A study led by Icahn School of Medicine at Mount Sinai has identified and mapped methylation across a number of different genetic regions associated with Alzheimer’s disease to try and better understand how epigenetic factors may influence disease onset and progression.
Alzheimer’s disease is the most common form of dementia and is a growing problem amongst older individuals. Today, 6.5 million Americans are predicted to have Alzheimer’s, but this is projected to double by 2050.
One of the reasons Alzheimer’s is difficult to treat is its complexity and heterogenous nature. Genetics, such as carriage of the APOE ε4 genetic variant, plays a strong role in susceptibility to this neurodegenerative condition, but environmental factors are also important.
Recent research has shown links between abnormal changes in methylation, the epigenetic process through which gene expression is impacted by factors such as the environment, and Alzheimer’s disease. However, epigenetic regulation is a complex process and can be hard to interpret.
This study, published in the journal Alzheimer’s & Dementia, profiled genome-wide methylomic variation in the parahippocampal gyrus—a region involved in a variety of functions including memory processing—in 201 post-mortem brain samples from healthy individuals, those with mild cognitive impairment and individuals with Alzheimer’s disease.
As well as looking for methylation changes, the team also assessed the influence of the changes on mRNA and other aspects of gene expression. They discovered 270 distinct genetic regions that were methylated differently in individuals with Alzheimer’s versus normal controls.
The researchers used the information they collected to develop a method of quantifying methylation impact on individual genes and proteins, which they hope will help clarify the Alzheimer’s disease process further.
During the course of the study the team identified potential upstream epigenetic regulators of Alzheimer’s disease and also combined their findings with multi-omic data to show how methylation can impact chromatin accessibility and therefore gene and protein expression.
“Our study represents the first comprehensive effort to integrate high-throughput profiling of multi-omics in Alzheimer’s disease,” said senior author, Bin Zhang, Willard T.C. Johnson Research Professor of Neurogenetics and Director of the Mount Sinai Center for Transformative Disease Modeling, in a press statement.
“It provides a framework for future data integration at the multi-scale network level and could lead to the discovery of new targets for drug discovery in Alzheimer’s disease.”
Zhang and colleagues now plan to continue their work on methylomic variation and focus in on the impact of these changes at a single cell level. They believe the latter will help to map methylation impact on different cell types.
