One of the best ways to understand the genetics underlying Alzheimer’s disease is through large DNA studies. These studies are known as genome-wide association studies (GWAS) and involve analysing the genetic make-up of people with and without Alzheimer’s or other causes of dementia, in great detail. GWAS studies have ‘flagged up’ different versions of certain genes that can affect a person’s risk of developing the disease and often end up in the headlines. However, we still have a lot to learn about how these genetic variations affect Alzheimer’s disease risk. Scientists are now also turning to more subtle genetic changes called epigenetics to look for clues. In this blog, we will explore how epigenetic changes may influence the risk of developing Alzheimer’s disease.
What is epigenetics?
The 40,000,000,000,000 or so cells in the human body all contain the same set of genetic instructions and yet they are different cell types with varying roles. It’s amazing that the identical genetic code can be used to produce different cells, which perform different functions. There must be a mechanism that controls whether genes are switched on or off or fine-tunes their activity. This mechanism is called ‘epigenetics’ and involves chemically tagging DNA next to a gene. These small chemical additions on our genetic material are called ‘epigenetic marks’ and there are many different types.
DNA methylation is the most commonly researched type of epigenetic mark and involves the addition of a molecule called a methyl group (simply a carbon molecule with three hydrogens atoms) to the sequence of letters that makes up a gene. This causes the gene to be switched off.
Epigenetic marks can also have an effect in a number of other ways. One of these is to influence how tightly wrapped the DNA is and therefore how accessible it is to the machinery that needs to translate it into the right message. There are about 1.8 metres of DNA per cell, tightly wrapped around proteins called histones. Histones can also be decorated by a variety of epigenetic marks, which can affect how ‘readable’ the genetic information is. This can also determine whether a gene is switched on or off.
So how is this relevant to Alzheimer’s?
Previous studies suggest that lifestyle factors such as diet and exercise, which raise the risk of Alzheimer’s disease, may be having some effects through epigenetic changes. However, it is not clear where these epigenetic changes are taking place in the genetic code, or how they affect the risk of Alzheimer’s disease. Recent epigenome-wide association studies (EWAS) – a sophisticated technique that analyses these chemical tags – have shed light on the epigenetic changes that occur in people with Alzheimer’s disease. Researchers, including those based at the University of Exeter and King’s College London, have used brain tissue donated via the Brains for Dementia Research scheme, to study the levels of DNA methylation in the cortex – an important part of the brain affected by Alzheimer’s.
The team found that the DNA next to a gene called ANK1, a known risk gene for type 2 diabetes, had higher levels of methylation in people with Alzheimer’s disease compared to those without the disease. Some of this work was supported in part through an Equipment Grant from Alzheimer’s Research UK. The researchers suggested that the silencing of ANK1, a gene which had not previously been linked to Alzheimer’s, may be an important process in the disease. Now, they need to tease apart the molecular mechanisms that can explain this.
Investigating how epigenetic marks influence genes in Alzheimer’s disease is still a relatively new area of study. As these changes may be reversible, identifying those involved in Alzheimer’s disease could provide new targets for the development treatments. The research carried out to date also suggests that some of these epigenetic changes may occur early in the disease process and so may hold potential for diagnosis and prediction strategies. However, more work needs to be done to understand whether epigenetic changes play a causal role in Alzheimer’s disease, or occur as a result of it.
Alzheimer’s Research UK is helping to fund research to take us a step closer to understanding and defeating this devastating disease. Dr Lunnon, a scientist at the University of Exeter and Network Administrator for the South West Alzheimer’s Research UK Network, has played a key role in bringing these epigenetic changes to light. Now, with support from Alzheimer’s Research UK, she is carrying out a pilot project to study whether epigenetic changes interfere with how nerve cells can use energy in Alzheimer’s.
The importance of understanding this area of research is highlighted by the fact that epigenetic changes have been linked to the development of other diseases, including cancer. Epigenetic marks, including DNA methylation, have been proposed as a potential way to detect prostate cancer, and drugs that influence the so-called ‘epigenome’ are already licensed for clinical use, with more in development for the treatment of certain cancers.
Alzheimer’s affects over half a million people in the UK, and there is, as yet, no treatment that can stop or slow the spread of the disease through the brain. We urgently need more pioneering research to understand exactly why the disease occurs and to find new potential avenues for treatment research.
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