Hunting for genes: A source of new insights into dementia

From the Autumn 2016 edition of Care and cure magazine, find out how lifestyle and genetics affect who gets dementia.

Our risk of developing dementia is a complex interaction between lifestyle and genetics. While we cannot do anything about our genes, knowing more about them can help researchers to better understand dementia and find new treatments.

The genetics of dementia is highly complicated, with dozens of genes linked to different types of the condition. Some rare genetic mutations directly cause dementia, while others might raise the risk of developing it over your lifetime.

It can be difficult to get to grips with if you are not an expert, but if you are then it is a great way to understand dementia. 'Genetics is fairly straightforward when you compare it to other fields,' says Dr Jose Bras, an Alzheimer's Society fellow at University College London.

'DNA is DNA - there aren't many things that can affect your results.' Jose is studying the genetics of dementia with Lewy bodies (DLB), a form of dementia that has similarities with both Alzheimer's and Parkinson's disease.

'We haven't done as much research into DLB as we have into Parkinson's or Alzheimer's. When I started we didn't know much about the genetics of DLB. In the past four years, we have found four or five genes that increase a person's risk of developing DLB by a small amount. It doesn't mean that a person will develop DLB, but it raises their lifetime risk.'

Some of these genes can only increase the risk of DLB by 0.5 per cent, so it is very difficult to detect them. One of the main ways to do this is to compare large numbers of people with the disease and people without. Finding a gene that is more common in people with the disease suggests that it could be a contributing factor.

To find genes that have such a small effect, researchers need a large number of DNA samples.

'When you look at work on Parkinson's, it's about 100,000 people that are included in these studies. We currently have about 1,400 for DLB and when I started it was only 50,' says Dr Bras.

New insights

Finding these genes can reveal new insights into the disease.

'These genes for DLB are involved in Parkinson's and Alzheimer's disease, so that means they are linked not just in how they present clinically but also in their biology.

'If you can understand genetics, it opens new doors for treating the disease.'

Dr Rita Guerreiro, Jose's colleague and wife, understands this well. She previously discovered that mutations in the immune system gene TREM2 could increase the risk of developing Alzheimer's disease. Although these mutations are quite rare, only found in 2 per cent of people with Alzheimer's, the identification of TREM2 emphasised the importance of the immune system in the development of the condition.

'There are now drugs that are being tested to target the immune system to treat Alzheimer's disease,' she says.

Rather than searching through DNA samples from thousands of people, Dr Guerreiro discovered this aspect of TREM2 through a rare form of dementia found in three Turkish families where people inherited two mutated copies of this gene- one from each parent.

'They had a dementia that was similar to frontotemporal dementia, which was due to mutations in both copies of TREM2. So we searched for these same mutations in larger groups and found that having only one copy of the gene raised the risk of developing Alzheimer's disease.'

Although this TREM2 mutation triples the risk of Alzheimer's, it is too rare to have been detected by earlier attempts to screen large numbers of people. To have such a strong effect on the risk of dementia indicates that it could be an important avenue of research.

Since the discovery, Rita has been given several awards for her work, including an Alzheimer's Society Dementia Research Leaders award in 2015, which Jose also won this summer.

'I am now trying to do the same with other rare forms of dementia and we have already found two other interesting genes,' says Rita, now an Alzheimer's Society Senior Fellow.

'Finding these genes is important for the families too, so they can get a diagnosis. We work closely with clinicians in Portugal and Turkey, where the families can be underserved for genetic testing.'

Changing pace

In genetics, the pace of change in technology has been dramatic over the past few years.

'Each one of us has 20,000 genes and when we started in genetics we could only look at one gene at a time,' says Jose.

'Now we are looking at the whole genetic makeup of a person and that's quite amazing,' says Rita. 'We can now start to look at thousands of patients with this scale.'

Genomics England is aiming to do this through the 100,000 Genomes project, to understand more about the genetic causes of cancer and various rare conditions. As part of this, they plan to analyse every gene in hundreds of people with rarer forms of dementia. This will include people who have inherited forms of Alzheimer's disease, which are very rare and account for only one in 1,000 people with dementia. This is due to a small number of mutations that directly cause Alzheimer's, often by the age of 50. The effect of these mutations is so strong that you only need to inherit one damaged copy of the gene from one parent for it to trigger Alzheimer's.

Previous studies of families where these mutations had passed down through generations have revealed a lot about how the disease develops. The first of these mutations, discovered in 1991, showed the importance of the build-up of amyloid protein - a crucial piece of evidence that focused drug development efforts to target amyloid.

This type of genetic defect was relatively straightforward to identify because of its profound impact and pattern of inheritance in a family. Today's searches are looking for much more subtle effects - it may be the total impact of dozens of genes that come together to give each person their overall risk. Advances in technology are helping us to see that bigger picture.

'It will get to a point where we each know all of our genetic makeup,' says Jose. 'But understanding it is a completely different matter.'

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