Toward an integrated genetic and epigenetic approach to Alzheimer's disease

doi:10.1016/j.neurobiolaging.2010.10.021

Neurobiology of Aging

Volume 32, Issue 7, July 2011, Pages 1188-1191

https://doi.org/10.1016/j.neurobiolaging.2010.10.021 Get rights and content

Abstract

Epigenetics is the study of mitotically heritable, but reversible, changes in gene expression brought about principally through alterations in DNA methylation and chromatin structure. The comprehensive review by Mastroeni et al. (Mastroeni, D., Grover, A., Delvaux, E., Whiteside, C., Coleman, P., Rogers, J., 2010. Epigenetic mechanisms in Alzheimer's disease. Neurobiol. Aging, doi:10.1016/j.neurobiolaging.2010.08.017) in this issue describes mounting evidence for an involvement of epigenetic alterations in the etiology of Alzheimer's disease (AD), highlighting the potential of epigenomic approaches for uncovering novel molecular pathways involved in pathology. Here, we briefly describe some methodological issues related to epigenomic studies using postmortem brain tissue in Alzheimer's disease, and argue for an integrated genetic-epigenetic approach to disease etiology.

Section snippets

Looking “above” the DNA sequence: epigenetics in Alzheimer's disease

Although the neuropathological changes associated with Alzheimer's disease (AD) have been well characterized, there is still considerable debate regarding the underlying etiology of the disorder and the precise mechanism(s) behind disease progression. Given the high heritability estimates for AD (Gatz et al., 2006), much research has focused on uncovering a genetic contribution to the disorder. While autosomal dominant mutations in 3 genes (APP, PSEN1, and PEN2) can explain early onset familial

Considerations for epigenetic studies in AD

The rapid growth in epigenetic research, combined with new high-throughput technologies for epigenomic profiling (Laird, 2010), promises to revolutionize our understanding about the molecular changes associated with complex disease. While it is now possible to systematically profile DNA and histone modifications across the genome, little empirical research has directly studied the role of epigenetic factors in AD, especially taking an unbiased, genome-wide approach across multiple brain

Allelic effects on DNA methylation: implications for an integrated genetic-epigenetic approach to AD

We have recently argued for the adoption of an integrative etiological research paradigm based on the combination of genetic and epigenetic data (Meaburn et al., 2010). Of particular relevance to the etiology of complex disease phenotypes such as AD is increasing evidence for the widespread occurrence of allele-specific epigenetic marks. Outside of classically imprinted autosomal regions, and regions subject to X-chromosome inactivation in females, DNA methylation is generally assumed to be

Future research directions in AD epigenetics

Technological advances in epigenomic profiling methodologies mean that it may soon be feasible to economically map the epigenome at single base pair resolution in large cohorts of samples; the first reference single base resolution map of the methylome was recently published for 2 human cell lines, providing detailed information about the extent and location of methylated loci (Lister et al., 2009). Moving forward, it will be important to establish cause and effect in epigenetic studies of AD;

Disclosure statement

No conflicts of interest exist.

Acknowledgements

This work was supported by NIH grant AG036039.

References (23)

L. Chouliaras et al.
Epigenetic regulation in the pathophysiology of Alzheimer's disease
Prog. Neurobiol
(2010)
J. Hardy
A hundred years of Alzheimer's disease research
Neuron
(2006)
S. Henikoff et al.
Exploring and explaining epigenetic effects
Trends Genet
(1997)
S.B. Nelson et al.
Probing the transcriptome of neuronal cell types
Curr. Opin. Neurobiol
(2006)
R. Pidsley et al.
Epigenetic studies of psychosis: current findings, methodological approaches, and implications for postmortem research
Biol. Psychiatry
(2011)
L.C. Schalkwyk et al.
Allelic skewing of DNA methylation is widespread across the genome
Am. J. Hum. Genet
(2010)
K. Sleegers et al.
The pursuit of susceptibility genes for Alzheimer's disease: progress and prospects
Trends Genet
(2010)
B.E. Bernstein et al.
The NIH Roadmap Epigenomics Mapping Consortium
Nat. Biotechnol
(2010)
D.C. Dolinoy et al.
Environmental epigenomics in human health and disease
Environ. Mol. Mutagen
(2008)
A.P. Feinberg
Phenotypic plasticity and the epigenetics of human disease
Nature
(2007)

A. Fischer et al.

Recovery of learning and memory is associated with chromatin remodelling

Nature

(2007)

Cited by (34)

Epigenetic processes in Alzheimer’s disease
2019, Chromatin Signaling and Neurological Disorders
Alzheimer's disease (AD) is the most common cause of dementia and is characterized by memory loss and cognitive decline, which are consequences of chronic progressive neurodegeneration and synaptic loss. Although histopathologic hallmarks of the disease have been well described, we still have only a limited understanding about the specific mechanistic changes that lead to disease onset, progression, and prevention; therefore, current therapies are mainly focused on treating the symptoms of the disease.
Genomic studies have identified a number of genetic variants that can increase one's risk of developing AD, allowing a better understanding of the biological pathways involved in the disease. At the epigenomic level, robust changes have been described in both the brain and blood, with DNA methylation being the most studied epigenetic process to date. Given the recent technological and methodological advancements, a number of new epigenome-wide association studies are expected in the field, which will bolster our understanding of the role of epigenetic processes in AD and their potential as novel therapeutic targets.
Epigenetics and Pharmacoepigenetics of Age-Related Neurodegenerative Disorders
2019, Pharmacoepigenetics
Neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD), are major problems of health in developed countries. NDDs are polygenic/complex disorders in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Aging is associated with epigenetic changes, resulting in alterations of gene expression and disturbances in broad genome architecture and the epigenomic landscape. Age-related epigenetic modifications affect the brain, representing additional risk factors for NDDs. Paternal age can influence behavioral traits in offspring. Epigenetic changes (DNA methylation, histone modifications, miRNA dysregulation) are involved in the pathogenesis of NDDs by regulating the expression of pathogenic genes and influence the response to conventional treatments acting on mechanistic, metabolic, transporter, and pleiotropic genes. Alterations in the epigenetic machinery that regulates the pharmacoepigenetic network can contribute to drug efficacy, safety, and resistance. A few epigenetic drugs have been tested for the treatment of NDDs with poor results.
Systems biology and gene networks in Alzheimer's disease
2019, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
To date, the NIH Roadmap Epigenomics Program has funded certain investigations focused on the role of epigenetics in AD pathogenesis (Chadwick, 2012). The integration of epigenomics data with other databases will provide researchers an in-depth understanding of AD pathophysiology at system level (Mill, 2011). A typical study integrating epigenomics, genomics, and environmental data suggested that epigenetic changes were caused by the accumulation of environmental damage.
Gene mining has been a fruitful approach in the study of Alzheimer’s disease (AD). As a new starting point for studying AD, genetic and genomic investigations consistently strive to discover causative variants that are related to disease pathophysiology. Currently, genetic and genomic approaches have identified numerous loci. However, the elaboration of AD mechanism lagged behind gene discovery. The extensive use of parallel, high-throughput, next-generation sequencing techniques has improved our understanding of the roles of genetic variants in the brain at the highest level of functional hierarchy. We highlight three molecular systems (the transcriptome, proteome and epigenome) in this review to ascertain whether the methods used in systems biology studies of AD are useful. Here, we present many advantages of the high-throughput molecular, integrative and network methods, which may provide a good reference for future studies employing network biology approaches and large datasets.
Epigenetic Modulation of Human Neurobiological Disorders
2018, Epigenetics in Human Disease
Epigenetic regulation is essential for normal development and maintenance of tissue-specific gene expression pattern in mammals. Up to now, three main interrelated types of epigenetic inheritance have been studied more thoroughly, such as DNA methylation, histone modification, and RNA-associated silencing, yet much remains to be revealed. Disruption of epigenetic regulation process can lead to inappropriate expression or silencing of genes, resulting in “epigenetic diseases.” In particular, because of the complex structure of the nervous system, many neurobiological disorders have an epigenetic component or involve epigenetically regulated genes. Here, the author discusses current knowledge about this matter including some current epigenetic therapies and future directions in the field.
The epigenetics of aging and neurodegeneration
2015, Progress in Neurobiology
Citation Excerpt :
To map the sequence of events leading to the development of complex diseases fully, epigenomic data should not be investigated in isolation, but should be complemented with other modalities, including genomic, transcriptomic and proteomic data (Meaburn et al., 2010). As such, through the integration of genetic and epigenetic approaches (Mill, 2011), non-coding genetic variation might be found to influence gene expression through epigenetic mechanisms. Such integrated data may also help in determining where in the etiopathogenesis of complex neurodegenerative conditions epigenetic players start to play a role.
Epigenetics is a quickly growing field encompassing mechanisms regulating gene expression that do not involve changes in the genotype. Epigenetics is of increasing relevance to neuroscience, with epigenetic mechanisms being implicated in brain development and neuronal differentiation, as well as in more dynamic processes related to cognition. Epigenetic regulation covers multiple levels of gene expression; from direct modifications of the DNA and histone tails, regulating the level of transcription, to interactions with messenger RNAs, regulating the level of translation. Importantly, epigenetic dysregulation currently garners much attention as a pivotal player in aging and age-related neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, where it may mediate interactions between genetic and environmental risk factors, or directly interact with disease-specific pathological factors. We review current knowledge about the major epigenetic mechanisms, including DNA methylation and DNA demethylation, chromatin remodeling and non-coding RNAs, as well as the involvement of these mechanisms in normal aging and in the pathophysiology of the most common neurodegenerative diseases. Additionally, we examine the current state of epigenetics-based therapeutic strategies for these diseases, which either aim to restore the epigenetic homeostasis or skew it to a favorable direction to counter disease pathology. Finally, methodological challenges of epigenetic investigations and future perspectives are discussed.
The role of nutrient-based epigenetic changes in buffering against stress, aging, and Alzheimer's disease
2014, Psychiatric Clinics of North America

View all citing articles on Scopus

View full text

Open peer commentaryToward an integrated genetic and epigenetic approach to Alzheimer's disease

Abstract

Section snippets

Looking “above” the DNA sequence: epigenetics in Alzheimer's disease

Considerations for epigenetic studies in AD

Allelic effects on DNA methylation: implications for an integrated genetic-epigenetic approach to AD

Future research directions in AD epigenetics

Disclosure statement

Acknowledgements

Prog. Neurobiol

Neuron

Trends Genet

Curr. Opin. Neurobiol

Biol. Psychiatry

Am. J. Hum. Genet

Trends Genet

The NIH Roadmap Epigenomics Mapping Consortium

Nat. Biotechnol

Environmental epigenomics in human health and disease

Environ. Mol. Mutagen

Phenotypic plasticity and the epigenetics of human disease

Nature

Recovery of learning and memory is associated with chromatin remodelling

Nature

Open peer commentary
Toward an integrated genetic and epigenetic approach to Alzheimer's disease