Abstract
In late 2014, the first epigenome-wide association studies of DNA modifications in Alzheimer's disease brain samples were published. Over the last 5years, 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 5years of epigenomic studies of DNA modifications in Alzheimer's disease brain samples and propose new avenues for future research.
Highlights
It is well established that autosomal dominant mutations in genes that are part of the amyloid b (Ab) production pathway, such as amyloid precursor protein (APP) and the presenilin genes (PSEN1, PSEN2), result in familial Alzheimer’s disease (AD) (FAD) [19], which is typically early onset (EOAD), this only accounts for 1–6% of diagnoses [21]
It was only owing to more recent advances in genomic technology that 5 years ago, the first epigenome-wide association studies (EWAS) of DNA modifications were published, which used the Illumina Infinium Methylation 450 K BeadChip Array (450 K array) [35,36], with more studies appearing on a year-by-year basis (Figure 2)
When this can be achieved at the level of the single cell, this will represent a particular advancement in the field
Summary
Defining the etiology of AD has proven more elusive than the characterization of the pathological and clinical features. It was only owing to more recent advances in genomic technology that 5 years ago, the first epigenome-wide association studies (EWAS) of DNA modifications were published, which used the Illumina Infinium Methylation 450 K BeadChip Array (450 K array) [35,36], with more studies appearing on a year-by-year basis (Figure 2) Those first large-scale EWAS were illuminating as different cohorts, tissues and sample sizes were used in the two studies, a number of differentially methylated positions (DMPs) were common to both studies including ANK1, CDH23, RHBDF2 and RPL13 [37]. Further EWAS using the same technology and principles have provided additional evidence for DNA methylomic alterations in AD; Watson and colleagues identified 479 diagnosis-associated DMRs by profiling the superior temporal gyrus in 34 control and 34 AD samples These regions were enriched for genes involved in neuronal function and development, and a subset of the DMRs were independently associated with aging [39]. Owing to recent advances in technology, it is becoming feasible that these could be addressed in the wave of studies
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