September 19, 2023 | Researchers in the U.S. and Sweden have identified a biomarker (MTBR-tau243) for Alzheimer’s disease that tracks with the amount of damaging tau tangles in the brain and, when combined with a specific phosphorylated tau species (p-tau205), is nearly as predictive of cognitive function as tau-positron emission tomography (tau-PET) imaging, according to Randall J. Bateman, M.D., professor of neurology at Washington University School of Medicine. Both biomarkers are readily discoverable in cerebrospinal fluid (CSF) via lumbar puncture (roughly $1,000), which is five times cheaper than a PET scan and in capable clinical hands no more painful than a routine blood draw.
Clinical trials are already underway using the novel biomarker to assess the performance of Eisai’s anti-MTBR tau antibody (E2814), under investigation by the Dominantly Inherited Alzheimer’s Network Trials Unit at Washington University, he reports. The company presented the latest study findings at the Alzheimer’s Association International Conference, held last month in Amsterdam, indicating that the drug succeeded in cutting MTBR-tau243 levels in half.
Bateman previously co-developed a CLIA-certified plasma protein assay for diagnosing Alzheimer’s disease, the commercial version of which is known as PrecivityAD (base-priced at $1,250 per test) that is being used in both clinical trials and to evaluate patients in real-world settings. Its focus is plaque deposits of the amyloid beta peptide, one of the two hallmark pathologies required for a diagnosis of Alzheimer’s disease.
The other is the flame-shaped neurofibrillary tangles made from the microtubule binding region (MTBR), which gets at the beauty of the MTBR-tau243 and p-tau205 pairing. “One of the recent realizations is that the [soluble] phosphorylated forms of tau are not the same as insoluble aggregates of tau tangles ... [and] the prior phospho-tau forms correlate much better with amyloid plaques and seems to be a response to [them],” Bateman says.
Study findings published recently in Nature Medicine (DOI: 10.1038/s41591-023-02443-z). “This is the first report of a pure soluble tau tangle marker of Alzheimer’s disease, and it’s going to change the way we do research and, someday soon, potentially the way that we diagnose people,” says Bateman.
If approved for use in the clinic, Bateman adds, he expects it will be to confirm if a patient’s symptoms are related to Alzheimer’s. “Someone can have plaques and have no symptoms at all, and someone can have plaques and have symptoms, but they may or may not be due to those plaques,” he explains. But for anyone who has tau tangles and cognitive symptoms, it is highly likely that some if not all those symptoms are due to Alzheimer’s disease.
For purposes of tracking the longitudinal progression of the disease once it has been diagnosed, patients could be tested roughly once per year, Bateman adds. That’s the estimated pace at which researchers expect tau pathology to change.
Bateman and his colleagues previously identified MRBR-tau243 when searching for chunks of tau in fluids that would signal the presence of tangles. Among a few of the study participants, the mid-section fragment was found to track with tau-PET and disease progression.
In the latest study, they used mass spectrometry to measure MRBR-tau243 as well as several phosphorylated tau markers in the CSF of 667 individuals, including both those who were and were not cognitively impaired. As MTBR-tau243 levels went up, tau levels in the brain also went up while scores on cognitive tests went down. Levels of phosphorylated tau tracked mainly with brain amyloid levels but not with either brain tau levels or cognitive function, although combining MTBR-tau243 with p-tau205 improved predictions for both tau-PET and a common clinical assessment of dementia—enough to rival tau-PET imaging in predicting cognitive decline.
Bateman and his team are intent on stopping tau pathology and, it is hoped, preventing the cognitive decline and memory loss that occurs in the later stages of Alzheimer’s disease when anti-amyloid therapies may become less effective. Patients might thereby be maintained at the level of mild impairment rather than descend to the point where they are unable to even carry out simple tasks and activities of daily living, such as a simple conversation.
A growing number of drugs under development target tau, says Bateman, citing a new pipeline report (Alzheimer’s & Dementia: Translational Research & Clinical Interventions, DOI: 10.1002/trc2.12385). Among the 111 disease-modifying therapies being investigated, 13 (9%) are targeting tau, while 22 (16%) agents target amyloid and 24 (17%) inflammation. “Initially, these were almost all amyloid drugs.”
Both regulatory and payer approval of a new diagnostic test will require more and larger clinical studies, says Bateman, adding that the longer-term goal is detection of MTBR-tau243 in plasma. Unlike Europeans, Americans tend to be “terrified of spinal taps” due to the belief that they are painful. This is rarely the case, but “it is very hard to change society’s perception” and the terminology around it (i.e., lumbar “puncture”) doesn’t help. On the other hand, much less training is required to do a blood test than a spinal tap and so it would be more widely deployable.
Development of a diagnostic blood test comes with a “50,000-fold problem,” Bateman notes. Since CSF is in direct contact with the brain, its concentration of proteins is 50 times higher than in the blood, he explains. The blood also has 1,000 times more irrelevant proteins, meaning that a blood-based assay needs to have a 50,000 times better signal-to-noise ratio as a CSF test.