Invited Review – A 5‐year update on epigenome‐wide association studies of DNA modifications in Alzheimer’s disease: progress, practicalities and promise

Abstract

In late 2014, the first epigenome‐wide association studies of DNA modifications in Alzheimer’s disease brain samples were published. Over the last 5 years, further studies have been reported in the field and have highlighted consistent and robust alterations in DNA modifications in AD cortex. However, there are some caveats associated with the majority of studies undertaken to date; for example, they are predominantly restricted to profiling a limited number of loci, are principally focused on DNA methylation, are performed on bulk tissue at the end stage of disease and are restricted to nominating associations rather than demonstrating causal relationships. Consequently, the downstream interpretation of these studies is limited. Owing to recent advances in state‐of‐the‐art cell profiling techniques, long‐read genomic technologies and genetic engineering methodologies, identifying cell‐type‐specific causal epigenetic changes is becoming feasible. This review seeks to provide an overview of the last 5 years of epigenomic studies of DNA modifications in Alzheimer’s disease brain samples and propose new avenues for future research.

ZNF718, HOXA4, and ZFP57 are differentially methylated in periodontitis in comparison with periodontal health: Epigenome‐wide DNA methylation pilot study

“…21 However, for genome-wide DNA methylation analyses, the process of obtaining the amount of DNA required using laser microdissection is very labor-intensive. 22,23 Technically, the cell sorting flow cytometry technique can be used to separate peripheral leukocytes or even infiltrated leukocytes to analyze methylation patterns. However, it would increase the cost of the analysis and require one hundred thousand cells per cell type of each sample analyzed.…”

Neurodegenerative movement disorders: An epigenetics perspective and promise for the future

“…Furthermore, studies in healthy human brain tissue [47,48] strengthen the hypothesis that DNA methylation/hydroxymethylation patterns display temporal and regional specificity. Such specificity transcends brain regions, as there are differential roles for 5mC and 5hmC in regulating gene expression in different brain cell types, adding [50,51]); therefore in the following section, we will focus on studies utilising brain tissue from NMDs, including PD, MSA, PSP, HD and FRDA (Figure 3). For a more comprehensive overview of the biological significance of the results discussed, we provide a summary table of differentially methylated genes that have been identified in two or more studies, both within an NMD or between different NMDs (Table S1).…”

“…Most studies, however, have analysed total methylation patterns (5mC + 5hmC), and only a few have investigated 5mC and 5hmC individually. Within neurodegenerative diseases, the role of DNA methylation has been most extensively studied in Alzheimer's disease (AD) and has been reviewed elsewhere (e.g., [ 50 , 51 ]); therefore in the following section, we will focus on studies utilising brain tissue from NMDs, including PD, MSA, PSP, HD and FRDA (Figure 3 ). For a more comprehensive overview of the biological significance of the results discussed, we provide a summary table of differentially methylated genes that have been identified in two or more studies, both within an NMD or between different NMDs (Table S1 ).…”

Truncated Tau caused by intron retention is enriched in Alzheimer’s disease cortex and exhibits altered biochemical properties

“…Synaptic and neuronal loss in AD is caused by interplay between the pathology of amyloid-β plaques and Tau neurofibrillary tangles with impairment of innate clearance pathways ( 2 ). Accumulated evidence indicates that epigenetic alterations ( 3 ) and aberrant RNA splicing events at several AD susceptibility loci during aging might predispose healthy brains to AD pathogenesis ( 4 – 6 ), with reports showing differential intron retention (IR) events at the Tau gene ( Fig. 1 A ) ( 7 – 9 ).…”