wide. Adjusting for these effects and other pertinent covariates, we find that the 319 subjects with AD at the time of death have higher levels of DNA methylation in many sites throughout the genome. However, the difference in the extent of methylation in the tissue sample at any given CpG site is modest. In the current model, the best result is returned by CpG1211454 which has a p=1.84x10^-9 in the AD vs. non-AD analysis, which exceeds our threshold of methylome-wide significance (p Conclusions: Our study provides evidence for loci where the extent of DNA methylation correlates with a diagnosis of AD, suggesting that the brain9s transcriptional potential may play a role in aging-related diseases such as dementia. Disclosure: Dr. De Jager has received personal compensation for activities with Merck Serono and Teva Neuroscience as a consultant.Dr. De Jager has received research support from Biogen Idec. Dr. Srivastava has nothing to disclose. Dr. Eaton has nothing to disclose. Dr. Chibnik has nothing to disclose. Dr. Kellis has nothing to disclose. Dr. Bennett has received personal compensation for activities with Danone, Inc., Dr. Wilmar Schwabe GmbH & Co, KG Pharmaceuticals, Eli Lilly & Company as a consultant. Dr. Bennett has received research support from Danone, Inc.