How Epigenetics May Affect Alzheimer’s Disease
Alzheimer’s disease (AD) is a neurodegenerative disease affecting approximately 5.5 million people. Each year, more and more information is uncovered about AD and, recently, studies are attempting to validate the hypothesis that epigenetics significantly affects AD pathology. Recognizing the need for these studies the National Institute on Aging and Alzheimer’s Association (NIA-AA) published a new research framework in an effort to redefine the disease based on biological marker, as opposed to syndromal markers. This review considers two published works, inclusive of three studies, that analyze the location of methylated CpG sites within the human genome and their effects on AD. Lord & Cruchaga (2014) discussed methylated CpG sites in or close to specific AD-related genes. Gasparoni, et. al. (2018) study looked to identify methylated CpG sites within a neuron and glia cells and classified them as age-related or AD-related methylated sites. There is note of commonality in all three studies, validating findings and defining a clear path for future studies.
A Review of How Epigenetics May Affect Alzheimer’s Disease
Alzheimer’s disease (AD), like many chronic conditions in the United States, is increasingly affecting more and more people each year. As the most common form of dementia, it was estimated, in 2017, that approximately 5.5 million people suffered from this neurodegenerative disease (Martone & Piotrowski, 2013). AD affects the medial temporal lobes, specifically the hippocampus, and the prefrontal cortex; presenting symptoms of memory loss and cognitive impairment (Snowden, 2010). As of today, confirmed diagnosis is only offered through autopsy when the identification of two microscopic pathological lesions, senile plaques and neurofibrillary tangles, also referred to as Braak staging, are key indicators of the disease (Martone & Piotrowski, 2013). However, medical diagnosis of AD is managed through various clinical assessments that include patient history, mental state examination, physical examination, neuropsychological assessment, blood tests, and electroencephalogram (EEG) (Pitkanen, Jaldow, & Kopelman, 2010). While research is continuing and evolving, the derivative of AD is definitively unknown. For instance, accretion of Alzheimer’s beta peptide (A?), resulting from the ?-amyloid precursor protein (APP) contained in chromosome 21, is associated with causation but only hypothesized as to what manner (Martone & Piotrowski, 2013). Furthermore, gene mutations, such as those in cystatin C (CST3), are associated with genetic inheritance of AD, but only accounts for a small percentage of locus (Lord & Cruchaga, 2014). In recent years, research has been expanded to include epigenome-wide association studies (EWAS) in an attempt to validate the hypothesis that epigenetics significantly affects AD pathology. The epigenome is a host of inheritable biomarkers within the human genome that modifies how genes are expressed without changing the DNA sequence. One type is epigenetic marker that has been closely studied in relation to AD is DNA methylation (methylation). In April 2018, the National Institute on Aging and Alzheimer’s Association (NIA-AA) outlined a new research framework redefine the disease as biological rather than a syndromal (Jack Jr, Bennettb, Blennowc, Carrillod, Dunne, Budd Haeberlein,… Sperling, 2018).
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According to Lord & Cruchaga (2014), methylation, occurring mainly at CpG dinucleotides, or CpG sites areas of the DNA sequence that contain a cytosine nucleotide trailed by a guanine nucleotide is related to the decrease of cellular mechanisms and is thought to be a component in AD causation. In a review of two EWAS, one by De Jager and the other by Lunnon, evidence implied causation when examining methylated CpG sites compared with locations of senile plaques (Lord & Cruchaga, 2014). The De Jager study discussed by Lord & Cruchaga (2014), found two AD related loci; connected by GWAS, ABCA7, and BIN1; within 60 methylated CpG sites. The De Jager group attempted to replicate their findings to support this data and found tendencies supporting those in the initial population (Lord & Cruchaga, 2014). De Jager’s study highlighted that, when accrued, methylated CpG sites provided a better hypothesis for total senile plaque when compared to known AD contributing genes. Lunnon, whose study had similar findings, identified two AD related loci, connected by ANK1 gene, in ten methylated CpG sites located in the medial temporal lobe, and in the replication of these populations it was further determined that Braak staging was connected to these methylated sites (Lord & Cruchaga, 2014). Figure 1 in Appendix A identifies the overlap in findings between the De Jager and Lunnon studies (Lord & Cruchaga, 2014).
A study performed by Gasparoni, Bultmann, Lutsik, Kraus, Sordon, Vlcek,… &Walter (2018) sought to further link methylated CpG sites with Braak staging through a cell-type-specific source by analyzing neurons and glia separately. Gasparoni, et. al. (2018) noted that while DNA methylation occurs in both neuron and glia, hypomethylation, specifically, is detected with aging, and neuron and glia methylation differences decline in old samples when compared to young samples. While Lord & Cruchaga (2014) stated that a main concern is that it is undetermined if DNA methylation is causation or consequence of AD, Gasparoni, et. al. (2018) attempted to address this by identifying methylated CpG site on both age-related and AD-related cell-type-specific basis. The Gasparoni, et. al. (2018) study took care to analyze and identify age-related methylated CpG sites in neuron and glia, then expanded their research to include AD related methylated CpG sites noting there was a small overlap between the two, suggesting that methylation is different for aging and AD. This study identified methylated CpG sites in new AD loci, SEC14L1, MCF2L, and LLRC8B genes involved with neurotransmitter stabilization (Gasparoni, et. al., 2018). Of particular importance is LLRC8B, as the methylated CpG sites affect neuron and glia cells, meaning it may play several roles in AD progression (Gasparoni, et. al., 2018). Additionally, Gasparoni, et. al. (2018) recognized methylation in two genes, HOXA3 and APP, previously identified in other EWAS, were more noticeable in sorted cell samples than bulk samples, and predominantly in glial cells.
Discussion and Further Research
The importance of these studies is to determine if there are markers that are identifiable prior to onset of AD, as many times the disease is classified as late-onset AD due to the timing of symptom manifestation. Therefore, it is important that these studies show commonality. For instance, although not discussed by Lord & Cruchaga (2014), Gasparoni, et. al. (2018) highlighted that their study had identified two of the six methylated CpG site in HOXA3 has also been identified in the Lunnon study. This lead Gasparoni, et. al. (2018) to use public data published from other EWAS included in the examination of their results; validating findings.
Limitations of these Studies
Presently, technology appears to be the main limitation in the progression of AD discoveries. All the studies mentioned, from Lord & Cruchaga (2014) and Gasparoni, et. al. (2018) used an Illumina’s Human Methylation 450 beadset; this device utilizes the most prominent technology available for identifying DNA methylation. Lord & Cruchaga (2014) stated the device was only able to target ~2% of CpG sites located in the human genome and is unable to differentiate between methylation and hydroxymethylation. Gasparoni, et. al. (2018) did not mention this as a limitation, so it is unclear if this study experienced the same limitations with the device or if the technology improved in the four years between publications. Another restriction noted by Gasparoni, et. al. (2018) included the use of bisulfite conversion chemistry and its limits identifying two specific types of methylated CpG sites.
Future studies may include further sorting of neuron and glia into subtypes which may allow for improved screening of methylated CpG sites. However, the technology used to achieve this level of sorting, fluorescence-activated cell sorting (FACS), has only been implemented for two types of methylation and only been completed in mice (Gasparoni, et. al., 2018). Single nuclei analysis is another method for further investigation into the human genome and, while application on human tissues samples has been explored, it is not ready to large scale implementation (Gasparoni, et. al., 2018). Other research may include cell-type-specific changes related to DNA methylation or other epigenetic biomarkers, such as histone acetylation.
Lord & Cruchaga (2014) and Gasparoni, et. al. (2018) both support the hypothesis that epigenetics plays a major role in AD development and progression. The studies discussed in Lord & Cruchaga (2014) sought to identify methylated CpG sites in or close to specific AD-related genes. The Gasparoni, et. al. (2018) study took this a step further and pursued identification of methylated CpG sites within a neuron and glia cells and classified them as age-related or AD-related methylated sites; noting overlap in the two areas to be uncommon. As technologies improve and more studies are completed, it appears pinpointing causation for AD is imminent. It is now clear the epigenome plays a significant role in AD and other diseases prevalent in society today. Therefore, it is important for the general public to have a basic understanding of epigenetics and the daily choices we make that may impact the development or degeneration of our bodies and minds.