Exploring Beyond the DNA Sequence: A Review of Epigenomic Studies of DNA and Histone Modifications in Dementia

Purpose of Review Although genome-scale studies have identified many genetic variants associated with dementia, these do not account for all of disease incidence and so recently attention has turned to studying mechanisms of genome regulation. Epigenetic processes such as modifications to the DNA and histones alter transcriptional activity and have been hypothesized to be involved in the etiology of dementia. Here, we review the growing body of literature on dementia epigenomics, with a focus on novel discoveries, current limitations, and future directions for the field. Recent Findings It is through advances in genomic technology that large-scale quantification of epigenetic modifications is now possible in dementia. Most of the literature in the field has primarily focussed on exploring DNA modifications, namely DNA methylation, in postmortem brain samples from individuals with Alzheimer's disease. However, recent studies have now begun to explore other epigenetic marks, such as histone modifications, investigating these signatures in both the brain and blood, and in a range of other dementias. There is still a demand for more epigenomic studies to be conducted in the dementia field, particularly those assessing chromatin dynamics and a broader range of histone modifications. The field faces limitations in sample accessibility with many studies lacking power. Furthermore, the frequent use of heterogeneous bulk tissue containing multiple cell types further hinders data interpretation. Looking to the future, multi-omic studies, integrating many different epigenetic marks, with matched genetic, transcriptomic, and proteomic data, will be vital, particularly when undertaken in isolated cell populations, or ideally at the level of the single cell. Ultimately these studies could identify novel dysfunctional pathways and biomarkers for disease, which could lead to new therapeutic avenues.