Correlation Between CpG DNA Methylation Levels in peripheral CD4+ T cells and brain in aging individuals. C. M. McCabe1,2,3, L. L. Rosenkrantz1,2,3, G. Srivastava1,2,3,4, A. Kaliszewska1,2,3,4, S. Imboywa1,2,3, J. Schneider5, D. A. Bennett5, P. L. De Jager1,2,3,4 1) Program in Medical and Population Genetics, The Broad Institute, 7 Cambridge Center, Cambridge, MA; 2) Center for Neurologic Disease, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; 3) Program in Translational NeuroPshychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, NRB168, Boston MA; 4) Harvard Medical School, Boston, MA; 5) Rush Alzheimer's Disease Center, Rush University Medical Center, 600 S Paulina St., Chicago IL.

   Background: DNA methylation has been reported to be strongly affected by aging. Here, we explore the extent of DNA methylation changes found in subjects from two prospective cohort studies of aging: the religious order study (ROS) and the memory and aging project (MAP). We have previously characterized a profile of DNA methylation from the dorsolateral prefrontal cortex of 748 subjects from these studies to identify loci whose level of methylation in cortex is altered relative to aging and Alzheimers disease. Here, we have evaluated the utility of profiling a peripheral blood cell population, CD4+ T cells, in the same subjects for studies of cognitive aging and dementia. Materials: Forty-eight deceased subjects with archived frozen PBMC were sampled at two time points, one obtained at study enrollment, up to 12 years prior to death (t1) and one within a year of death (t2), and 216 subjects were sampled at one time point (t2). CD4+ T cells were purified from frozen PBMCs using a Miltenyi Biotec autoMACS machine. The Qiagen All-Prep DNA kit was used for DNA extraction. Epigenomic data was obtained on 470,913 CpGs using the Illumina HumanMethylation450 beadset. Results: Profiles from the 216 subjects sampled only once are being generated currently and will be analyzed in relation to the subjects trajectory of decline. In looking at the subset of subjects with two time points, there is a large excess of positive correlation highlighting the existence of stable methylation signals in an individuals CD4+ T cells over several years time. Further, when comparing brain methylation to methylation in one of the CD4+ time points, the mean of the distribution of total correlations is near zero, but we see a skewed heavy tail to these distributions, i.e., there is an excess of CpGs with high levels of positive correlation in methylation levels between blood and brain. The proportion of CD4+ T cell CpGs methylation is more highly correlated (r>0.5) with brain methylation in the blood samples proximal to death (t2) (11.5% of the total CpGs) than in those obtained at enrollment into the study (t1) (4.3% of the total). Conclusion: These initial results demonstrate that for a subset of CpGs, methylation levels in CD4+ T cells are correlated with brain methylation levels. This intriguing result requires validation and suggests that, in this subset of loci, further investigation into the role of CD4+ T cell methylation as a surrogate for brain is warranted.

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