Anyone would think a revolution is imminent: “Blood tests could reshape Alzheimer’s care.” “Blood tests improve diagnosis in primary care.” “Predicting Alzheimer’s years before symptoms.”

These headlines are all based on the promise of a single blood-based predictor of brain pathology: phosphorylated tau.

It is indeed a great biomarker. But in my view, it’s not enough.

The Problem: Amyloid and Tau Tangles Don’t Move Together  

Tau is a protein that is normally involved in memory generation, and when it gets phosphorylated it becomes a promising predictor of brain pathology: the accumulation of sheets of amyloid protein which form plaques, one of the key features of Alzheimer’s disease. But there is another key feature of Alzheimer’s disease beyond amyloid plaques: the accumulation of tangles of tau in the brain. While tau protein is an essential component of normal brain function, these tangles shouldn’t be there. The coincidence of plaques and tangles is diagnostic of later-stage Alzheimer’s disease as it affects cognitive function. We want to measure them both, and somewhat confusingly, phosphorylated tau alone predicts amyloid protein in the brain much more accurately than it predicts tau tangles.

Looking narrowly at Alzheimer’s disease, the key unmet need now is to find a non-invasive and scalable way of predicting brain tau tangles. If amyloid and tau increased together, we could just use amyloid as a proxy, via measuring phosphorylated tau in the blood. But they don’t; they are on vastly different timetables. Phosphorylated tau in the blood can increase years before a diagnosis or eligibility for treatment. People can have a high level of brain amyloid but no tau tangles, and some of them will be relatively resistant to cognitive decline and an Alzheimer’s diagnosis. So while phosphorylated tau alone can act as a very early marker of risk in a population, some of these individuals never become cognitively impaired, and even among people with high phosphorylated tau, roughly 20% don’t lose cognitive function. Nonetheless, today, with only one approved treatment mechanism (amyloid reduction), the combination of high phosphorylated tau and impaired cognitive function can be viewed as “good enough” to make a diagnosis and establish eligibility for therapy with its merely modest effect on slowing cognitive decline. But this isn’t ideal.

And now that promising treatments are being developed to remove tau protein, in addition to those for amyloid, clinical triallists today, and clinical practitioners of the future, also need to know what blend of both of these proteins is present, in order to match the right patients to a trial or a treatment for Alzheimer’s disease. Things are only going to get more complicated.

So we need blood-based proxies simultaneously for the two key pathologies in Alzheimer’s disease: brain amyloid plaques (hurray, we have this) and brain tau tangles, missing in action. Until now.

Why Tau Tangles Have Been So Hard to Measure in Blood

The first problem with tau tangles is that only very few fragments break off and make their way into the blood. So an assay needs to be extraordinarily sensitive to measure them. The second problem is that the part of the protein that reaches the blood is a very specific processed fragment of the tau protein called eMTBR (the extended microtubule-binding region), so an assay needs exquisite specificity to that fragment, and not any others, in the presence of much higher concentrations of total tau.

One approach to overcome these issues originated at Washington University School of Medicine and Lund University. They were able to increase the concentration of the targeted proteins by immuno-precipitation from a large volume of sample. This enabled them to use mass spectrometry to identify a related fragment, MTBR-tau243, and showed in a 2025 Nature Medicine study that it tracks tau-PET binding and cognitive decline better than p-tau217 or p-tau205 (Horie et al., 2025). That work, done on specialized mass-spectrometry instruments largely confined to academic reference labs, was proof of concept that this class of fragment mattered. Some clever workarounds have also been attempted. Rather than measuring eMTBR directly, Di Molfetta et al. (Jama Neurology 2026) used machine learning to derive a model from the NULISAseq™ CNS 120 panel (prior to the development of the NULISA eMTBR assay) that combined p-tau217 with seven other proteins in plasma to create an improved prediction of brain tau. But mathematically derived surrogates and mass-spec-only methods are harder to scale into the multiplexed, high-throughput immunoassays that clinical trials, and eventually clinics, need, and surrogates that are not directly causal are viewed as riskier for monitoring therapy than a direct measure.

Our Breakthrough: Measuring eMTBR-Tau Directly, at Scale

That’s where our breakthrough comes in. NULISA™ is the first multiplexed immunoassay platform able to measure eMTBR-Tau directly. To measure it at all, we had to optimize antibody pairs that recognized this exact tangle fragment, and confirm they didn’t cross-react with the much more abundant pool of total tau. Then we had to show we could characterize it consistently in blood: that the assay was sensitive enough in small volumes of plasma, at concentrations in the attomolar (quintillionths of a mole) range. Then, having done that, our academic collaborators, including Dr. Nicholas Ashton’s team in the Fluid Biomarker Laboratory at Banner Health, who had measured actual tau pathology, either with tau-PET imaging or in people who had died and donated their brains, helped us show that the blood-based measurements were consistent with those ground truths.

The combination of eMTBR-Tau and phosphorylated tau, especially brain-derived tau phosphorylated at position 217 (BD pTau-217), can therefore improve the diagnosis of Alzheimer’s disease, the staging of the disease over time, estimating an individual’s risk of cognitive decline, and predicting response to anti-amyloid and anti-tau therapies. All through blood tests.

And now, more than 100 laboratories running Alamar’s ARGO^® HT System can measure eMTBR-Tau alongside other key neurodegeneration assays in Alzheimer’s research, as part of the NULISAseq™ Neuro 220 panel. The scaling is immediate.

It Doesn’t End There

We are also looking for ways to make phosphorylated tau measurements more consistent in elderly people. While measuring only the brain-derived fragments helps, there are other ways of reducing the false-result rate caused by common age- and metabolic disease-driven variation in kidney function, which affects most proteins in the blood and which recent research confirms is already complicating interpretation of existing plasma p-tau217 platforms (Arslan, Zetterberg & Ashton, 2025).

Additionally, it turns out from autopsy studies that most of us are carrying several brain pathologies at once. Clinical observations and suspicion of cognitive impairment are relatively non-specific, and share features across multiple conditions such as impairment in the brain’s blood supply, Parkinson’s disease, chronic traumatic encephalopathy (CTE), and fronto-temporal dementia. The next unmet need, then, is to detect the burden of all of these in any individual, so the most appropriate mechanistically relevant treatments can be given, and the wrong ones avoided. For that, we need non-invasive, scalable, cost-effective methods of detecting them all at once, such as multiplexed proteomics. Then we will have arrived.

In short: a blood test for phosphorylated tau (p-tau217) is an excellent predictor of brain amyloid plaques, but it is a poor predictor of the tau tangles that drive cognitive decline in Alzheimer’s disease. Alamar’s NULISA™ platform now measures eMTBR-Tau, a specific tau fragment that reaches the blood only when tangles are forming, closing that gap for the first time in a scalable, multiplexed immunoassay.

Key Takeaways

• Phosphorylated tau (p-tau217) predicts amyloid plaques far better than it predicts tau tangles. The two core pathologies of Alzheimer’s disease move on different timetables.
• Roughly 20% of people with high phosphorylated tau never lose cognitive function, underscoring why amyloid-only or p-tau-only staging is incomplete.
• eMTBR-Tau (extended microtubule-binding region tau) is a specific, low-abundance fragment of the tau protein that only reaches measurable blood levels when tangles are actively forming.
• NULISA’s eMTBR-Tau immunoassay, run on the ARGO^® HT System, is the first multiplexed blood test able to measure eMTBR-Tau directly, at attomolar sensitivity, and is already available across more than 100 research laboratories.
• In the future, combining eMTBR-Tau with brain-derived phosphorylated tau (BD pTau-217) may improve diagnosis, disease staging, prediction of cognitive decline, and prediction of response to anti-amyloid and anti-tau therapies.

Frequently Asked Questions

What is eMTBR-Tau?

eMTBR-Tau is a specific, processed fragment of the tau protein (the extended microtubule-binding region) that is released into the blood when tau tangles form in the brain. Unlike total tau, it is specific enough to reflect tangle pathology rather than the much larger, non-specific pool of tau in the body.

How is eMTBR-Tau different from phosphorylated tau (p-tau217)?

Phosphorylated tau (p-tau217) is an excellent predictor of brain amyloid plaques but a poor predictor of tau tangles, because amyloid and tangle pathology accumulate on different timetables. eMTBR-Tau specifically tracks tangle pathology, so measuring both together gives a fuller picture of Alzheimer’s disease than either alone.

Why has measuring tau tangles in blood been so difficult?

Only a small number of tangle-derived tau fragments reach the bloodstream, and they’re present at attomolar concentrations alongside far higher levels of total tau. Detecting them requires both extreme sensitivity and extreme specificity, a combination most blood tests can’t achieve.

What platform measures eMTBR-Tau, and how widely is it available?

Alamar Biosciences’ NULISA™ technology, run on the ARGO^® HT System, is the first multiplexed immunoassay platform to measure eMTBR-Tau. It is available as part of the NULISAseq™ Neuro panel on more than 100 ARGO HT systems already installed in research laboratories.

Can eMTBR-Tau predict response to Alzheimer’s treatments?

Combined with brain-derived phosphorylated tau (BD pTau-217), eMTBR-Tau measurements can help stage disease, estimate risk of cognitive decline, and predict response to both anti-amyloid and anti-tau therapies. That is increasingly important as tau-targeted treatments move through clinical trials.

Is eMTBR-Tau testing available for clinical diagnosis today?

Not yet. The NULISA eMTBR-Tau assay is currently for research use only and is not intended for use in diagnostic procedures. Its near-term impact is in research and clinical trial patient selection and monitoring, ahead of eventual clinical validation.

References

1. Horie K, Salvadó G, Koppisetti RK, et al. Plasma MTBR-tau243 biomarker identifies tau tangle pathology in Alzheimer’s disease. Nature Medicine. 2025;31(6):2044–2053. doi:10.1038/s41591-025-03617-7. PMID: 40164726.
2. Alamar Biosciences. Alamar Biosciences Launches the First Multiplexed Blood-based Immunoassay for eMTBR-Tau, One of the Most Important Biomarkers in Alzheimer’s Disease Research. GlobeNewswire. July 7, 2026.
3. Arslan B, Zetterberg H, Ashton NJ. Integrating kidney function assessment into the clinical interpretation of plasma Alzheimer’s disease biomarkers. Journal of Alzheimer’s Disease. 2025. doi:10.1177/13872877251375101.
4. Alamar Biosciences. NULISAqpcr™ BD-pTau217 Assay. alamarbio.com.