Researchers from the University of Exeter Medical School and King’s College London have produced some of the clearest evidence to date that epigenetic changes in the brain are linked to Alzheimer’s disease.
Epigenetic modifications alter how genes are expressed without changing the underlying DNA sequence. These changes are one way the environment can influence the genome, and because they can be reversible, they represent promising targets for new therapeutic approaches.
Alzheimer’s disease currently affects more than 26 million people worldwide. As populations age, that number is expected to rise, making it essential to uncover new biological mechanisms behind the disease. Post-mortem studies have shown that Alzheimer’s damages some brain regions far more than others: for example, the entorhinal cortex is highly vulnerable, while the cerebellum is comparatively spared. Yet the reasons why the disease targets particular brain areas have remained unclear.
The new study identifies chemical changes to DNA within the ANK1 gene that correlate strongly with Alzheimer’s-related neuropathology. Published in Nature Neuroscience, the research shows that individuals with greater Alzheimer’s pathology in the brain had elevated levels of DNA modification in the ANK1 gene. This association was strongest in the entorhinal cortex and was also present in other cortical areas typically affected by the disease. By contrast, no meaningful changes were seen in less-affected regions such as the cerebellum or in blood samples.
Professor Jonathan Mill of the University of Exeter Medical School and King’s College London, who led the study, commented: “This is the strongest evidence yet that epigenetic changes in the brain occur in Alzheimer’s disease, and it offers a promising avenue for understanding the mechanisms that lead to dementia. We don’t yet know why these changes happen — they might contribute to disease onset, or they could be consequences of the disease.”
Dr Katie Lunnon, first author on the study from the University of Exeter Medical School, added: “It is notable that these changes are specific to the brain regions involved in Alzheimer’s disease. Future research will aim to separate the different cell types in those regions to determine whether the changes are specific to neurons or other cell populations.”
The international research team included collaborators from The Icahn School of Medicine at Mount Sinai, the JJ Peters VA Medical Center, Johns Hopkins University School of Medicine, Harvard Medical School, the University of Oxford, and Rush University Medical Center in Chicago. They used advanced molecular methods to profile brain tissue from multiple regions across three independent cohorts: the MRC London Brain Bank for Neurodegenerative Disease, the Oxford Thomas Willis Brain Bank, and the Mount Sinai Alzheimer’s Disease and Schizophrenia Brain Bank. Brain samples covered three cortical regions and the cerebellum, and the study also included blood samples. Several hundred individuals were analysed, representing the full spectrum from no detectable neurodegeneration to advanced Alzheimer’s pathology.
Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, which also funded part of the study, noted: “Genetic changes in certain genes are known to increase Alzheimer’s risk, but the role of epigenetic changes is a relatively new field. Epigenetic mechanisms have been implicated in other diseases, including cancer, so exploring these changes in Alzheimer’s is important. This study highlights ANK1 as a potential player in the disease and opens the door to further investigation of how epigenetic alterations may contribute to Alzheimer’s.”
Alzheimer’s Research UK emphasises the need for innovative studies to reveal why the disease begins and how it progresses. This work contributes to that effort by linking epigenetic deregulation of ANK1 to cortical changes seen in Alzheimer’s and by identifying specific brain regions where these alterations are present.
The research was mainly funded by the National Institutes of Health (NIH), U.S. Department of Health and Human Services, through its Epigenomics Roadmap Initiative (grant number R01-AG036039 awarded to Jonathan Mill). The NIH initiative aims to accelerate research into epigenetics and its role in human disease.
Source: Jonathan Mill – University of Exeter
Contact: University of Exeter press release
Image source: The image is credited to PublicDomainPictures and is in the public domain.
Original research: Abstract for “Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer’s disease” by Katie Lunnon et al., Nature Neuroscience. Published online August 17, 2014. doi:10.1038/nn.3782