Epigenome-wide association studies (EWAS) appear to be the natural evolution of GWAS that has given neuroscience a epigenomic renaissance. Jonathan Mill and team from the University of Exeter Medical School and King’s College London have shown that sometimes it’s best to cover all angles and in their latest report(s) offer up some new epigenetic targets for studying the neuroscience of Alzheimer Disease (AD). Here’s what they found:
- Ankyrin 1 (ANK1) is the differentially methylated region (DMR) of main interest in post-mortem AD brains when compared to matched controls.
- The ANK1 DMR was hypermethylated in the entorhinal cortex, AD’s brain region of preference, which serves as an interface between the hippocampus (the brain’s declarative memory centre) and the neocortex (humanity’s claim to fame).
- This region is substantially hypermethylated in two other cortices, the superior temporal gyrus and prefrontal cortex, both related to AD.
- The results confirmed in cortical samples from independent brain cohorts.
- Interestingly, these changes were not seen in the cerebellum, a brain region typically protected from neurodegeneration in AD, or whole blood obtained pre-mortem from the same individuals.
The gene regions identified are significantly associated with AD symptoms such as the proliferation of amyloid plaques and clinical features of neurodegeneration. And oh yeah, 4 of the 7 genes of interest — ANK1, RHBDF2, RPL13 and CDH23 — were found in another AD EWAS by Phil De Jager, which identifies 11 DMRs. This second study, published together in the same Nature Neuroscience issue, provides a convenient cross replication of the results across a total of 1,200 patients.
Mill shares that “This is the strongest evidence yet to suggest that epigenetic changes in the brain occur in Alzheimer’s disease, and offers potential hope for understanding the mechanisms involved in the onset of dementia. We don’t yet know why these changes occur – it’s possible that they are involved in disease onset, but they may also reflect changes induced by the disease itself.” Lead author Katie Lunnon concludes “It’s intriguing that we find changes specifically in the regions of the brain involved in Alzheimer’s disease. Future studies will focus on isolating different cell-types from the brain to see whether these changes are neuron- specific.” The results also add to the complexity of environmental interaction in neurodegenerative disease given the environmentally responsive nature of the epigenome.
Check out more on the neuroepigenomics of AD in Nature Neuroscience, August 2014