Is dementia in your genes?
Dementia is an umbrella term that covers a range of neurodegenerative diseases, including Alzheimer’s (which is the most common form), fronto-temporal dementia, vascular dementia and more. Yet although these conditions all have different symptoms and affect different parts of the brain, they all boil down to the same biological principle: nerve cells dying. And while there are treatments that can help with the symptoms of some types of dementia, we still have no cures.
To find out how scientists are using genetics to understand dementia, Kat Arney went to the UCL Institute of Neurology to meet husband and wife team Rita Guerreiro and Jose Bras. She started by asking Jose to explain what we know so far about the role of genes in dementia. In particular, Kat wanted to know whether these conditions are caused by genetic changes that we pick up during a lifetime - as is the case with cancer - or whether they’re influenced by genetic variations that have always been there.
Jose - As far as we know, it’s more from birth. So in cancer, it’s slightly different because you can go into a tissue that has the disease, that has cancer, and you can see if there are changes.
In people with dementia, you can't go into the areas of the brain where the disease is occurring and look at the DNA of those cells only. You can't stick a needle into a brain of a living person and get some DNA out of it. So, as far as we know, it’s more changes that come with the person’s genetic makeup.
Kat - What sort of genetic variations and changes seem to be the chief suspects?
Jose - So for all of these diseases, for all of these dementias, we have a number of genes that we know are involved, and they're different for almost all of the diseases. There's a couple of ways in which we look at genetics involved in dementias. We look at genes that cause each of these diseases and these are genes where very rare mutations occur, and when they're there you get disease.
Kat - Would those be the kind of conditions that you can see going through families? You get some families with lots of the same type of dementia.
Jose - Exactly. These are exactly those types of mutations that lead to these diseases. They are very rare. It’s a small proportion of – for example, in Alzheimer's disease – small proportion of all Alzheimer's disease is familial, has these mutations in a small proportion. But on the other hand, even knowing that a gene that’s very rare is involved in a disease is incredibly informative for us because it enables us to identify biological pathways that are involved in these diseases. And so, it’s a very active area of research finding these genes.
Kat - So Rita, in terms of trying to understand how these genes, these faulty pathways might be involved, what sort of approaches are you taking in the lab, working together?
Rita - We use two main approaches in the lab. We look at genetic variability in families and we compare this genetic variability between individuals that, for example, are living with dementia and individuals in the family that are healthy. By comparing the genetic variants within the family, we are – in some cases – able to identify the mutations and the genes that cause the disease in that family. And so, this is used mainly to find causative mutations.
When a patient has that mutation, he or she will develop the disease within their lifetime. But we also use this genetic variability to compare between large groups of individuals living with dementia and large groups of healthy individuals. When we do this type of comparison, what we are trying to do is to identify risk factors. Variants in the genome of these individuals that will either be protective for dementia or that will increase the risk for the development of dementia in these individuals.
We have moved from being able to look at maybe a handful of variants in maybe a couple of hundred individuals at the same time. Now, we can look at the whole genome base pair by base pair, so a really incredible resolution when we do this. And we can do this in an enormous number of patients and of people, so this really was a very, very big advance in the past decade.
Kat - If there's one thing I know about genetics, it’s that there has been a huge explosion of data and techniques, but - oh my goodness! - it has made things very complicated. So how do you go from – as you described, you’ve got these very kind of strong affecting gene variations, mutations that track through families, you know they definitely evolve, they definitely make cells go wrong, cause the cells to die in certain types of dementia.
Then you’ve got all these genetic variations in thousands and thousands of people that kind of subtly raise or lower their risk of the condition. How then do you pin those genetic variations to actually doing something? How do you know what all these hundreds, thousands of genetic variations might actually be doing?
Jose - That's a very good question and it’s a very difficult question to answer. So when we do these studies that Rita was mentioning – these association studies – we identify really regions of the genome that are involved in the disease. We don’t identify genes and we don’t necessarily identify variants that are themselves increasing or reducing risk for disease.
Again, from the region so the actual variants and their effect is incredibly difficult. And so, these are things we’re working on at the moment. It’s a very important question to answer, but for the vast majority of these regions, we haven't really been able to identify the driving mechanism of those associations.
Kat - Given that you are finding these variations, you're trying to study them, it sounds like a terrible question to ask but, what's the benefit? How can this actually improve the situation for people living with dementia, with their families? What do you do with this knowledge?
Rita - The first answer to that is directly to the patients. It’s very difficult to see what is coming out from here, but from a disease perspective, it gives us an enormous knowledge about the biology and the pathobiology of what we are seeing in the patients. Of course, the goal is to have this information and develop therapies, and develop new drugs that are targeted to these genes or to these proteins.
Now in terms of genetic variability and risk, what can be done and what is currently being worked on is to just model the risk of which per cent according to all the variants that they have and put this all into the same model and just get a score at the end that will tell us eventually if that person will have a much higher risk of developing disease or not.
Jose - One of the things for which these scores are important is for clinical trials. So we want to have the best cohorts in our clinical trials so that we get the most powerful answers from these trials. If we can identify the individuals that are more relevant to each study that we’re doing based on their genetic makeup, this is going to enable us to have much better clinical trials and what we’ve been able to do so far.
Kat - So there are direct to consumer tests – things like 23andMe and they look at – particularly, there's one variation that’s associated with the risk of Alzheimer's. I think it’s the APOE gene. What can people take away from this kind of test?
Rita - So, it is the strongest genetic risk factor for Alzheimer's disease. With this said, this means that if you do have the risk allele which we call the E4 allele, it doesn’t mean that that person is going to develop Alzheimer's disease. It just means that it’s at an increased risk for the development of the disease.
Jose - Personally, I am in favour of direct-to-consumer tests. I always think that having information is a good thing. Of course, you need to be able to deal with the information as what Rita was eluding to. But on the other hand, you want to know as much as you can about yourself. This is one very good way of knowing quite a few things about yourself.
Kat - If you did discover you carry this variation that increases your risk of Alzheimer's, is there anything that can actually be done? We hear about things like – to reduce your risk of heart disease, you should exercise, you should eat healthily. What could people do – if anything – to reduce their risk of dementia?
Jose - Well, you can exercise your mind. That’s one of the ways that we think helps. You can keep an active mind, keep an active body. We think all of these things are helpful, but of course, we don’t have therapies. So having a strong risk factor for Alzheimer's disease perhaps will enable you to start to do these things earlier.
Perhaps this will delay the onset of the disease if you ever get to develop the disease because as Rita said, having an E4 allele doesn’t mean you'll get the disease. So, having the information is perhaps in many instances is a very useful thing.
Kat - Jose Bras and Rita Guerreiro from UCL’s Institute of Neurology.