Invited Review - A 5-year update on epigenome-wide association studies of DNA modifications in Alzheimer's disease: progress, practicalities and promise

In late 2014, the first epigenome-wide association studies of DNA modifications in Alzheimer's disease brain samples were published. Over the last 5 years, further studies have been reported in the field and have highlighted consistent and robust alterations in DNA modifications in AD cortex. However, there are some caveats associated with the majority of studies undertaken to date; for example, they are predominantly restricted to profiling a limited number of loci, are principally focused on DNA methylation, are performed on bulk tissue at the end stage of disease and are restricted to nominating associations rather than demonstrating causal relationships. Consequently, the downstream interpretation of these studies is limited. Owing to recent advances in state-of-the-art cell profiling techniques, long-read genomic technologies and genetic engineering methodologies, identifying cell-type-specific causal epigenetic changes is becoming feasible. This review seeks to provide an overview of the last 5 years of epigenomic studies of DNA modifications in Alzheimer's disease brain samples and propose new avenues for future research.