Unlike the Elecsys® pTau 181 plasma test which helps rule out Alzheimer’s disease, the newer Elecsys® pTau 217 plasma test helps to both rule in and rule out Alzheimer’s pathology in patients with cognitive symptoms. This means a positive result carries a high likelihood that amyloid pathology is present, while a negative result makes it less likely.
Amyloid plaques and neurofibrillary tangles are the two major hallmarks of Alzheimer’s disease. Amyloid deposition leads to phosphorylation of tau proteins, and pTau217 is a product of this process, explains Emma Devenney, a cognitive neurologist with NeURA and Associate Professor in the School of Medicine and Health at UNSW Sydney.
For patients being assessed for disease-modifying therapy, a positive test will still require confirmation of amyloid pathology via cerebrospinal fluid (CSF) or amyloid PET scan.
The pTau 217 test performs best in people with objective cognitive impairment or where there is a strong clinical suspicion of Alzheimer’s disease, says Associate Professor Devenney.
In this population, the Roche assay has sensitivity above 90% and specificity of approximately 90%, a performance approaching established PET scan and CSF biomarkers.
In a patient with cognitive symptoms, a positive indicates a high likelihood that amyloid pathology is present but does not by itself establish a diagnosis of Alzheimer’s disease.
“People start to accumulate this pathology in their brain for decades before they ever develop symptoms, and we know people can have this pathology in their brain without ever developing dementia,” Associate Professor Devenney says.
But if a patient is symptomatic, a positive result makes an AD diagnosis much more likely.
“If the pTau 217 is high and they’ve got memory symptoms, you can say quite confidently they do have Alzheimer’s disease,” says geriatrician Professor Michael Woodward, Director of Dementia Research at Austin Health.
If that person wants to try amyloid-targeting therapy or participate in a research trial they would need to be referred for confirmatory testing – but if they aren’t interested or are not an ideal candidate, they would not need further evaluation, Professor Woodward says.
However, false positives and negatives still occur, and around 15-20% of patients will return an indeterminate result, he says.
Indeterminate results should prompt further testing.
A negative result indicates a low likelihood of Alzheimer’s pathology, but if the person has significant memory problems, they will still need further evaluation to look for other causes of cognitive decline.
It’s also essential to consider the broader clinical picture, Associate Professor Devenny stresses, noting chronic kidney disease, age, body mass index and possibly head injury may influence results.
Practice tip: Use caution in people with eGFR less than 60 and in BMI over 30, as these can lead to inaccurate results
Chronic kidney disease in particular may raise the chance of a false positive result, though Associate Professor Devenney says she’d still use the test in these patients, with the caveat that she wouldn’t let the results trump clinical judgement.
Because people with cognitive symptoms can move from negative or indeterminate to positive over time, it may be helpful to repeat the test in 12 months, she adds.
The test has been described as a ‘simple blood test,’ and misinformation has been widespread, so it’s anticipated there will be demand from people without symptoms or those who have only a family history.
Although higher pTau217 levels in asymptomatic people are reported to increase risk of future cognitive decline and progression to Alzheimer’s, a positive test in this group is more difficult to interpret, and the likelihood of false positives is higher.
Thus, Professor Woodward notes, “You should not be using it as a screening test for people who have no memory problems.”
Associate Professor Steve Macfarlane, geriatric psychiatrist and Head of Clinical Services at Dementia Support Australia agrees. “The test shouldn’t be given to everybody who walks in off the street requesting it because they’re worried about their risk of developing Alzheimer’s disease.”
Roche says the test is intended for use in patients who are at least 55 years old and have either subjective or objective cognitive decline, though the result must be interpreted in conjunction with a thorough clinical work up.
In line with that, Professor Woodward says the test is “appropriate where there is subjective cognitive decline (SCD) – but not when the person is just worried that they may be at risk of AD and have no concerns about their current cognitive function.”
However, testing in people with SCD is a more nuanced decision.
Associate Professor Devenney recommends restricting testing to those with objective cognitive impairment.
“The test is most accurate when you have a strong suspicion that someone has Alzheimer’s disease,” she stresses.
“Subjective cognitive complaints can represent so many different things … especially if the test is used for people 55 and up, most subjective cognitive complaints in that age group are related to other things like poor sleep, mood disorder, all those other things that contribute to cognitive impairment. And if you don’t have objective changes on a cognitive test, then your likelihood that these changes are due to Alzheimer’s disease are pretty low,” Associate Professor Devenney says.
Dr Stephanie Daly, a GP with special interest in cognition and dementia, says it’s important take care in this group, but testing can still have a place.
“The accuracy of the test depends on pretest probability and in the subjective cognitive group the chance of AD is lower so the accuracy will be lower. That means that we might see more false positives,” Dr Daly says.
And while this group has an increased risk of progressing to dementia, not everyone will, “so the advice needs to be clear that even with a positive result you may not develop dementia. In fact, the risk may be as low as 50:50,” she says.
“However, we also know that in some people the accuracy of our cognitive assessment tools is lower due to higher education levels and sometimes this group are harder to assess so the use of the test may help use predict who is most at risk in this group,” Dr Daly says.
She recommends getting robust education in the principles of cognitive assessment, and initially using the test in more obvious clinical cases before broadening to the SCD space.
Australian guidelines for using the tests are being developed with a Delphi consensus approach, and are expected to be out by the end of the year, Associate Professor Devenney notes.
Professor Woodward says testing can give people the impetus to implement strategies to slow cognitive decline, like a healthy diet, exercise, social engagement, cognitive activity, control of cardiovascular risk factors, and staying up to date with vaccines.
Testing is a useful first step to help determine if someone may be suitable for disease-modifying therapies, and Professor Woodward recommends referring interested patients with a positive result to a centre offering these treatments. Patients who can’t afford the therapies may want to take part in clinical trials, he adds.
Testing also gives people an opportunity to get their affairs in order, he says. For example, patients may need to make medico-legal decisions while they still have capacity, arrange an aged care package, and research the resources available to them—such as support from Dementia Australia.
Associate Professor Devenney agrees. “More and more, I find that people want the knowledge,” she says. “If you know that Alzheimer’s pathology is present, you might decide to do things you were planning to do in the future now. And you can get all the legal stuff sorted out. It gives people back some of the control.”
Families may also benefit from understanding what’s going on and preparing for future care needs.
Will the old test still have a place?
Associate Professor Devenney cautions against consigning the pTau181 test to the shelf just yet, noting it may still prove useful as clinicians get more familiar with blood-based biomarkers and as evidence-based testing pathways evolve. Associate Professor Macfarlane and Professor Woodward agree the pTau217 test is likely to supersede testing for pTau181.
Two sites are currently offering the pTau217 test, a spokesperson for Roche said: the National Dementia Diagnostics Laboratory at the Florey Institute in Victoria, and the Sullivan Nicolaides Pathology Queensland. “We are also actively working with additional private pathology, public hospital pathology networks and other research facilities to make pTau 217 testing accessible across Australia.”
Key takeaways:
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For more on applying the blood based biomarkers for Alzheimer’s disease check out this clinical algorithm developed for primary care.
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