Two new NIH-supported studies have shown that a person’s epigenome—the chemical modifications, or marks, on our DNA that turn gene activity on and off—may influence Alzheimer’s disease-related changes in the brain. The two groups of researchers examined brain tissue donated by volunteers with Alzheimer’s and those free of the disease and linked a specific epigenome marker, DNA methylation, with Alzheimer’s pathology in the brain. Because the epigenome can be affected by lifestyle and the environment, these findings may offer new targets for therapies to delay, prevent or treat Alzheimer’s disease.
The independently-run, epigenome-wide association studies (EWAS) reported online in Nature Neuroscience on August 17, 2014, were led by: Philip L. De Jager, M.D., Ph.D., Brigham and Women's Hospital, Boston, in collaboration with co-author David Bennett, Ph.D., Rush University Medical Center, Chicago; and by Jonathan Mill, Ph.D., of the University of Exeter Medical School and King’s College London, in collaboration with colleagues in the United Kingdom and United States.
Because the epigenome determines gene expression—that is, which genes are active and what proteins they produce—it can impact health and longevity. These new studies show for the first time that DNA methylation may impact specific gene regions, several of which are thought to play a role in Alzheimer’s disease risk, onset and progression.
- Dr. De Jager’s team analyzed samples from 708 donated brains from the Religious Orders Study and Rush Memory and Aging Project led by Dr. Bennett. They found that greater methylation levels correlated with Alzheimer's disease in 71 of the 415,848 markers analyzed. The 71 markers were found in the ANK1 and RHBDF2 genes, as well as in ABCA7 and BIN1 genes (two known Alzheimer’s risk variants.) They also identified nearby genes with altered expression that may be related to Alzheimer’s: ANK1, CDH23, DIP2A, RHBDF2, RPL13, RNF34, SERPINF1 and SERPINF2. This work was funded in part by the National Institute on Aging (NIA) at NIH.
- Dr. Mill’s team analyzed brain tissue from nearly 300 donated brains in the U.S. and U.K. They linked higher levels of DNA methylation in the ANK1 gene to greater levels of Alzheimer’s pathology, especially in brain regions known to be susceptible to the disease. This research was primarily funded by the NIH Epigenomics Roadmap Initiative, which seeks to accelerate research into the relatively new and fast-developing area of epigenetics. NIA also provided support.
De Jager PL., et al. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nature Neuroscience, published online Aug. 17, 2014; DOI:10.1038/nn.3786
Lunnon K., et al. Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease. Nature Neuroscience, published online Aug. 17, 2014; DOI:10.1038/nn.3782