Drugs that modify DNA methylation have been shown to alter Alzheimer's disease (AD) pathology in animal models. Two recent studies therefore investigated whether DNA methylation underlies some of the changes in gene expression that occur in AD, De Jager et al. performed gene discovery analysis, comparing autopsied brain tissue from patients with AD with that from control individuals. They found 71 CpG dinucleotides in which the level of methylation correlated with the severity of AD neuropathology. Moreover, several of the genes located near the hypermethylated CpG dinucleotides, including ANK1, were members of a group of genes known to confer susceptibility for AD. ANK1 was the focus of the second, related study. Lunnon et al. showed in post-mortem cortical brain tissue from patients with Alzheimer's disease that CpG sites in ANK1 were hypermethylated (compared with controls). The hypermethylation was associated with neuropathological changes in areas of the cortex typically affected in AD, but not the cerebellum, which is usually protected in AD. Because these DNA methylation patterns were observed in presymptomatic patients as well as those with the disease, they might play a part in both the onset and neuropathology of AD.
References
De Jager, P. L. et al. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nature Neurosci. 17, 1156–1163 (2014)
Lunnon, K. et al. Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease. Nature Neurosci. 17, 1164–1170 (2014)
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Lewis, S. Hypermethylation raises AD risk. Nat Rev Neurosci 15, 630 (2014). https://doi.org/10.1038/nrn3825
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DOI: https://doi.org/10.1038/nrn3825