Title:Imaging Epigenetics in Alzheimer’s Disease
Volume: 19
Issue: 36
Author(s): Simone Lista, Francesco G. Garaci, Nicola Toschi and Harald Hampel
Affiliation:
Keywords:
Alzheimer’s disease, AD, disease concept, pathophysiology, mechanisms, genetics, epigenetics, biomarkers, DNA methylation
and histone modifications, genome-wide association studies, NGS, MRI, magnetic resonance imaging, PET, positron emission tomography,
systems biology, endophenotypes, neuroimaging, imaging genetics.
Abstract: Sporadic Alzheimer’s disease (AD) is a prevalent, complex and chronically progressive brain disease. Its course is non-linear,
dynamic, adaptive to maladaptive, and compensatory to decompensatory, affecting large-scale neural networks through a plethora of
mechanistic and signaling pathway alterations that converge into regional and cell type-specific neurodegeneration and, finally, into
clinically overt cognitive and behavioral decline. This decline includes reductions in the activities of daily living, quality of life, independence,
and life expectancy.
Evolving lines of research suggest that epigenetic mechanisms may play a crucial role during AD development and progression. Epigenetics
designates molecular mechanisms that alter gene expression without modifications of the genetic code. This topic includes modifications
on DNA and histone proteins, the primary elements of chromatin structure. Accumulating evidence has revealed the relevant
processes that mediate epigenetic modifications and has begun to elucidate how these processes are apparently dysregulated in AD. This
evidence has led to the clarification of the roles of specific classes of therapeutic compounds that affect epigenetic pathways and characteristics
of the epigenome. This insight is accompanied by the development of new methods for studying the global patterns of DNA
methylation and chromatin alterations. In particular, high-throughput sequencing approaches, such as next-generation DNA sequencing
techniques, are beginning to drive the field into the next stage of development. In parallel, genetic imaging is beginning to answer additional
questions through its ability to uncover genetic variants, with or without genome-wide significance, that are related to brain structure,
function and metabolism, which impact disease risk and fundamental network-based cognitive processes. Neuroimaging measures
can further be used to define AD systems and endophenotypes. The integration of genetic neuroimaging methods with epigenetic markers
in humans appears promising. This evolving development may lead to a new research discipline - imaging epigenetics - that will provide
deeper insight into the causative pathogenetic and pathophysiological pathways through which genes and environment interrelate during
life and impact human brain development, physiology, aging and disease. This knowledge may open doors for the development of novel
biomarkers and preventive and disease-modifying treatments.