A new study led by researchers at Brigham and Women's Hospital (BWH) and Rush University Medical Center, reveals how early changes in brain DNA methylation are involved in Alzheimer's disease. DNA methylation is a biochemical alteration of the building blocks of DNA and is one of the markers that indicate whether the DNA is open and biologically active in a given region of the human genome.
The study is published online August 17, 2014 in Nature Neuroscience.
According to the researchers, this is the first large-scale study employing epigenome-wide association (EWAS) studies -- which look at chromosomal make-up and changes -- in relation to the brain and Alzheimer's disease.
"Our study approach may help us to better understand the biological impact of environmental risk factors and life experiences on Alzheimer's disease," said Philip L. De Jager, MD, PhD, Program in Translational Neuropsychiatric Genomics, BWH Departments of Neurology and Psychiatry, lead study author. "There are certain advantages to studying the epigenome, or the chemical changes that occur in DNA. The epigenome is malleable and may harbor traces of life events that influence disease susceptibility, such as smoking, depression and menopause, which may influence susceptibility to Alzheimer's and other diseases."
The researchers analyzed samples from 708 donated brains from subjects in the Religious Orders Study and Rush Memory and Aging Project, conducted by study co-author, David A. Bennett, MD, Rush Alzheimer's Disease Center in Chicago. They found that methylation levels correlated with Alzheimer's disease in 71 of 415,848 CpG markers analyzed (these are a pair of DNA building blocks consisting of a cytosine and a guanine nucleotide that are located next to each other). These 71 markers were found in the ANK1 and RHBDF2 genes, as well as ABCA7 and BIN1 which harbor known Alzheimer's disease susceptibility variants.
Further, investigation of these CpG associations revealed nearby genes whose RNA expression was altered in brain samples with Alzheimer's disease: ANK1, CDH23, DIP2A, RHBDF2, RPL13, RNF34, SERPINF1 and SERPINF2. This suggests that the CpG associations identify genes whose function is altered in Alzheimer's disease.
Further, "because these findings are also found in the subset of subjects that are not cognitively impaired at the time of death, it appears that these DNA methylation changes may play a role in the onset of Alzheimer's disease," said De Jager. "Moreover, our work has helped identify regions of the human genome that are altered over the life-course in a way that is associated with Alzheimer's disease. This may provide clues to treating the disease by using drugs that influence epigenomic function."
This research was supported by the National Institutes of Health (R01AG036042, R01AG036836, R01 AG17917, R01AG15819, R01 AG032990, R01AG18023, RC2 AG036547, P30 AG10161, P50 AG016574, U01 ES017155, KL2RR024151, K25 AG041906-01, AG036039), Siragusa Foundation, Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program, and Alzheimer's Research UK.
- Philip L De Jager, Gyan Srivastava, Katie Lunnon, Jeremy Burgess, Leonard C Schalkwyk, Lei Yu, Matthew L Eaton, Brendan T Keenan, Jason Ernst, Cristin McCabe, Anna Tang, Towfique Raj, Joseph Replogle, Wendy Brodeur, Stacey Gabriel, High S Chai, Curtis Younkin, Steven G Younkin, Fanggeng Zou, Moshe Szyf, Charles B Epstein, Julie A Schneider, Bradley E Bernstein, Alex Meissner, Nilufer Ertekin-Taner, Lori B Chibnik, Manolis Kellis, Jonathan Mill, David A Bennett. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nature Neuroscience, 2014; DOI: 10.1038/nn.3786
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