Plasma biomarkers have now been clinically validated, which could make biological diagnosis of Alzheimer’s disease more accessible. Previously MRI, PET scanning or CSF assays were needed to make a biological diagnosis.
“Until recently, in primary care, we have only been able to make a clinical diagnosis using standardised diagnostic criteria to support our history, examination and investigations,” says Dr Marita Long, a GP at Dementia Training Australia (DTA).
“This has been problematic because even with expert clinicians this approach has low sensitivity and low specificity— in the order of 70-80%. This really impacts on your ability to feel confident to give a diagnosis like dementia as it has significant implications for a patient,” Dr Long explains.
“Equally though, not giving a diagnosis often results in missed opportunities to intervene and improve the quality of life for people living with dementia.”
“With the current approach to diagnosing Alzheimer’s dementia, you also have to wait for someone to have symptoms of both cognitive and functional decline, and we now know that the pathology in the brain has been accumulating for some 20+ years before symptoms develop. So in many ways this is too late,” Dr Long adds.
New diagnostic criteria that incorporate plasma biomarkers were proposed at the world dementia conference in Amsterdam last month, and are currently out for public comment (closing 31 Aigust).
Up until now the biomarkers have come from either MRI, PET scans or CSF fluid obtained from a lumbar puncture—which are invasive, expensive and difficult to access. These markers detect amyloid Aβ42/40, tau or neurodegeneration, and form the ATN classification system that can categorise people on the Alzheimer’s disease continuum.
The draft guidelines propose that Alzheimer’s disease diagnosis can be based on the presence of any core biomarker, including fluid Aβ42/40 or ptau. The rationale is that “the disease exists when the earliest manifestation of Alzheimer’s disease pathophysiology can be detected by biomarkers, even though onset of symptoms may be years in the future.”
Dr Long says earlier diagnosis could dramatically change clinical care.
“If we can detect the presence of Alzhiemer’s disease before there are cognitive changes or early in the process, there may be hope that various medications that are now being developed can slow down, reverse or even prevent the disease process,” Dr Long says.
For example, monoclonal antibodies like Lecanemab can reduce the markers of amyloid in Alzheimer’s disease. This results in a modest slowing of decline on measures of cognition and function, compared to placebo at 18 months. “While promising, they are not without risk, they are very expensive and they require fortnightly or monthly infusions,’ Dr Long adds.
“However, there is hope that the earlier these treatments are offered, the greater the benefit may be. More research is needed to see if this theory is indeed correct— it is likely that there is more to the puzzle and we need to be targeting more than just amyloid. The research is still in relative early days, and we need to see how these drugs work in the real world.”
While we are a way off from having blood tests in primary care in Australia, University of Gothenburg Professor Nicholas Ashton shed some light on what it might look like in practice in his keynote address at the Australian Dementia Network Research Forum in the Gold Coast this year, where he drew on both his own research and the Swedish experience. Dr Long says her understanding is that if a patient sees their GP with either objective cognitive changes or subjective concerns, the GP would still do the usual diagnostic work up of history, examination and investigations, and depending on the result, they may offer the patient this blood biomarker test.
In Sweden, the test uses phosphorylated tau181, the person’s APOE genetic status and their age. The Swedish test has a high sensitivity because rather than a straight positive or negative result, it uses a three-way cut-off. Results fall into either a high, intermediate or low probability of having Alzheimer’s disease.
Those with high probability will then be eligible for symptomatic treatments and potentially the new monoclonal antibodies, while patients with low probability group will need work-up for a different condition. Those with intermediate probability will need further testing, like a PET scan or lumbar puncture, looking for further evidence of Alzheimer’s disease biomarkers.
Dr Long says things are progressing rapidly and we can likely expect a blood test here in the next year or two. What that will look like in practical terms, remains to be seen.
“Like all new tests, there are some finer details to consider, and in Australia we still don’t know which biomarker we will use, how and where it will be processed, who will be eligible and what the cost will be – but none the less, this is very exciting.”
Dr Marita Long will be speaking on this topic at Healthed’s Medical Update in Sydney. Register here to attend the event in Melbourne on 2 September or in Sydney on 9 September.
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