Chapter 9 - Epigenomics of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a large and growing public health problem. It is characterized by the accumulation of amyloid-β peptides and abnormally phosphorylated tau proteins that are associated with cognitive decline and dementia. Much has been learned about the genomics of AD from linkage analyses and more recently, genome-wide association studies. Several but not all aspects of the genomic landscape are involved in amyloid-β metabolism. The moderate concordance of disease among twins suggests that other factors, potentially epigenomic factors, are related to AD. We are still at the early stages of examining the relation of the epigenome to the clinical and pathologic phenotypes that characterize AD. Our literature review finds evidence of age-related changes in human brain methylation and that aberrant alteration of brain methylation is implicated in AD. Unfortunately, the investigation of the epigenomic component of AD remains a nascent field with limited coverage of the methylation sites and of microRNAs, let alone the many other epigenomic marks. We recently completed two large studies of human brains including coverage with more than 420,000 autosomal cytosine–guanine dinucleotides using the Illumina Infinium HumanMethylation450 BeadArray and with histone acetylation (H3K9ac) with chromatin immunoprecipitation sequencing. We share our prior work on genome-wide brain DNA methylation profiles and describe our experience profiling histone marks. We then discuss future directions to inform on the epigenomic architecture of AD.