Advances in Genetics and Epigenetic Alterations in Alzheimer's Disease: A Notion for Therapeutic Treatment

Abstract

Alzheimer's disease (AD) is a disabling neurodegenerative disorder that leads to long-term functional and cognitive impairment and greatly reduces life expectancy. Early genetic studies focused on tracking variations in genome-wide DNA sequences discovered several polymorphisms and novel susceptibility genes associated with AD. However, despite the numerous risk factors already identified, there is still no fully satisfactory explanation for the mechanisms underlying the onset of the disease. Also, as with other complex human diseases, the causes of low heritability are unclear. Epigenetic mechanisms, in which changes in gene expression do not depend on changes in genotype, have attracted considerable attention in recent years and are key to understanding the processes that influence age-related changes and various neurological diseases. With the recent use of massive sequencing techniques, methods for studying epigenome variations in AD have also evolved tremendously, allowing the discovery of differentially expressed disease traits under different conditions and experimental settings. This is important for understanding disease development and for unlocking new potential AD therapies. In this work, we outline the genomic and epigenomic components involved in the initiation and development of AD and identify potentially effective therapeutic targets for disease control.

Keywords: Alzheimer’s disease; dementia; epigenetic mechanisms; genetic risk factors; genome-wide association study (GWAS); missing heritability; older adults.

Figure 1

Epistatic interactions between the major susceptibility loci of Alzheimer’s disease (AD). (A) Cluster analysis of the protein–protein interaction network of the major susceptibility loci of AD, generated with STRINGdb (http://string-db.org) (accessed on 15 November 2021). The ATP-binding cassette member 7 gene (ABCA7) (in bold) was used as the reference protein for the query to identify potential epistatic interactions between all the protein-coding genes. Nodes represent proteins, and edges represent functional and physical protein–protein associations with a significant contribution of the proteins to a common function, regardless of their physical binding to each other. The color of the lines indicates the type of interaction, and the line thickness indicates the strength of the data support. The PPI network analysis was performed with greater than 70% confidence (required minimum interaction score of 0.7). The analysis used a k-means clustering approach with an average local clustering coefficient of 0.729. Four clusters were identified for the network, highlighted in different colors, with dashed lines indicating edges between clusters. The network contains 29 nodes with an average node degree of 7.86; the confidence threshold was set to 0.7 (high). The enrichment of the connectivity in the network was significant (p < 0.001), suggesting that the proteins as a group are at least partially biologically connected and have significantly more interactions with each other than expected (114 edges compared to 31 expected edges) from a random group of proteins of the same size and degree distribution from the genome. (B) Heatmap of predicted functional associations between search protein ABCA7 and the other risk loci for AD. Scores refer to the strength of evidence found in a series of experiments for correlated expression between two coding protein genes based on RNA expression patterns and protein coregulation data from ProteomeHD (https://www.proteomehd.net/proteomehd) (accessed on 15 November 2021). Legend: The color intensity indicates confidence in the predicted functional association between ABCA7 and a given protein (adapted from STRINGdb). Created with BioRender.com.

Figure 2

The epigenetic drivers of Alzheimer’s disease (AD). The major mechanisms of epigenetic regulation include DNA methylation and post-translational histone modifications associated with the activation or repression of a gene expression. A number of enzymes catalyze DNA methylation/demethylation reactions, as well as various histone modification processes, such as methylation/demethylation, acetylation/deacetylation, ubiquitination and phosphorylation. DNA methylation/demethylation: DNMT enzymes catalyze DNA methylation by covalently transferring a methyl group from SAM to the 5′-end of cytosine residues (5mC) in CpG islands (CGIs) near gene promoter regions that trigger gene silencing. One widely studied mechanism is DNA hypermethylation in a region of the HOXA gene associated with AD neuropathology in the human cortex. In contrast, TETs demethyltransferase enzymes catalyze DNA demethylation by hydroxymethylation from 5mC to 5hmC at CGIs near gene promoter regions, triggering their activation. Histone (Ac) ethylation/deacetylation: covalent binding of an acetyl group to amino acid residues in the histone tail is mediated by HAT enzymes and leads to the regulation of gene activity. The levels of HDAC enzymes such as HDAC2 and HDAC6 tend to be elevated in AD brains. Their deacetylation activities cause gene silencing, while their inhibition helps slow cognitive decline. Histone methylation/demethylation: HMT enzymes methylate histone amino acid residues, thereby inhibiting gene transcription, while HDMT enzymes demethylate them, thereby activating transcription. Ubiquitination of histones: the binding of ubiquitin to lysine residues promotes the proteasomal degradation of tagged proteins, preventing the accumulation of tau and Aβ aggregates, whereas proteasomal inhibition promotes the accumulation of tau and Aβ. Histone Phosphorylation: associated with increased gene expression. Dysregulation of acetylation of non-histone proteins is associated with the pathogenesis of AD. The histone acetyltransferases CBP and p300 are involved in the selective Aβ-induced acetylation of several lysine residues, including those of the transcription factor NF-κB. Mutant variants of PSEN1 inhibit the degradation of HAT by the proteasome and promote gene expression. The activity of p300 regulates the acetylation of tau by repressing the degradation of p-tau, promoting the microtubule destabilization associated with tauopathy. The histone deacetylase Sirtuin 1 (SIRT1) also regulates NF-κB and is involved in the deacetylation of tau and protection against AD neurodegeneration. Expression of the gene encoding the same enzyme (SIRT1) can be altered by the action of p300, leading to hyperacetylation in AD brains. Created with BioRender.com.

Figure 3

Epigenetic regulatory mechanisms of miRNAs. By regulating the target genes, miRNAs have the ability to alter the processing of amyloidogenic APP into neurotoxic Aβ-42/40 and p-tau aggregates through the sequential action of the cleavage enzymes BACE1 and γ-secretase. Inhibition of the CAMK4 gene, which is responsible for regulating synaptic functions in neuronal cells, by miRNAs promotes tauopathy and amyloid plaque formation. Similarly, inhibition of the Dicer/Drosha enzyme complex leads to the cessation of miRNA biogenesis and is indirectly associated with the downregulation of DNMT enzymes and, thus, DNA methylation. The ADAM10 gene is involved in APP processing and Aβ-amyloidosis in AD brains, where its inhibition by specific miRNA molecules leads to overexpression of the gene. Created with BioRender.com.