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Research published in the journal Brain describes a recently recognised brain disorder similar to Alzheimer’s disease.
Dr Carol Routledge, Director of Research from 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 underway 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 subtypes 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.”
Prof Tara Spires-Jones, UK Dementia Research Institute Programme Lead and Deputy Director, Centre for Discovery Brain Sciences, University of Edinburgh, said:
“This paper led by Prof Schnieder in Chicago and Prof Nelson in Kentucky in the USA examined what is known from multiple studies about brain changes in a form of dementia called “LATE” or Limbic-predominant age-related TDP-43 encephalopathy. In this disease, a protein called TDP-43 or Transactive response DNA binding protein of 43 kDa, clumps in parts of the brain important for memory and emotion.
“LATE” pathology was found in over 1 in 5 people over 80 years of age, which implies that this disease is common in the oldest-old. The symptoms and genetic risk factors for late overlap with two other causes of dementia, Alzheimer’s disease and frontotemporal dementia. This paper is important because we know that dementia symptoms can be caused by many underlying diseases, and it is essential to understand what causes the diseases in order to develop targeted treatments.”
Prof Robert Howard, Professor of Old Age Psychiatry, University College London (UCL), said:
“This is probably the most important paper to be published in the field of dementia in the last 5 years. Limbic-predominant age-related TDP-43 encephalopathy (LATE) has clearly been an under-recognized contributor to dementia, particularly in people over the age of 80, and the paper will draw the attention of the field to this massively.
“Alzheimer’s disease is the most common cause of dementia and we give this diagnosis to patients who present with a progressive memory disorder, accompanied by difficulties in other cognitive areas that affect normal daily living.
“But, those of us who work in dementia have long been puzzled by our patients who have all the symptoms of Alzheimer’s disease, but whose brains do not contain the pathological features of the condition. We have also been puzzled by a group of often very old patients whose dementia does not progress as rapidly as we would expect with Alzheimer’s disease. We now know that these puzzling patients are probably suffering from LATE and not Alzheimer’s disease and that LATE may be “mimicking” Alzheimer’s in about 20% of cases.
“Why is this so important? Firstly, recognition that some of our patients who have been diagnosed with Alzheimer’s disease may in fact have a different condition will be important in terms of offering a slightly better prognosis. Second, treatment trials of drugs that are designed to work against Alzheimer’s will not have any efficacy against LATE and this has important implications for the choice of participants in future trials.
“It’s not often that I have a new and potentially useful diagnosis to share with my patients and colleagues, but I am sure that I will be introducing LATE to several of them over the next few weeks.”
Prof Bart De Strooper, Director of the UK Dementia Research Institute, University College London (UCL), said:
“Dementia is a symptom of diseases with many different molecular causes. The current work is excellent as it makes us to realize that the TDB-43 protein on its own is likely, next to the amyloid plaques and neuronal tangles in Alzheimer’s disease, a cause of late in life dementia. The work will help to define in better ways the different forms of dementia and makes it necessary to have a second look at the failed amyloid trials: maybe part of the negative results are explained by the fact that we treated the wrong patients with the wrong drugs.”
Prof De Strooper also answered the following questions:
What is the difference between Alzheimer’s disease and LATE?
“It is the type of protein that is aggregating and accumulating. Alzheimer’s Disease is characterized by amyloid beta and Tau aggregation, this new disorder is characterized by TDB-43 aggregation. Notice that the two disorders in many cases go together.
Is this good quality research? Are the conclusions backed up by solid data?
“It is a review of existing data and to what extent they should be re-interpreted taking in mind this new disease category. It makes sense to me and it could be very helpful for understanding the TDB-43 aspect of dementia,
Have the authors accounted for confounders? Are there important limitations to be aware of?
“The major issue is that this diagnosis can only be made post-mortem, much alike twenty years ago we were saying for Alzheimer’s Disease. It is a descriptive and mainly morphological definition, and we will need to see how this further pans out. I would have preferred a molecular definition with TDB-43 as the starting point and putting the inherited forms of dementia caused by mutations in TDB-43 in the same disease entity. I assume that this was not done because of the clinical manifestations of these diseases, despite all having the same molecule as main marker, come out very differently clinically.
What are the implications in the real world? Is there any overspeculation?
“(1) it will refocus attention to TDB-43 physiology and stimulate work to find biomarkers for this pathology so that we can make more refined diagnosis
(2) it explains possibly to a certain extent why some trials in the Alzheimer field failed: while they were curing the amyloid pathology, TDB-43 pathology just went on
(3) it will stimulate industry to find drugs against TDB-43 or related pathways.”
Dr James Pickett, Head of Research at Alzheimer’s Society, commented,
“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.
“Although diagnosis rates are improving there are still many people living in limbo without an explanation for their symptoms. That is why Alzheimer’s Society is investing over £3.5 million into research to accurately diagnose different types of dementia so people can access the support they need and take part in relevant clinical trials.”
‘Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report’ by Nelson et al. was published in Brain at 17:00 UK time on Tuesday 30 April.
Declared interests:
Dr Carol Routledge: Dr Routledge has no conflicts of interest.
Prof Tara Spires-Jones: “I have no conflicts of interest with this paper.”
Prof Robert Howard: “No conflicts or disclosures.”
Dr James Pickett: “Nothing”
None others received.