July 28, 2020

expert reaction to two papers looking at a blood-based biomarker for Alzheimer’s disease

Two studies, one published in JAMA and one published in the Journal of Experimental Medicine, looked at at a blood-based biomarker for Alzheimer’s disease.

Prof David Curtis, Honorary Professor, UCL Genetics Institute, UCL, said:

“These papers both report that a blood test to measure p-tau-217 can predict who will develop Alzheimer’s disease.  The results seem to be robust.  From a clinical point of view, this kind of research is enormously important.  Many researchers believe that effective treatment for Alzheimer’s disease will need to be started before symptoms develop.  This will entail mass-screening, just as is now done to detect people with high cholesterol, and it will be essential that reliable methods of detecting those at high risk become available.

“Unfortunately we do not yet have treatments to prevent Alzheimer’s disease, although tests such as this will greatly facilitate developing them.  For now, the potential implications of such predictive tests could raise some challenging issues for society.  Do people want to know that they will develop Alzheimer’s disease, given that there is no treatment?  Would people want to use this information for retirement-planning or making advance arrangements for care?  There may well be some difficult ethical issues to think about.”

Prof John Gallacher, Director of Dementias Platform UK, Department of Psychiatry, University of Oxford, said:

“The search for an Alzheimer’s disease blood test grows in importance.  These studies show how plasma Tau (measured using different techniques) is correlated with Tau levels from expensive imaging (Barthelemy) and from invasive lumbar puncture (Palmqvist).  The results from both studies are encouraging for conducting further clinical studies, and as a direction of travel for clinical practice.  However, we remain a long way from a blood test to detect Alzheimer’s disease.  Simply, the predictive value of a test is much lower in a general population than in the laboratory, and the ethical concerns of getting it wrong much greater.  The search continues.”

Prof Nick Fox, Professor of Clinical Neurology, Honorary Consultant Neurologist, Director of the Dementia Research Centre, and Joint Head of Department of Neurodegenerative Disease, UCL Institute of Neurology, UCL, said:

“I think we are now seeing convincing evidence that blood tests really can identify Alzheimer’s disease with high sensitivity – and I believe we will see these entering clinical practice rapidly.  They have the potential to extend and “democratise” biomarker-supported diagnosis in dementia with wide applicability including in low resource settings.

“These papers provide robust evidence of the ability of plasma p-tau to identify Alzheimer’s disease and, importantly, to discriminate it from other causes of cognitive decline.  Together with other very recent reports we are seeing replication of this impressive diagnostic performance in several different cohorts totalling well over a thousand individuals – and of the different plasma p-tau measures p-tau217 appears particularly impressive performing as well as more invasive and more expensive scans or CSF measures.

“Complementing these reports we have also shown (O’Connor et al Mol Psych July 2020) that plasma p-tau181 can identify Alzheimer’s disease prior to symptoms in those at-risk of inheriting AD – and ptau217 is likely to do even better.”

Dr Amanda Heslegrave, Senior Research Fellow, UK Dementia Research Institute at UCL, Fluid Biomarker Laboratory, UCL, said:

“These two papers add to increasing evidence that modified tau proteins in the blood can accurately reflect Alzheimer’s disease in processes occurring in the brain.  Since the methods previously used to measure these proteins such as lumbar puncture for CSF measurement or scans are either invasive or extremely costly, this is important.  Testing for these proteins in blood would allow for screening so we can better predict (at an early stage) who is likely to develop Alzheimer’s and therefore enroll into trials for treatments or further investigations.

“At present these assays are research grade – this means validation in much bigger and probably more diverse patient groups will be required across many laboratories to ensure results are accurate and comparable wherever you are tested.  So, while these are exciting results you could not say that they indicate a definitive test for potential Alzheimer’s disease is available right now.”

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

“These two studies from Sweden and the US add to growing support for the potential of a blood test detecting tau protein being useful for diagnosis of Alzheimer’s disease.  Tau protein is modified and clumps abnormally in the brains of people with Alzheimer’s disease and some frontotemporal dementias, and some of this tau protein leaks out of the brain into the blood.

“The blood tests detected a specific type of modified tau more in people with Alzheimer’s disease than in healthy participants.  The results are very solid and the experiments well conducted.

“This will be important for moving forward with early detection of Alzheimer’s disease; however it is important to note that this blood test is not fool proof – there are some people with Alzheimer’s in the studies who have test results in the same ranges as healthy people.

“Further, while this test will help find people in early stages of Alzheimer’s disease to participate in research studies, at the moment there are not effective treatments to give people that will stop disease progression, so more fundamental research is needed in order to develop life-changing treatments.”

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

“Over the last 5 years, the possibility of using plasma/blood based tests to aid in the diagnosis and assessment of Alzheimer’s disease versus other causes of dementia has improved enormously and these well performed studies are a further step in that process: blood based markers of disease and disease progression are now a reality and this will help with drug trial assessment and clinical practice.  It is also giving us insights into the biology of the disease: Alzheimer’s disease has two pathologies, amyloid and tau and there has been much discussion about the relationship between them.  These studies (and others) show that blood based tau is a marker of amyloid pathology.  Very interesting and not what would have been predicted 5 years ago.”

Prof Clive Ballard, Professor of Age-Related Disease, University of Exeter Medical School, said:

“This research represents an exciting step towards developing a blood test that could help identify Alzheimer’s disease by focusing on specific sub-types of tau, one of the key proteins that becomes abnormal as part of the Alzheimer’s disease changes in the brain.  The findings come from a top research group and this is an encouraging and robust development.

“Although this research looks extremely promising, further validation in people from more routine clinical settings are still needed, and a lot of work will be needed to achieve standardisation of the test across laboratories – so it could still be at least five years before we see an accurate blood biomarker test for dementia it in the clinic.”

Prof Carol Brayne, Professor of Public Health Medicine, University of Cambridge, said:

“These need to be subject to the criteria for screening – early detection implies screening of asymptomatic populations and all the elements of evidence requirement need to be met before it is rolled out into any clinical practice or even as detection for trials.”

Dr Rosa Sancho, Head of Research at Alzheimer’s Research UK said:

“We know that brain changes in Alzheimer’s disease can occur decades before symptoms start to show and the early stages of disease are likely to be the time when future drugs are most effective.

“These studies suggest that changes in levels of a specific form of tau, one of the hallmark proteins of Alzheimer’s, may be detectable in the blood in the very early stages of the disease.  The research also indicates that the changes seen in blood track protein build-up measured by brain scans.

“The tests can discriminate Alzheimer’s from other diseases that cause dementia, however, these findings are from small scale and early-stage research studies.  Further work will need to be carried out at a larger scale and with tests that are clinically feasible before they could be used by doctors making a diagnosis in the clinic.

“Currently people only receive an Alzheimer’s diagnosis once symptoms appear.  Many of the diagnostic tools that can detect early changes are expensive, like brain scans, or invasive such as spinal fluid tests.  A reliable blood test for Alzheimer’s disease would be a huge boost for dementia research, allowing scientists to test treatments at a much earlier stage which in turn could lead to a breakthrough for those living with dementia.”

Dr Fiona Carragher, Director of Research and Influencing at Alzheimer’s Society, said:

“A cost effective, accurate and non-invasive diagnostic test is a vital step in developing new treatments for the 850,000 people living with dementia in the UK today.  Excitingly, this blood test for tau appears to not only show signs of being able to accurately distinguish between Alzheimer’s disease and other neurodegenerative conditions, but also may detect changes before symptoms even appear.  It’s important that dementia research represents the many different people who live with Alzheimer’s disease across the globe so it’s great to see this research was carried out in a diverse population.

“Now we need longer and larger studies to validate these results and find out if this test could accelerate our ability to develop new treatments for Alzheimer’s disease in the future.”

JAMA paper: ‘Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders’ by Sebastian Palmqvist et al. was published in JAMA at 17:30 UK time on Tuesday 28 July 2020.

DOI: 10.1001/jama.2020.12134

JEM paper: ‘Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease’ by Nicolas R. Barthelemy et al. was published in the Journal of Experimental Medicine at 17:30 UK time on Tuesday 28 July 2020.

DOI: 10.1084/jem.20200861

Declared interests

Prof David Curtis: “I carry out research to identify genetic risk factors for Alzheimer’s disease in order to provide information which may assist drug development.  I have no conflict of interest to declare.”

Prof Nick Fox: “I am collaborator with authors on both papers and I am part of a large consortium (the dominantly inherited Alzheimer network – DIAN); our Centre receives funding from DIAN which is led by the Wash U team.  Separately, we had a paper (attached) published 10 days ago showing plasma p-tau can detect familial AD presymptomatically.”

Dr Amanda Heslegrave: “I work at the DRI and should say that I work with Henrik Zetterberg but not on this.”

Prof Tara Spires-Jones: “No conflicts.”

Prof John Hardy: “No conflicts”

Dr Rosa Sancho: “No conflicts of interest.”

None others received.