Driver or passenger: Epigenomes in alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a fatal neurodegenerative disease which is on the rise worldwide. Despite a wealth of information, genetic factors contributing to the emergence of AD still remain incompletely understood. Sporadic AD is polygenetic in nature and is associated with various environmental risks. Epigenetic mechanisms are well-recognized in the mediation of gene environment interactions, and analysis of epigenetic changes at the genome scale can offer new insights into the relationship between brain epigenomes and AD. In fact, recent epigenome-wide association studies (EWAS) indicate that changes in DNA methylation are an early event preceding clinical manifestation and are tightly associated with AD neuropathology. Further, candidate genes from EWAS interact with those from genome-wide association studies (GWAS) that can undergo epigenetic changes in their upstream gene regulatory elements. Functionally, AD-associated DNA methylation changes partially influence transcription of candidate genes involved in pathways relevant to AD. The timing of epigenomic changes in AD together with the genes affected indicate a critical role, however, further mechanistic insight is required to corroborate this hypothesis. In this respect, recent advances in neuronal reprogramming of patient-derived cells combined with new genome-editing techniques offer unprecedented opportunities to dissect the functional and mechanistic role of epigenomic changes in AD.