New form of Alzheimer’s-like dementia recognised by scientists

A new form of dementia has been identified by scientists that mimics Alzheimer’s but affects the brain in a completely different way.

Lack of understanding about the disorder, given the name Late, could be one reason why so many trials of Alzheimer’s drugs have failed, according to the researchers.

Late stands for limbic-predominant age-related TDP-43 encephalopathy.

Studies suggest it is caused by an abnormal version of the TDP-43 protein, which in its healthy form helps regulate gene activity in the brain.

New guidelines for recognising and diagnosing the disease are reported in the journal Brain.

Late does not share a common feature of Alzheimer’s – beta-amyloid peptide, a harmful protein building block which accumulates in the brain in sticky clumps.

It also has nothing to do with another Alzheimer’s hallmark, knots of protein in nerve cells known as tau tangles.

The abnormal “misfolded” protein involved in Late is also thought to play a causative role in motor neurone disease, a relatively rare condition.

But misfolded TDP-43 is very common in older adults. Roughly a quarter of individuals over the age of 85 have enough abnormal TDP-43 to affect memory and thinking ability, say the scientists.

Dr Peter Nelson, from the University of Kentucky, who co-chaired the group of international experts who drew up the Late guidance, said: “More than 200 different viruses can cause the common cold, so why would we think there is just one cause of dementia?

“Late probably responds to different treatments than AD (Alzheimer’s disease), which might help explain why so many past Alzheimer’s drugs have failed in clinical trials.

“Now that the scientific community is on the same page about Late, further research into the ‘how’ and ‘why’ can help us develop disease-specific drugs that target the right patients.”

The group established that Late progresses more gradually than Alzheimer’s and tends to affect people near the end of their lives – the “oldest of the old”.

However when Late occurred in combination with Alzheimer’s – which was common – the two diseases together caused a more rapid decline than either would alone.

Dr Nina Silverberg, director of the Alzheimer’s Disease Centres Programme at the US National Institute on Ageing (NIA), the expert group’s other co-chair, said: “Recent research and clinical trials in Alzheimer’s disease have taught us two things. First, not all of the people we thought had Alzheimer’s have it; second, it is very important to understand the other contributors to dementia.”

Dr Carol Routledge, science director at UK charity Alzheimer’s Research UK, said: “While the research indicates that Late could be contributing to damage to the brain in around 17% of older people diagnosed with Alzheimer’s, this isn’t yet something doctors will be able to diagnose in the clinic.

“People are diagnosed with a specific form of dementia based on the symptoms they experience. When the symptoms of diseases overlap, it is very difficult to reliably determine the underlying cause.

“Although we tend to look at the brain changes that cause dementia as separate diseases, multiple processes are often under way at the same time. It can be difficult to say where one disease starts and the next one stops.

“As we learn more about the complex brain changes involved in dementia, it’s not surprising that new sub-types of diseases could emerge.

“Alzheimer’s Research UK is investing in research into a number of culprit proteins implicated in dementia including TDP-43. To have the best chance of developing effective treatments, we have to improve the diagnosis of specific causes of dementia and develop targeted drugs that can be tested in the right patients at the right time.”

Dr James Pickett, head of research at Alzheimer’s Society, said: “Dementia is an extremely complex condition that may be caused by many different underlying diseases. Though at an early stage, this research is taking a real step forward by proposing a new sub-type of dementia.

“This type of research is the first step towards more precise diagnosis and personalised treatment for dementia, much as we’ve started to see in other serious diseases such as breast cancer.

“This evidence may also go some way to help us understand why some recent clinical trials testing treatment for Alzheimer’s disease have failed – participants may have had slightly different brain diseases. But more research into Late is required to clarify specific symptoms, identify biomarkers, understand risk factors and develop treatments.”

Robert Howard, Professor of Old Age Psychiatry at University College London, said: “This is probably the most important paper to be published in the field of dementia in the last five years.”