We are funded under the NIH Epigenomics Roadmap initiative to identify epigenetic changes in brain and blood associated with Alzheimer's disease (AD). AD is a neurodegenerative disease characterized by progressive cognitive deterioration affecting in excess of 25 million people worldwide. In addition to the characteristic dementia seen in AD, many patients exhibit a range of non-cognitive symptoms that include depression, aggression, delusions and hallucinations. Whilst the neuropathological changes associated with AD have been well characterized in post-mortem brain tissue, little is known about either the underlying etiology of the disorder or the precise mechanisms behind disease progression.
In this project we are looking beyond the traditional genetic and neuropathological etiological approaches to AD by testing the hypothesis that epigenetic phenomena play a crucial role in the development of the disorder. Using a highly-powered sequential replication design and two complementary methylomic profiling methodologies (Illumina 450K arrays and MeDIP-seq), we are identifying epigenetic dysfunction associated with the disorder across multiple brain regions in a large sample of well-characterized post-mortem AD brains. We also plan to determine whether specific epigenomic signatures are associated with AD+psychosis and AD+depression clinical subtypes using a unique collection of post-mortem brains from individuals for whom detailed clinical data has been collected prior to death. Where verified promoter DNA methylation changes are consistently observed, the expression of downstream genes is being assessed using RNA obtained from the same tissue source. In addition, other epigenetic modifications linked to transcriptional regulation will be investigated using gene-specific chromatin immunoprecipitation (ChIP) to further investigate loci nominated by the genome-wide methylomic screen. Furthermore, we will utilize laser capture microdissection of affected brain tissue to investigate whether observed epigenetic changes are a consequence of the neurodegenerative processes associated with AD (i.e. differential cell death and gliosis) or the result of epigenomic changes in the remaining neurones.
The final stage of our project will be to test verified epimutations, detected in our screen of post-mortem brain tissue, in peripheral blood DNA samples obtained from the same individuals prior to their death, and subsequently in a large independent collection of blood DNA samples obtained from ongoing clinical cohort studies.