Epigenomic alterations in Alzheimer disease

Specific epigenetic changes - a mechanism by which environmental factors may influence gene expression - in the brain of Alzheimer disease (AD) patients correlate with the pathological symptoms of the disease. These findings, reported in two independent epigenome-wide association papers published online this week in Nature Neuroscience, present new targets for studying the neurobiological basis of AD and developing potential therapies.

Philip De Jager, David Bennett and colleagues, and Jonathan Mill and colleagues profiled DNA methylation changes of postmortem AD brains at a genome-wide scale from a combined total of approximately 1200 distinct patients. The two studies find 11 and 7 gene regions, respectively, that show increased or decreased levels of methylation - a type of epigenetic change indicating DNA expression - when compared healthy controls. These gene regions are significantly associated with AD symptoms such as the proliferation of amyloid plaques, protein formations commonly seen in AD, and clinical features of neurodegeneration. Four of these genes - ANK1, RHBDF2, RPL13 and CDH23 - were found in both studies, thus representing a cross replication of the results.

While the exact cellular functions of these genes are still unclear, these results present new targets to study the neurobiological basis of AD and develop potential therapies. As DNA methylation is a mechanism by which gene expression can be influenced by the environment, these modifications may account for some of the causes of age-related neurodegenerative diseases such as AD, and may also suggest a mechanism by which sporadic forms of the disease can occur.