Diseases and Disorders

Epigenetic Mechanisms in the Pathology of Alzheimer's Disease

Nikhil Dholaria


The presence of early-onset, familial Alzheimer’s disease (AD) is rare (around 3% to 5% of cases) and may be accredited to disease-causing mutations. More prevalent, by contrast, is the late-onset, sporadic (non-Mendelian) form of AD, which reflects the interaction of both genetic and environmental risk factors as well as the disruption of epigenetic mechanisms regulating the expression levels of genes [1, 2]. Abnormal patterns of histone acetylation and methylation with anomalies in global and promoter-specific DNA methylation and a deregulation of non-coding RNA have been noted in AD patients as attenuating epigenetic shifts. Epigenetic dysfunction in AD has been linked to core pathophysiological features of the disease including excess production and accumulation of Aβ42, atypical post-translational modification of tau, axonal-synaptic dysfunction and neuritic dystrophy. Accordingly, DNA methylation, histone marks and the levels of multiple species of microRNA are moderated by oxidative stress, neuroinflammation, and Aβ42. Despite novel discoveries in transgenic mouse models and human brain tissue, further analysis and research of epigenetic shifts are of critical importance in elucidating the pathogenesis, biomarkers, and potential treatments for AD [2].


Genetic Risk Factors in Familial and Sporadic AD

Dominant, autosomal mutations in the gene encoding the Aβ42 precursor, amyloid precursor protein (APP), and in the genes encoding Presenilin (PS) 1 and Presenilin 2, the catalytic components of the γ-secretase complex that processes APP following β-secretase (BACE-1), induce a minority (approximately 5%) of familial AD cases [3,4]. APP is a single-pass transmembrane protein highly expressed in the brain, while also being metabolized in a rapid and highly complex mechanism by a series of sequential proteases, one being the intramembranous γ-secretase complex [5]. Mutations in the APP gene or the genes encoding the components of the γ-secretase complex alter the normal metabolism of the precursor protein, leading to an accumulation of neurotoxic peptides. APP processing (proteolysis) by γ-secretase generates β-amyloid (Aβ) peptides of various lengths, including the two major isoforms: Aβ40 (about 90% of all amyloid peptides) and Aβ42 - the only difference being that Aβ42 has two extra C-terminal residues [6,7]. The result of these mutations generates extracellular senile plaques of aggregated Aβ42 (due to their hydrophobicity) and Aβ40 at times [7,8]. In addition, genome wide association studies (GWAS) and meta-analysis have tracked down other gene variants which are common in patients diagnosed with AD [8]. Further study, however, is necessary to ascertain how many and which genes in the human genome could be pathogenic.

Late-onset, sporadic (non-Mendelian) AD is considered to be multifactorial; however, it involves a strong genetic predisposition [9]. The apolipoprotein-E (APO-E) ɛ4 allele is the greatest genetic risk factor with more than 60% of patients being Apo-E4 carriers. Increased APP membrane insertion and processing decreased glial and blood-brain barrier Aβ42 clearance, and promotion of Aβ42 aggregation (though Aβ42-independent mechanisms are involved) are related to Apo-E4-accrued risk [2,10-12]. Nonetheless, an Apo-E4 phenotype is not sufficient enough on its own to provoke the disorder. And although additional risk genes have been identified by unbiased GWASs, genetic factors alone cannot explain late-onset AD [2,12]. It is also quite important to note that the APOE gene contains three major allelic variants at a single gene locus (ɛ2, ɛ3, and ɛ4), each encoding for different protein isoforms (ApoE2, ApoE3, and ApoE4) that only differ in two sites of the peptide sequence. ApoE is a polymorphic glycoprotein expressed in the liver, brain, macrophages, and monocytes. It participates in cholesterol and lipid transportation involved in neuronal growth, repair from injury, nerve regeneration, immunoregulation, and activation of lipolytic enzymes. The variant alleles pose rather contradictory functions, where the APOE ɛ2 allele is thought to have a protective effect, while the APOE ɛ4 allele increases risk in late-onset AD [8].


Environmental Risk Factors in AD

It is important to not neglect environmental factors when discussing the mechanisms and pathology of AD. Research suggests that a host of factors beyond genetics may play a role in the development of AD. Risk factors include age, gender, cerebral trauma, stroke, hypertension, diabetes, chronic stress and depression. A strong deal of interest lies upon the relationship between cognitive decline and vascular conditions like heart disease, hypertension, and stroke. Also, metabolic conditions, such as diabetes and obesity, seem to play a role in the development of AD. Other findings also state that the climate and physical quality of the environment may have an effect on developing dementia, particularly AD. These environmental factors are superimposed on a genetic foundation and act via cellular mechanisms like inflammation, apoptotic cell loss, and oxidative stress. Ongoing research may help people understand how to reduce the risk factors of this disease and how one may also reduce the risk of AD. From previously compiled research, physical activity, nutritious diets, social engagement, and mental stimulation have been associated with keeping people healthy with age. As research continues, scientists and specialists may be able to propose specific models for people to follow to reduce the risk of AD pathology as well as the risk of other neurocognitive and neurodegenerative conditions [2, 13, 14, 15].


Regulating Gene Expression: Epigenetics

Epigenetics, in simple terms, refers to gene expression. The level at which a gene is expressed can have a significant large-scale impact, even potentially causing a change in phenotype. Upregulation and downregulation are direct products of epigenetics, and this change in protein products can increase the risk of AD. Upregulation of the amyloid precursor protein may result in increased plaque quantities, increasing the risk of AD. On the other hand, the downregulation of the protein products of neuroplasticity genes could result in cognitive decline, also increasing the risk of AD.

It is generally accepted that epigenetics works through two mechanisms: modification of histones, the proteins that package DNA, and direct methylation of DNA. These two mechanisms can lead to changes in gene expression, either greatly increasing or greatly reducing the availability of mRNA, and down the line, peptides and proteins. Understanding these mechanisms may go a long way in elucidating possible treatments for AD, including the possible allosteric or competitive blocking of deacetylases and demethylases or even the hyperactivation of these enzymes. Generally, these alterations on epigenetic modifications may provide novel therapies for treating AD, and they may be added to existing therapies to construct a patient-specific therapy. Other epigenetic mechanism, though not considered pure mechanisms under epigenetics, are chromatin remodelers and non-coding RNAs (ncRNAs) [16, 17, 18].


Histone Modification

Histone Acetylation: Based on the identity, histone modifications performed post-translationally have varying effects on gene expression. Generally speaking, increased gene activity is associated with histone acetylation [19]. This marked gene activation is the result from the diminished basic charges of histones following acetylation, reducing the electrostatic interaction it has with the negatively charged DNA backbone. Nucleosome compaction is, therefore, relaxed, allowing transcriptional machinery to do its work [20]. The enzymes responsible for this are classified as histone acetyltransferases (HATs), and in AD, they can upregulate the proteic products of inflammatory genes, contributing to the major symptoms that are involved in the pathology of the disorder. Neuroinflammation and gliosis can, therefore, be exacerbated.

Antagonistic to HATs are histone deacetylases (HDACs), and their actions could cause a downregulation in the products of neuroplasticity genes, leading to neuronal apoptosis and neuritic dystrophy [16]. On a larger scale, the interplay between HATs and HDACs at various locations on the genome can lead to cognitive decline and personality changes, which are commonly seen in AD or pathologically similar disorders.

Histone Methylation: Unlike acetylation, histone methylation depends on both the form of modification and the residue of the specific amino acid in which it occurs. Facilitated by histone methyltransferases (HMTs), methylation is similar to the activity of acetylation, where the genome can vary in terms of expression. Similar to those enzymes under HDACs, histones can be demethylated via histone demethylases.

DNA Methylation

DNA methylation is the most studied epigenetic modification. It includes the introduction of a methyl group at cytosines preceding guanines, coined CpG dinucleotides [22]. DNA methylation is considered an epigenetic mark of repression. This, alongside the enzymes under the HDAC category, can repress the expression of neuroplasticity genes, ultimately leading to AD symptoms. The enzymes that carry this function of methylation are known as DNA methyltransferases (DNMTs) [23].



The nervous system is a highly specialized system in which millions of neurons and supporting glia are organized into varying structures with characteristic epigenetic and expression profiles that are associated with particular functions [24]. The importance of epigenetic mechanisms in the functioning of the nervous system is underscored by the idea that mutations in epigenetic genes cause severe mental disorders [25]. The treatment of these disorders can be interconnected with the epigenetic mechanism commonly seen in somatic cells, including histone acetylation and DNA methylation. Altering these mechanisms may play a role in symptomatic relief or even a cure. Research in AD has been focused on explaining the genesis of these epigenetic mechanisms and how they can be altered to prevent the progression of the disease. While HDAC inhibitors, such as valproic acid, sodium butyrate and others, potentiate learning and memory formation in animal models and have been useful in treating different neurological disorders, including AD, further research is required to truly elucidate the mechanism of these epigenetic enzymes [26,27]. Future research is directed towards answering these mechanisms, and in doing so, neurological research can get one step closer to treating neurological disorders.


Nikhil Dholaria

Nikhil Dholaria

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