A Plasma Test for Tangles?

Series - Alzheimer's Association International Conference (AAIC) 2024:

Clinicians may soon have a blood test for neurofibrillary tangles. At AAIC 2024, held July 27-31 in Philadelphia, Randall Bateman, Washington University, St. Louis, reported that a fragment of tau containing the microtubule-binding region, called eMTBR-243, can be detected in plasma and that it identifies people who have neurofibrillary tangles in their brains. When combined with a plasma marker of amyloid, such as p-tau217, it could help confirm when a person has AD.

  • Tau fragment MTBR-243 is found in plasma.
  • Levels rise in late Braak stages.
  • It could help confirm Alzheimer’s disease in people with brain amyloid.

“We can’t be assured that just because someone has amyloid plaques, their symptoms are due to Alzheimer’s disease,” noted Bateman. “This is where eMTBR-243, tau PET, or another measure of tau tangles will help.”

Thomas Karikari, University of Pittsburgh Medical Center, said the data was exciting. “The field has been missing a good marker for tau aggregates, and it will be great to have a blood-based assay that correlates.”

A multiplex blood test indicating both the presence of amyloid plaques in the brain, such as with p-tau217, and the presence of tau tangles in the brain, such as with eMTBR-243, would essentially meet the definition of Alzheimer’s disease set out by Alois Alzheimer. It would also reflect, during life, neuropathology-based criteria of AD (Hyman et al., 2012, Jack et al, 2024). 

Henrik Zetterberg, University of Gothenburg, Sweden, told Alzforum that the eMTBR-243 data looked very promising. “It will be interesting to see if this marker increases in neurodegenerative diseases that are not amyloid-dependent, such as primary tauopathies,” he said.

Bateman and colleagues had previously reported that MTBR-243 in cerebrospinal fluid tracks with tangles (Dec 2020 news). Would this fragment, like various p-tau fragments found in the CSF, also turn up in the blood? After all, if it gets laid down in intraneuronal tangles, it might not. Sure enough, Kanta Horie at WashU, who had discovered the CSF marker, found it in plasma.

Alas, its levels there did not budge when tangles accumulated in the brain. Horie told Alzforum that the extraction protocol was the problem. The mass spectrometry-based test for CSF MTBR relies on tryptic digestion. Lo and behold, when Horie skipped this step and used a proteomic approach to find endogenously cleaved fragments, he found an MTBR-243 fragment in plasma that did track with tangles. The lab calls this endogenously cleaved marker eMTBR-243 to distinguish it from the CSF version.

In Philadelphia, Bateman reported that plasma eMTBR-243 showed extremely high specificity and sensitivity at identifying people who had tangles. In 108 people from the Swedish BiofFinder2 cohort, it boasted an AUC of 1.0 at distinguishing the 41 whose tau PET scan was positive. Horie told Alzforum that this high accuracy surprised him, and that he plans to test other and larger cohorts. In the present analysis, eMTBR-243 outperformed plasma p-tau217 and the p-tau217/217 ratio, which had AUCs of 0.87 and 0.89, respectively.

Looking more closely at tangle load, Bateman reported that eMTBR-243 correlates much more tightly with Braak stages III to VI than with Braak I and II. Among people who had brain amyloid, Spearman correlations between eMTBR-243 and tangle load, as judged by regional tau PET, was 0.54 in Braak stages I to III, 0.79 in stages III to IV, and 0.86 in V to VI. In keeping with this, among 55 volunteers at the Knight Alzheimer’s Disease Research Center at WashU, those with a clinical dementia rating of 1.0 had much higher levels of eMTBR-243 in their plasma than did people with a CDR of 0.5, who, in turn, had just slightly more eMTBR-243 in their blood than cognitively normal people who had brain amyloid. “This work indicates that eMTBR-243 greatly increases as people transition from very mild to mild dementia,” said Bateman, “namely CDR 0.5 to CDR 1.0.”

Horie told Alzforum that, in this regard, the marker behaves differently from CSF MTBR-243, which, like p-tau217, ticks up gradually as disease progresses. “Plasma eMTBR-243 shows an exponential increase after symptom onset, so it is much more specific to later-stage tau aggregation,” he said. Karikari thinks this may not be unusual. “If we expect the signal to come from the brain, then we should see less in the blood, and it may take more time and be dose-dependent,” he said.

Plasma eMTBR-243 could be useful to help stage or rule out AD, said Bateman. “If p-tau217 is elevated and eMTBR-23 is completely normal, then I would question whether that person’s symptoms are due to AD, and would consider another cause,” he said.

What about those other causes? Could plasma eMTBR-243 help identify other tauopathies? Horie said that CSF MTBR-243 appears to be a specific marker of tangles containing tau isoforms with three and four repeats of the microtubule-binding region. In addition to AD, some forms of primary tauopathy, including frontotemporal dementia caused by the R406W mutation in the tau gene, have 3R/4R tangles. “I have high confidence that we can differentiate 3R/4R tauopathies with CSF MTBR-243,” said Horie.

Testing of other tauopathy cohorts for eMTBR-243 is ongoing. Zetterberg thinks there’s a slight chance eMTBR-243 might be amyloid-dependent, like p-tau217. “It will be interesting to see what they find,” he said.—Tom Fagan

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References

News Citations

  1. MTBR-243 Tau: A Fluid Biomarker for Tangles Themselves?

Paper Citations

  1. Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Thies B, Trojanowski JQ, Vinters HV, Montine TJ. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement. 2012 Jan;8(1):1-13. PubMed.
  2. Jack CR Jr, Andrews JS, Beach TG, Buracchio T, Dunn B, Graf A, Hansson O, Ho C, Jagust W, McDade E, Molinuevo JL, Okonkwo OC, Pani L, Rafii MS, Scheltens P, Siemers E, Snyder HM, Sperling R, Teunissen CE, Carrillo MC. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimers Dement. 2024 Jun 27; PubMed.

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