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expert reaction to tau levels in blood as a predictive biomarker for dementia

Research published in JAMA Neurology suggests that total tau levels in blood may improve the prediction of future dementia.

Dr James Pickett, Head of Research at Alzheimer’s Society, said:

“For the 850,000 people living with dementia in the UK and their families, the long wait for new treatment has been agonising, so any new hope for a breakthrough is welcome.

“It’s exciting that these researchers were able to measure levels of a protein – tau – in blood and predict who would be diagnosed with dementia 4-8 years later. But the approach isn’t accurate enough yet to be used in the clinic to diagnose dementia.  The test could be useful for identifying people at higher risk of dementia at the very earliest stages of the condition, who could then take part in clinical trials. We know that the sooner dementia is identified, the better the chance of finding treatments to slow down or even stop its progress.

“This study represents a potentially important advance in the study of dementia, as it builds on previous research from others and our own researchers which suggests that blood tests could be used to test for dementia risk. The group they looked at, though large, were mainly white, so we’d need to look at how the test works in diverse populations before it can be useful for clinical trials.”

Dr David Reynolds, Chief Scientific Officer at Alzheimer’s Research UK said:

“We know that the tau protein is strongly implicated in diseases like Alzheimer’s. A key goal for dementia research is to develop blood-based tests to detect early changes in these diseases. Searching for reliable markers of disease in blood is a tricky task, as protein levels can be influenced by so many factors that change from person to person.

“Given the risk of false positives or negatives from tests like this, it’s unlikely this test for tau will help to diagnose people in the near future, but it may help researchers to identify people to take part in clinical trials of potential treatments or preventions.”

“Alzheimer’s Research UK is funding research to speed up the search for better diagnostic tests for diseases like Alzheimer’s. Detecting these diseases is vital for allowing current and future treatments to be given at a time when they’ll have the biggest impact on lives.”

Paul Francis, Professor of Neurochemistry at the University of Exeter Medical School, said

“Selecting the right people who are at risk of developing dementia at an early stage is important for conducting effective advances in future therapies.  This study uses easily accessible blood measurements to provide a window on the build-up of the protein tau in the brain. We know it’s implicated in dementia and correlates with clinical symptoms of dementia as they develop to a greater extent than alternatives such as amyloid beta.

“In general, blood based biomarkers could be of considerable value in assessing risk of dementia and hence assessing who might be included in clinical trials. In this study, the fact that the measure is of total tau – a marker of neurodegeneration, rather than a specific condition – is important but not the best marker. To be more specific for Alzheimer’s disease, it might need to have been a measure of a phosphorylated tau isoform. It is another step as it is not amyloid beta. Tau in general correlates better with clinical measures of dementia and Alzheimer’s disease than does amyloid beta.

“The strengths of this study include that it uses two good cohorts with clinical information for correlates of the blood tau. It replicates and extends two other studies that total tau increases with dementia risk. The team has used a very sensitive assay, which means the measurements are robust.

“The authors have been suitably cautious and noted several limitations. To note the association with vascular pathology is perhaps significant in this context.

“Taking serial samples would have also helped to understand the possible progression of this marker and understand whether it might have some value in checking whether anti-dementia drugs engaged with their targets, as well as whether they were effective.

“Overall this is a useful contribution to the field that should stimulate other groups to confirm or reject the conclusions. While it’s not a diagnostic test, the study does show that, if confirmed, the risk assessment for who may develop dementia does not require cerebral spinal fluid to be measured, which would simplify the process.”

Dr Richard Unwin, Research Fellow, Division of Cardiovascular Sciences, University of Manchester, said:

“This is an interesting study which adds to a raft of recent work looking for compounds in the blood which can be used to predict someone’s risk of developing dementia. In this case, the researchers studied a protein called Tau, which we know to be important in the brain of people with dementia as it can build-up and form insoluble protein ‘tangles’, which contribute to disease.

“This study analyses two large groups of patients, one from the US and another from France, measures the amount of Tau in the blood, and then sees if this can be used to predict a range of outcomes. The results showed that individuals with a ‘high’ level of Tau were slightly more likely to develop dementia than those with lower levels and scored slightly worse in tests of brain function. They also showed, in a small subset of 42 patients, that blood Tau levels seemed to be related to level of Tau in the brain.

“These results are consistent with the findings of others, in that, while blood levels of Tau may predict a higher future risk of dementia it is not, on its own, a strong predictor of whether someone will, or will not develop disease. Given that we know that changes in the brain, including development of tau tangles, can occur a long time (20-years) before onset of symptoms, however, it is likely that these data are showing the early signs of this process, and this work will be useful to those looking at ways to reduce our risk or incidence of dementias.”

Dr Amanda Heslegrave, UK Dementia Research Institute at UCL, said:

“We know that we see increased Tau in cerebral spinal fluid in Alzheimer’s disease and we can use measures of this in combination with other clinical and biochemical measures to diagnose probable Alzheimer’s disease. This research further confirms our knowledge in the area, using a large well known cohort, and a replication cohort although this is smaller.

“A blood test to include or exclude someone from a trial is an extremely useful tool: in order to place a person into a trial to prevent AD we need to be as sure as we can that person has a high risk of getting AD so that we can be sure the drugs or interventions we are using actually work. However, this will not enable an individual to have a blood test and rule Alzheimer’s disease in or out as it is about looking at risks of developing dementia at a population level.

“Whilst this is a very promising area, we need to further understand tau before we can use it in a blood test as a predictor for developing dementia, as it can be elevated by many things as well as dementia.”

Prof Paul Morgan, Professor of Immunology and Director of the Systems Immunity Research Institute, Cardiff University, said:

“Clinical trials of candidate drugs for prevention or amelioration of Alzheimer’s disease are at a crisis point, a consequence not only of the many past failed trials but also of the enormous cost of trails that need to include very large numbers of participants followed up over several years.  The large sample size is in part a result of the lack of good predictors of disease risk in asymptomatic or early symptomatic individuals that would enable selection into trials of those most at risk.  Hence, most recruited individuals will not develop the disease during the course of the study and sample sizes need to be very large to compensate for this fact.  A simple, non-invasive and (relatively) cheap test that improved prediction of disease risk would enable the selection of those most at risk into trials with resultant reductions in sample size needed and, critically, cost.  As such, the search for an easily measured biomarker of risk, most likely a plasma biomarker, has become has become a key target of Alzheimer research.

“In this paper, Pase et al. have measured plasma levels of tau, a protein strongly implicated in Alzheimer pathogenesis.  Other studies have reported that plasma tau levels are higher in Alzheimer’s disease and in association with cognitive decline, but these have been relatively small and lacked replication.  The current work uses a high-sensitivity assay on the Simoa platform to measure plasma tau in a very large cohort derived from the famous Framingham study and replicate their findings in a smaller French cohort.  The principle finding is that, by stratifying individuals based upon plasma tau levels, they can substantially reduce the numbers of participants that need to be recruited into a trial to have sufficient power for a meaningful outcome. Just selecting those with a plasma tau level greater that the population median reduced the calculated sample size by 50%! Inclusion of age and ApoE status further improved stratification and reduced sample size needed to achieve significance. These findings are replicated in the smaller independent cohort. “The paper makes an important contribution to the field by demonstrating that a plasma-based test, when used to stratify individuals for selection into Alzheimer trials, could markedly reduce the required participant numbers and, of course, the cost of the trial. This work does need to be tested in the real world as, at the moment it is a statistical prediction. Measurement of plasma tau is not straightforward, requiring highly sensitive and specific assays currently available in only a few centres; nevertheless, the substantial impact described here makes a strong case for using this and other plasma markers, for example markers of inflammation as reported elsewhere, in trial selection.  Hopefully, this ability to get the right individuals into trials will re-invigorate interest from the Pharma sector in undertaking well-designed trials of emerging therapies.”

Prof Masud Husain, Professor of Neurology, University of Oxford, said:

“Currently we measure levels of tau in the spinal fluid which requires a lumbar puncture. This new method involves only a simple blood test which would be much easier, for both patients and doctors.

“The results are exciting. However, we need to be cautious. In its current form, the test would not be good enough to be used in the clinic as a useful measure to improve diagnosis.”

Dr Francesco Tamagnini, an Alzheimer’s researcher at the University of Reading, said:

“This is a very interesting study, as it provides evidence that a blood marker can be used as a predictive tool for the onset of dementia. One of its strongest points is that it is a prospective study, started in people with the first clinical signs of cognitive impairment which, in some cases, can lead to dementia.

“To date, we lack an affordable, reliable and accurate prognostic tool able to predict the onset of disorders leading to dementia, such as Alzheimer’s disease. While we’re still some way off from being able to routinely screen the population for dementia risk, this brings such tests a step closer.

“The link between plasma levels of tau and dementia is well known and its use to predict the onset of dementia has been previously inferred and supported by retrospective studies. By following up a large group of people who were first recruited when they had mild cognitive impairment, this study provides stronger evidence for a link.

“While we are still a long way from a treatment for dementia, more reliable screening would be a welcome first step. We now need to find ways to be able to screen people reliably, affordably and non-invasively for the early signs of dementia, to give patients, their families and society the chance to prepare and make informed decisions.”

Prof John Hardy, Professor of Neuroscience, University College London (UCL), said:

“This study shows that improving technology now allows the measurement of tau, the protein found in neurofibrillary tangles, to be detectable in blood and potentially useful in making the diagnosis of Alzheimer’s disease.  It replicated previous work in this area in smaller cohorts of patients.  In practice, a major issue we will want the answer to is whether this measurement will help in the differential diagnosis of Alzheimer’s disease from other dementias.  This study does not address this question.”

Prof Tara Spires-Jones, UK Dementia Research Institute Programme Lead and Deputy Director, Centre for Discovery Brain Sciences, University of Edinburgh, said:

“This paper by Dr Pase and colleagues at the Melbourne Dementia Research Centre looked at blood samples from over 1,400 people to see if levels of tau protein in blood predict whether someone will go on to develop Alzheimer’s disease. The scientists found that increased amounts of tau protein in blood samples were associated with increased risk of developing Alzheimer’s disease. Tau is one of the proteins that clumps up in the brains of people with Alzheimer’s disease and causes damage to brain cells.  This well-powered and important study indicates that measuring tau protein in blood with a sophisticated test could help researchers find people in the early stages of Alzheimer’s disease to participate in clinical trials.  It is worth noting that this is not a “blood test for Alzheimer’s” since increases in tau in the blood are a marker of any damage to the brain, not just dementia.”

‘Assessment of Plasma Total Tau Level as a Predictive Biomarker for Dementia and Related Endophenotypes’ by Matthew Pase et al. was published in JAMA Neurology at 16:00 UK time on Monday 4th March.

All our previous output on this subject can be seen at this weblink:

Declared interests

Dr James Pickett: No conflicts of interest

Dr Richard Unwin: No conflicts of interest

Dr Amanda Heslegrave: No conflicts of interest

Prof Paul Morgan: No conflicts of interest

Prof Masud Husain: No conflicts of interest

Dr Francesco Tamagnini: “My funders are Alzheimer’s Society, EPSRC and Royal Society. I have no other relevant interests to declare.”

Prof John Hardy: John Hardy is on the SMC Advisory Committee

Prof Tara Spires-Jones: I have no conflicts of interest with this study. 

None others received.

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