Genomics: New Light on Alzheimer's Disease Research

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease that represents a major cause of death in many countries. AD is characterized by profound memory loss, disruptions in thinking and reasoning, and changes in personality and behavior followed by malfunctions in various bodily systems. Although AD was first identified over 100 years ago, and tremendous efforts have been made to cure the disease, the precise mechanisms underlying the onset of AD remain unclear. The recent development of next-generation sequencing tools and bioinformatics has enabled us to investigate the role of genetics in the pathogenesis of AD. In this review, we discuss novel discoveries in this area, including the results of genome-wide association studies (GWAS) that have implicated a number of novel genes as risk factors, as well as the identification of epigenetic regulators strongly associated with the onset and progression of AD. We also review how genetic risk factors may interact with age-associated, progressive decreases in cognitive function in patients with AD.

Keywords: GWAS; aging; alzheimer’s disease; epigenetic modification; genetic risk factors; genomics.

Figure 1

Genome-wide association studies (GWAS) have identified Alzheimer’s disease (AD)-associated genetic risk factors unique to humans, suggesting that cellular and molecular functional changes occur in the early stages of AD. Such studies have identified several signaling pathways that may be involved in AD, as well as the role of aging in pathological processes [21,41].

Figure 2

Impact of APOE4 and TREM2 R47H variants on AD pathology. Lipidated ApoE binds Aβ for its internalization or transport to other cell types. ApoE4 exhibits lower Aβ-binding affinity than ApoE3. TREM2 in microglia mediates ApoE-driven Aβ clearance. It is also required for microglial phagocytosis and inhibition of the immune response. The genetic variant on this gene (TREM2 R47H) has been shown to exhibit lower ligand-binding affinity.

Figure 3

In AD brains, increased levels of HDAC2 have been shown to lead to defective chromosomes and reduced expression of genes associated with learning and memory.