Deconstructing the epigenomic architecture of human neurodegeneration

The past 10 years have seen a rapid advance in our ability to profile the epigenome from human pathologic material, opening up new study designs to investigate the role of epigenomic features in human disease. Moderate to large scale studies have now been conducted in the target tissue of neurodegenerative diseases, the brain, and, through the use of rigorous statistical methodologies, have laid a foundation of validated observations and successful study designs that inform our perspective on the role of the epigenome in these diseases, generate new hypotheses, and guide our path forward for a second generation of studies. It is clear that sampling the epigenome is not redundant with other "omic" profiling of the same tissue and that it can serve as an important vehicle for the integration of the effect of multiple environmental exposures on risk of disease. In some cases, change in the epigenome may thus have a causal impact on disease, but we now have evidence that such changes may also mediate some of the effect of tau proteinopathy and that other changes may moderate the impact of genetic risk factors. Thus, the epigenome may be involved at multiple different stages of the sequence of events that leads to human neurodegeneration, and we review the study designs that may begin to guide the development of a more comprehensive perspective on the aging brain's epigenome.