Uncovering the Role of the Methylome in Dementia and Neurodegeneration

Our understanding of the epigenome has advanced dramatically over the past decade, particularly in terms of DNA methylation, a modification found throughout the genome. Studies of the brain and neurons have outlined an increasingly complex architecture involving not just CG dinucleotide methylation but also methylation of other dinucleotides, and modifications of methylated bases such as 5-hydroxymethylcytosine. Different modifications may play an important role in brain development, function and decline; recent descriptions of the effects of aging and neurodegenerative processes such as Alzheimer disease on methylation profiles have ushered in an era of DNA methylome-wide association studies. Rapidly improving technologies and study designs are returning robust results, and investigations of the human brain's epigenome are increasingly feasible, complementing insights gained from genetic studies.

TrendsDNA methylation in the human brain exists in many different forms including non-CG methylation and CG hydroxymethylation, which are less common in other tissues.Aging has a strong effect on DNA methylation profiles in the brain, both during development and with advanced age, and some of these changes are shared with other tissues. Altered DNA methylation profiles may provide information related to age-associated diseases and dementia.An estimated ‘epigenetic age’ can be calculated from DNA methylation data and may reflect an individual's life experiences and environmental exposure. However, the current algorithm for this calculation does not account for confounding effects and needs to be refined to factor in advanced age, where the rate of methylation changes might be slower.Certain genetic loci present methylation levels that are associated with Alzheimer disease (AD), independent of disease-associated genetic variation. These associations have been reproduced in a collection of independent samples.AD-related changes in DNA methylation occur early in the disease, prior to the appearance of cognitive impairment; however, it is not yet clear whether these changes are causal.Some Parkinson disease and amyotrophic lateral sclerosis risk alleles may be linked to pathogenesis through methylation changes.