Untangling frontotemporal dementia

Dementia is thought to affect around 850,000 people in the UK. Most people associate the condition with Alzheimer’s disease, the most common cause of dementia. But there are other diseases that can cause the symptoms of dementia – including frontotemporal dementia (FTD). FTD is a much rarer disease than Alzheimer’s, thought to account for around one in 20 cases of dementia.

FTD usually occurs at a younger age than Alzheimer’s disease, typically affecting people in their 40s, 50s or 60s, and memory problems aren’t normally the initial symptom. This is because very specific areas of the brain are damaged in FTD, the frontal and temporal lobes.

The frontal lobe is the area of the brain that is important for our personality, emotions, and behaviour. The temporal lobe plays an important role in how we process speech. Many of the symptoms commonly associated with FTD are linked to these processes.  People can experience changes in how they deal with their emotions, they may struggle to say or understand words and sometimes their behaviour changes in ways that might be socially inappropriate.

The many faces of FTD

FTD is a broad term for the diseases that cause damage in the frontal and temporal lobes. But scientists and doctors also classify people with an FTD diagnosis into even more specific groups. Broadly FTD can be split into four major categories each with unique symptoms and brain changes:

• Behavioural variant FTD – damage to the frontal lobe often affecting social behaviour
• Semantic dementia – the temporal lobe is predominantly affected, which leads to a reduction in understanding of language and factual knowledge
• Progressive non-fluent aphasia – damage is primarily seen in the frontal lobe, but affects a person’s ability to speak fluently
• FTD associated with motor neurone disease

Protein clumps in FTD

There is one thing that we know is common across the different forms of FTD – the formation of protein clumps or tangles. It can be a bit like that drawer we all secretly have at home, the one that is full of forgotten cables and wires.

Individually those wires are all useful for something but now they’re tangled together in one big clump. They can no longer be used for what they were supposed to and to make matters worse, anything else that goes into that drawer becomes trapped in the wire clump.

In many of the diseases that cause dementia, proteins clump together much like the wires in that secret drawer. The proteins can no longer carry out the functions they are designed for and they damage the area of the brain around them. The damage leads to cell death which disrupts the normal function of the brain.

While protein clumps are common in all types of FTD, the specific proteins that form the clumps vary across different forms of FTD. Scientists know that the toxic protein clumps are usually made up of one of three proteins: tau, TDP-43 and FUS. This adds another level of complexity for researchers hoping to develop treatments for the disease, as different drugs may be needed to target each protein.

If you’ve read some of our other blogs, you may have heard of some of these proteins before. Like tau, which is known to form tangles in the brain in Alzheimer’s disease. A similar thing happens in some forms of FTD. The protein becomes overloaded with chemical tags and tangles together. This tangled protein is toxic to nerve cells in the brain and they begin to die.

FUS and TDP-43 might be less familiar. While they haven’t been linked to Alzheimer’s disease, TDP-43 has recently been associated with a newly identified disease that causes dementia known as limbic-predominant age-related TDP-43 encephalopathy or LATE. Both proteins have also been shown to be involved in a movement-related neurodegenerative disorder – motor neurone disease (also known as amyotrophic lateral sclerosis). The links between these proteins and other brain diseases can help provide scientists with clues about what may go wrong in FTD.

Genes and FTD

FTD is thought to be more commonly caused by faulty genes passed down through families than other diseases that cause dementia. Across all forms of FTD around one in 10 cases are inherited but this is much higher for instance in the behavioural variant of FTD. People with a diagnosis of FTD who can trace this back to a faulty gene are often referred to as having “familial frontotemporal dementia”.

Researchers have identified several faulty genes that can cause FTD, including C9ORF72, tau and progranulin. The different faulty genes lead to different symptoms within people and different proteins that form the infamous clumps seen in FTD. For instance, people with a faulty version of progranulin or C9ORF72 are more likely to have clumps made up of TDP-43. The genes we know can cause FTD have also provided another link to motor neurone disease. Faulty versions of the C9ORF72 gene can cause both conditions and sometimes result in an overlap between the diseases in people.

While we can’t change our genes, knowing about specific things that can trigger FTD is another clue for scientists hoping to discover life-changing treatments. It gives researchers potential targets to look at or pathways to explore in their research.

For some people with FTD however, there is no family history and scientists can’t find just one faulty gene. It is likely that there are a variety of different risk factors that may contribute, and researchers are constantly working to discover these.

Unpicking the clumps of FTD

At Alzheimer’s Research UK we believe that research is the only way to bring about our vision: a world where people are free from the fear, harm and heartbreak of dementia. Research into FTD is a key part of that vision.

The complexity of FTD, from the symptoms to the underlying problems in the brain, presents a huge challenge for researchers. They need to be able to accurately diagnose people and understand how to tackle the different forms of FTD.

Alzheimer’s Research UK has funded over 40 projects investigating FTD, including work by Prof Delphine Boche to understand how protein clumps in the brain trigger the immune system and what that means for FTD progression. Or researchers from Kings College London, who are interested in how two of the important proteins, tau and TDP-43, interact.

Each clue that scientists find to further our understanding of what goes wrong in FTD brings us closer to finding a life-changing treatment.