NEW YORK (360Dx) – Researchers at Washington University in St. Louis have established a link between tau protein levels in plasma and extracellular tau levels in the brain that could aid in the diagnosis Alzheimer's disease and other conditions characterized by elevated brain tau concentrations.
Detailed in a study published this week in Science Translational Medicine, the effort made use of an anti-tau antibody to aid detection of the molecule in plasma and suggests that this, and similar antibodies under development at various pharmaceutical firms, could prove useful both as therapeutic agents and for diagnosing and monitoring various tauopathies, said David Holtzman, chair of neurology at Washington University and senior author on the paper.
Along with amyloid-beta (Aβ), tau is one of the primary molecules of study in Alzheimer's disease and a major drug target for the condition. Dysregulation of tau is also involved in diseases including progressive supranuclear palsy, corticobasal degeneration, and chronic traumatic encephalopathy. In healthy individuals, the protein is mainly present in neuronal axons, but in patients suffering from tauopathies, it forms aggregates, or "tau tangles," that collect and spread throughout the brain.
Animal studies, the STM authors noted, have found that treatment with anti-tau antibodies can reduce tau pathology and improve cognitive function, and, Holtzman said, a number of drug makers are moving anti-tau antibody agents into human trials.
A major challenge for drug development in Alzheimer's and other neurodegenerative diseases is identifying patients at an early enough stage where the drugs being tested still have a chance to be effective. This issue has fostered research into various early detection markers, with tau being prominent among them.
Tau and Aβ as measured in cerebrospinal fluid are commonly used as biomarkers to aid in diagnosing Alzheimer's, though it is not firmly established how useful they may be for identifying patients in the earliest stages of the disease, or patients exhibiting mild cognitive impairment (MCI) who will progress to Alzheimer's.
Because obtaining CSF for testing requires a spinal tap, though, many researchers and clinicians are interested in plasma markers, which could be measured from a simple blood draw, making it more amenable to applications like repeated, longitudinal sampling, and sampling asymptomatic patients who might be reluctant to undergo a spinal tap.
A number of groups have worked to identify plasma markers for Alzheimer's. For instance, in 2012, a working group within the Alzheimer's Disease Neuroimaging Initiative used Myriad RBM's Human DiscoveryMAP platform to measure levels of 190 plasma proteins in around 600 patients. Molecular neuropsychiatry firm Genomind has since licensed those markers. Last year, a team at Cardiff University published on inflammatory plasma proteins that could be useful in identifying patients with MCI likely to progress to Alzheimer's.
Also, Proteome Sciences and King's College London have collaborated on large-scale plasma marker discovery efforts. In 2014, they published a study detailing a 10-protein panel stemming from those efforts that could help predict patients likely to progress from MCI to Alzheimer's.
With regard to tau, a major challenge of measuring the protein in plasma is its short half-life.
"When tau gets into the blood [from the brain], it is rapidly removed, and its levels go down very rapidly," Holtzman said, "probably because it's being degraded by one of the other organ systems, like the liver or the kidney."
When subjects are treated with an anti-tau antibody, the antibody binds free plasma tau, protecting it from degradation and allowing researchers to more effectively measure it. In the STM study, Holtzman and his colleagues found that when they injected tau protein into mice in the absence of the anti-tau antibody, the molecule's half-life was 8.5 minutes. In the presence of the anti-tau antibody, tau's half-life in plasma was around 3.4 hours. When they co-incubated tau and the anti-tau antibody before injecting it into mice, it extended the molecule's half-life to 13.2 hours.
Taking advantage of the antibody's ability to enable effective measurements of plasma tau, the Wash U team looked at plasma tau levels in a mouse model of tau pathology, comparing plasma tau levels in young mice prior to the onset of disease, and older, symptomatic mice. They found that plasma tau levels in the symptomatic nine-month mice were 60 percent lower than in the presymptomatic three-month old mice, which accorded with the decline in brain soluble tau and interstitial fluid tau that occurs with disease progression.
While the study was done only in a single mouse model, P301S, Holtzman said that the findings suggest a link between CSF tau levels and plasma tau levels that could hold across other experimental models and humans.
"We've only showed that in animals, but that would be the prediction," he said. "If you give this antibody or this type of antibody, tau will go up in everyone's blood [due to the extended half-life], but it should go up more in people who have more tau in their CSF."
Holtzman and his colleagues used for the study an anti-tau antibody from drugmaker AbbVie, HJ8.5, that he said is currently in Phase II trials as a treatment for neurodegenerative diseases including Alzheimer's. Holtzman said he did not know if AbbVie was interested in developing the antibody for diagnostic purposes, in addition to the company's therapeutic aims, but he said that he thought "it has a lot of potential to be used as a diagnostic."
AbbVie declined to comment on whether it has any plans to pursue the antibody's possible diagnostic use.
Holtzman added that, in theory, other drugmakers with anti-tau antibodies in their pipelines could likewise explore their diagnostic potential. "There are a lot of companies that are [developing anti-tau antibodies]," he said. "Whether or not they would find the same thing [as the STM study], I haven't seen their data yet. But it's certainly conceivable that this could be done by anybody who has an antibody that causes this kind of effect."
"Obviously, no one knows yet whether anti-tau antibodies will work as a therapy," he said. "But assuming they do, there's no reason why they couldn't be used as both a diagnostic and a therapeutic."