Tau protein could be key to an Alzheimer's blood test

Scientists attending the Alzheimer’s Association International Conference (AAIC) 2020 have reported the results of multiple studies on potential blood tests based on the tau protein phospho-tau217 (p-tau217), which may be able to detect changes in the brain 20 years before dementia symptoms occur.

Alzheimer’s disease is characterised by the presence of plaques in the brain formed by a protein called amyloid-β, as well as aggregates of a protein called tau that form neurofibrillary tangles in the neurons of Alzheimer’s patients. Amyloid-β and tau start to change years before any cognitive symptoms, such as memory loss and confusion, become apparent, but previously the only way to detect them was with a positron emission tomography (PET) scan to visualise the brain, or a spinal tap to measure changing levels of amyloid-β and tau in cerebrospinal fluid. These methods are expensive, invasive and often unavailable because they are not covered by insurance and/or difficult to access.

“There is an urgent need for simple, inexpensive, non-invasive and easily available diagnostic tools for Alzheimer’s,” said Dr Maria C Carrillo, Chief Science Officer of the Alzheimer’s Association. A blood test, for example, would enable interpretation and understanding of Alzheimer’s progression in much larger, more diverse and more robust populations.

“The possibility of early detection and being able to intervene with a treatment before significant damage to the brain from Alzheimer’s disease would be game changing for individuals, families and our healthcare system.”

Immunoassay

An international team of researchers has now identified a highly accurate, blood-based biomarker for the detection of Alzheimer’s disease by measuring blood plasma levels of p-tau217 — one of the forms of tau found in tangles — which seemed to correlate closely with build-up of amyloid. Measurements of p-tau217 could thus provide a relatively sensitive and accurate indicator of both plaques and tangles in living people.

The researchers studied three different cohorts comprising more than 1400 cases, including a large clinic-based study from Sweden (the BioFINDER-2 study), a cohort with neuropathological confirmation of Alzheimer’s (the Arizona Study of Aging and Neurodegenerative Disorders) and a large kindred with genetically caused Alzheimer’s (Colombian autosomal-dominant Alzheimer’s registry). They analysed current experimental biomarkers (p-tau217, p-tau181, Aβ42/40 and neurofilament light chain) in both blood and cerebrospinal fluid, as well as performed PET imaging for tau and amyloid pathology.

The main finding of the study was that blood p-tau217 could distinguish Alzheimer’s from other neurodegenerative disorders with diagnostic accuracy between 89 and 98%. The p-tau217 assessment was more accurate for Alzheimer’s than blood-based tests for p-tau181, neurofilament light or amyloid beta 42/40 ratio, as well as magnetic resonance imaging (MRI). In fact, the researchers claim performance was similar to significantly more costly methods, such as PET imaging and cerebrospinal fluid biomarkers.

The researchers also found that p-tau217 analysed in blood collected during life could detect tau brain changes measured in brain tissue analysed after death. These tau brain changes are thought to be related to amyloid plaque accumulation. P-tau217 distinguished persons who had plaques and tangles from those without Alzheimer’s pathology with 89% accuracy, those with plaques and more extensive tangles with 98% accuracy and the outcome of tau PET imaging with 93% accuracy.

The p-tau217 levels were increased about seven-fold in Alzheimer’s and, in individuals with a gene causing Alzheimer’s, the levels started to increase already 20 years before onset of cognitive impairment. The test thus opens the possibility of early diagnosis of Alzheimer’s before the dementia stage, which is important for clinical trials evaluating novel therapies that might stop or slow down disease progress.

The scientists stated that “the diagnostic precision of blood p-tau217 was as high as established diagnostic methods, including positron emission tomography (PET) imaging and cerebrospinal fluid biomarkers”. Their research has been published in JAMA.

“The p-tau217 blood test has great promise in the diagnosis, early detection and study of Alzheimer’s,” said Lund University’s Professor Oskar Hansson, who led the international study. “While more work is needed to optimise the assay and test it in other people before it becomes available in the clinic, the blood test might become especially useful to improve the recognition, diagnosis and care of people in the primary care setting.”

Mass spectrometry

A separate study, conducted by the Washington University School of Medicine in St. Louis, saw researchers evaluate the performance of a variety of amyloid and tau measures in blood. Their work reiterates that levels of p-tau217 are elevated during the early stages of Alzheimer’s and could lead to a simple blood test capable of diagnosing the disorder years before any symptoms begin to appear.

The Washington researchers had previously found that p-tau217 accumulates in the cerebrospinal fluid of Alzheimer’s patients before the onset of cognitive symptoms, increases with disease progression and can accurately predict the formation of amyloid plaques. They suspected that p-tau217 might also be present in the blood of Alzheimer’s patients, albeit at very low levels that would make it difficult to detect.

“We therefore wanted to quantify the levels of different tau proteins, especially p-tau217, in the blood and compare them with amyloid pathology and onset of dementia to assess their potential as blood-based Alzheimer’s disease biomarkers,” said Professor Randall Bateman, who co-led the study.

Working in Prof Bateman’s laboratory, the scientists developed a mass spectrometry-based method to measure the amount of p-tau-217 and other tau fragments in as little as 4 mL of blood, even though such small samples may contain less than a trillionth of a gram of p-tau-217. According to Nicolas Barthélemy, an assistant professor in the lab, “this is the lowest concentration ever measured by mass spectrometry for a protein marker in human blood plasma”.

The researchers found that, similar to p-tau217 levels in cerebrospinal fluid, p-tau217 levels in the blood were extremely low in healthy volunteers but elevated in patients with amyloid plaques, even in those who had yet to develop cognitive symptoms. Measuring blood plasma levels of p-tau217 was able to accurately predict the presence of amyloid plaques in PET scans, performing better than p-tau181, which had been previously proposed as a biomarker for Alzheimer’s disease. Their study was published in the Journal of Experimental Medicine.

According to the researchers, a blood test for Alzheimer’s disease that incorporates both amyloid and tau measures may allow earlier and more accurate dementia diagnoses not only in research participants but also in clinic patients. Additionally, their findings suggest that measuring levels of several different forms of p-tau in blood over time may enable clinicians and researchers to track the stages of Alzheimer’s progression in people living with the disease.

“Our findings support the idea that tau isoforms in the blood are potentially useful for detecting and diagnosing Alzheimer’s disease pathology,” Prof Bateman said. “Moreover, our assay for measuring plasma tau levels could be used as a highly sensitive screening tool to identify tau changes associated with amyloid plaque formation in normal subjects, replacing costly PET imaging.”

Reaction

Dr Carrillo described the two studies as “encouraging”, though she noted that they presented early results and there is no current timeline on when the tests may be available for clinical use.

“They need to be tested in long-term, large-scale studies, such as Alzheimer’s clinical trials,” she said. “In addition, we need to continue research to refine and verify the tests that are the current state of the art — including cerebrospinal fluid and PET imaging biomarkers.”

Australian scientists have also commented on the news, with The University of Adelaide’s Dr Ian Musgrave hopeful that the tests may be able to pick up Alzheimer’s before significant damage has occurred.

“However, there is still a way to go,” he said. “The numbers of subjects are relatively low and these tests will need to be trialled in larger population groups with more diverse clinical conditions to ensure accuracy. Also, the techniques are rather specialised and will not be generally available for some time.

“Finally, at the moment, our therapies for Alzheimer’s merely delay the progression of the disease. While early intervention is important, these tests may be more valuable for testing experimental therapies rather than routine diagnosis.”

Professor Colin L Masters from The University of Melbourne was more upbeat in his assessment, saying, “These two independent papers provide compelling evidence that it is possible to use blood plasma assays of p-tau to diagnose Alzheimer’s disease specifically and with a high degree of accuracy.

“Using a large cohort of subjects at genetic risk of early-onset Alzheimer’s disease, the test appears to work many years before the onset of clinical symptoms. It remains to be determined whether similar predictive results will be obtained in the more common forms of late-onset Alzheimer’s disease.

“The performance of this p-tau test will now have to be assessed against another sensitive test which measures plasma beta-amyloid. Together, both tests look very good, and give us a method for early detection and to identify individuals who could be suitable for clinical therapeutic trials which are now progressing.”

Image credit: ©stock.adobe.com/au/Andrea Danti

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