November 30, 2020

expert reaction to study of two blood biomarkers that may predict dementia in those with mild cognitive impairment

A study published in Nature Aging looks at plasma biomarker combinations that may predict risk of cognitive decline and dementia in those with mild cognitive impairment.

Dr Richard Oakley, Head of Research at Alzheimer’s Society, said:

“We all know clinical trials in Alzheimer’s have been facing huge challenges and disappointments. And a big factor is the struggle to find people early enough before Alzheimer’s has progressed too far to test new drugs on. This study only looked at a few hundred people, but if these blood biomarkers can predict Alzheimer’s in larger, more diverse groups, we could see a revolution in how we test new dementia drugs. Blood tests to predict dementia are moving at a break-neck speed, but if Government doesn’t double dementia research funding as they promised, people with dementia won’t benefit from these new breakthroughs.”

Dr Sara Imarisio, Head of Research at Alzheimer’s Research UK, said:

“Like dementia, Mild Cognitive Impairment (MCI) is an umbrella term describing several symptoms, and can be caused by a number of different underlying diseases. We know that over 50% of people with MCI will go on to develop dementia, and it is important that we try to identify those who will and those who will not progress to be able to offer appropriate treatment and advice.

“Blood tests for predicting the risk of Alzheimer’s disease are getting ever more advanced. In this well-designed study, levels of a form of tau coupled with a protein indicating neurodegeneration were able to predict who developed more severe memory and thinking problems. However, further studies in larger groups of people will need to replicate and verify the accuracy of this approach.

“One intriguing finding is that these markers predicted a change in memory in thinking in both people with and without the Alzheimer’s risk gene, APOE4. Genetic testing can present ethical challenges, especially as it can have implications for a patient’s family members. A blood test that does not need a genetic test would be most beneficial in the clinic.

“While there are other types of biological test that can help determine the cause and likely course of memory and thinking problems, blood tests are much more affordable than brain scans and more straightforward and acceptable to people than a lumbar puncture.

“Any future dementia treatments are likely to need to be given early in the disease process, making it even more important to take findings like these forwards to improve how we diagnosis early memory and thinking problems. We need to see a shift in how we think and deal with MCI including ways to bring blood-based markers into routine clinical practice.”

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

“This is a potential gamechanger. For the first time, we have a blood test that can predict well the risk of subsequent development of Alzheimer’s disease in people who have mild cognitive symptoms. We need further validation but in the context of other recent findings this could be a transformative step to earlier diagnosis, as well as testing new treatments at earlier stages of the disease.”

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

“This study by Dr Hansson and colleagues from Sweden shows that levels of 2 proteins in blood are a good predictor of whether someone with mild cognitive impairment will go on to develop Alzheimer’s disease over the next 4 years.  This is a robust study looking at data from over 550 people.  The study is an important step on the road to developing a blood test for Alzheimer’s, but it is important to note that we are not there yet.  Some of the people with a high predicted probability of disease based on these proteins in their blood did not go on to develop Alzheimer’s and some people with a low predicted probability did develop the disease, so this is not yet a fool proof way to predict disease. As the authors correctly note, more studies in larger populations and standardised ways of running and interpreting these tests will be needed to confirm their usefulness.”

Prof Tom Dening, Director of the Centre for Old Age and Dementia, Institute of Mental Health, University of Nottingham, said:

“Obviously it is important for accurate diagnostic markers for Alzheimer’s disease to be developed. Blood biomarkers are likely to be the most appropriate for clinical practice as obtaining blood is more convenient and more acceptable than obtaining samples of cerebrospinal fluid (CSF). It is also quite likely that combinations of biomarkers will prove to be more accurate than relying on a single marker. This paper appears to be a contribution in that direction, as they have looked at the predictive power of various combinations of possible markers. However, as the authors have acknowledged, even a sample size of over 500 is quite small for this kind of predictive work and, besides, longer periods of follow-up are needed to test how useful the predictions turn out to be.

“It should also be noted that even the combination of markers is not perfect in its predictive power. The paper reports a sensitivity of 89% and a specificity of 88% for the combined markers. This is impressive but in largescale practice it could need to a lot of misdiagnosis, both people wrongly diagnosed as having Alzheimer’s and people who in fact have AD being missed. The average memory clinic will see hundreds of people with possible dementia in a year, so these numbers would be considerable.

“It also still remains to be shown that predicting that someone with mild cognitive impairment (MCI) is more likely to develop dementia due to Alzheimer’s disease makes a difference to their health and social outcomes in the longer term. And it is still far too early for the tests described here to be adopted into routine clinical practice. However, there are signs that we are getting there, and it is easy to imagine that tests of this kind will become part of the diagnostic assessment for cognitive problems in the next few years.”

Prof John Hardy, Professor of Neuroscience, UCL, said:

“This is a welcome, but not an unexpected finding.  Plasma tau is almost certainly an indirect marker of amyloid plaque formation and neurofilament is a well established marker for neuronal damage, so together these two markers are indicating that Alzheimer plaques are forming and neurons are being damaged.”

Prof David Curtis, retired consultant psychiatrist and Honorary Professor at University College London and Queen Mary University of London, said:

“A number of methods are being developed to try to predict whether somebody will develop Alzheimer’s disease and/or how quickly this will progress and the present study explores this further. It suggests that measuring the levels of phosphorylated tau protein in the blood may provide some useful information. Increasingly, researchers are coming round to the idea that effective treatments to prevent Alzheimer’s disease will need to be started before there is any sign of problems and in order to do this it will be essential to recognise who is at high risk. Being able to recognise high risk subjects will also be necessary so that they can be recruited into drug trials of such preventative therapies. However, all this is in the future. The present study was conducted on people already showing signs of possible early Alzheimer’s disease and provides some additional knowledge. The hope is that one day people will be able to have a routine check for Alzheimer’s risk and then be started on treatment, just as nowadays a cholesterol test can lead to a prescription for a statin. However, at present such treatments are not available, so the usefulness of tests such as this will just be for research purposes.”

‘Individualized prognosis of cognitive decline and dementia in mild cognitive impairment based on plasma biomarker combinations’  by Nicholas C. Cullen et al. was published in Nature Aging at 16:00 UK time on Monday 30^th November.

DOI: https://doi.org/10.1038/s43587-020-00003-5

Declared interests

Dr Sara Imarisio: “is Head of Research at Alzheimer’s Research UK and co-founders of the UK DRI. We recently published a review on a new MCI consensus in Age and Ageing.”

Prof Tara Spires-Jones: “I have no conflicts of interest with this paper.”

Prof Tom Dening: “I have no interests to declare.”

Prof John Hardy: “No conflict of interest.”

Prof David Curtis: “I have no conflict of interest.”

None others received.