Frontotemporal dementia: lesser known than Alzheimer's, just as big an impact
Have you heard of frontotemporal dementia? This form of dementia is less well known than, for example, Alzheimer's disease, but its impact on patients and their families is just as profound. Rosa Rademakers (VIB/UAntwerp, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences) has made it her life's work to find out as much as possible about this rare brain disease.
Frontotemporal dementia affects cells in the front (frontal) and side (temporal) of the brain. This form of dementia can affect people relatively early in life, often those in their 40s or 50s, but sometimes even those as young as 30. It is an incurable disease, and most patients die within 10 years of diagnosis. This disease has, therefore, an enormous impact on both patients and their families. It is believed that about 1 in 5000 people live with this form of dementia.
Identifying the causes of this group of degenerative brain disorders has become the life's work of Rosa Rademakers. She achieved global acclaim for her research during a 14-year residency at the prestigious Mayo Clinic in Jacksonville (Florida, USA). In 2014, at the age of 36, she was appointed full professor, the youngest ever at the Mayo Clinic. In 2019, she returned to Belgium to head the VIB Centre for Molecular Neurology at the University of Antwerp, where she obtained her PhD in 2004.
Behavioural and language problems most noticeable
‘People with frontotemporal dementia don’t suffer from memory problems as much as people with Alzheimer’s do’, Rademakers explains. ‘However, they do show noticeable changes in their behaviour and personality: they can be uninhibited, their social behaviour isn’t always appropriate, and sometimes this means they can be aggressive. Also, people with frontotemporal dementia often have language and speech problems.’
This is essentially a diverse group of degenerative brain disorders, some of which are hereditary. Moreover, exactly what goes wrong in the brain is not the same for all patients.
Link between dementia and ALS
About 20 years ago, researchers came across several families in which two neurological disorders occurred simultaneously. Some family members developed typical symptoms of ALS: cramps, weakened muscles, and eventually paralysis in arms and legs. Other individuals in the same family lost control of their behaviour and emotions, and were diagnosed with frontotemporal dementia. A few also had a combination of both. It turned out that these two diseases were more related than initially thought.
Geneticists soon identified a link between whether a family member developed the disease and something on chromosome 9, but the exact DNA error proved more difficult to find. Rademakers also grappled with it for years. It wasn’t until 2011, with the help of more refined ways of reading DNA, did the puzzle pieces fall into place.
All the sick people in the family we studied had a really long repeated sequence and the healthy people didn’t. We were all holding our breath: “Wow! That actually might be it!”
‘We knew it had to be somewhere on the tiny remaining piece of chromosome 9’, says Rademakers. ‘We’d already done several tests, but found nothing.’ That was until she and a lab assistant realised it could be a mutation, a repeated sequence in the DNA. ‘Sure enough, all the sick people in the family we studied had a really long repeated sequence and the healthy people didn’t. We were all holding our breath, watching the computer screen while that rolled out of the machine and thinking “Wow! That actually might be it!”’, she explains.
The discovery of that DNA repeat in a previously unknown gene (C9ORF72) was a huge breakthrough. Within one family, people who were healthy had a small number of these repeats, while those with frontotemporal dementia or ALS sometimes had thousands of them.
Impact
The impact of that discovery only really became clear when the researchers looked at other families: they saw the same pattern in 1 in 3 of them. Rademakers and her team then looked at how this strange repeat in the C9orf72 gene appeared in other patients with frontotemporal dementia, where there was no family history. In that group too, 1 in 20 patients had these extremely long repeats in their DNA.
Although ALS and frontotemporal dementia are not hereditary in the vast majority of cases, this discovery was a massive boost in this field of research. Finally, there was now a clear lead, and the search for biological mechanisms, biomarkers and a treatment could begin.
Over the past 15 years, research by various labs worldwide has shown that the repeated expansion in the C9orf72 gene triggers various disease processes. Multiple strategies to counter those effects are currently being tested in clinical trials. ‘At the moment, these therapies are still very expensive. I don't know if they’re going to be effective, but the results are hopeful’, says Rademakers.
Generet Award for Rare Diseases
In 2021, as a result of her research, Rademakers became the first female and youngest ever recipient of the Generet Award for Rare Diseases, an award worth €1 million, from the King Baudouin Foundation. The award was given to advance research into the genetic causes and mechanism behind an even rarer form of frontotemporal dementia, known among specialists as aFTLD-U.
Unravelling the molecular background of frontotemporal dementia provides a springboard for better diagnosis and follow-up, and ultimately even for a potential treatment.
Thanks to this additional funding, Rademakers and her team recently came up with another breakthrough: they discovered a new genetic clue that significantly increases the risk of frontotemporal dementia. For the first time ever, this provides a clear lead for a disease which we have previously known very little about.
Rademakers concludes, ‘Unravelling the molecular background of the different forms of frontotemporal dementia not only gives us insight into the underlying disease mechanisms, but also provides a springboard for better diagnosis and follow-up, and ultimately even for a potential treatment.’
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Dementia has an enormous impact on our aging society. Estimates say that 50 million people suffer from dementia and that, in the next decade, this number will only increase. Research into causes and therapies is therefore indispensible. You can help by making a donation.