At Human Amyloid Imaging Conference, Plasma Tau Was the Star

Series - Human Amyloid Imaging 2025:

The hunt for blood-based biomarkers is continuing apace. At the Human Amyloid Imaging (HAI) meeting, held January 15-17, researchers focused on new techniques—all based on tau and blood, conference title notwithstanding—for identifying whether a person has tau accumulation in his or her brain. Even as this blood-PET work advances, uncertainty around which tau PET tracers are best is still dogging validation efforts.

  • Ratios of phosphorylated tau species in the plasma predict disease stage better than single markers.
  • New assays that assess tau’s ability to aggregate rather than its phosphorylation patterns may be the most sensitive and specific to date.
  • MK6240 picks up tau tangles earlier than other tau PET tracers, and it correlates tightly with p-tau217.

The conference, which left Miami after 14 years there and convened in San Juan, Puerto Rico, drew 419 attendees from 16 countries. It featured technical sessions on data harmonization, on ways to deal with the heterogeneity that makes Alzheimer’s and other tauopathies so difficult to image, and on evolving methods of measuring neuropathology, among other topics.

This year’s breakout? Several dozen of the meeting’s 222 abstracts dealt with relating blood-based biomarkers to brain-imaging data in hopes of defining the most informative peripheral indicator of what AD pathology might be afoot in the central nervous system. This, the thinking goes, will lead to cheaper blood tests that can become widely and routinely available, while pricier PET scans can remain useful in clinical trials and specialty applications such as uncertain diagnoses.

Much discussion was sparked by Gemma Salvadó’s talk. Salvadó, Lund University, Sweden, presented a study attempting to determine the stage of a person’s Alzheimer’s disease by analyzing the levels of multiple tau plasma biomarkers simultaneously. Using mass spectrometry, Salvadó and colleagues measured, cross-sectionally, the baseline concentrations of 12 phosphorylated and non-phosphorylated tau species in plasma samples from 549 people in the Swedish BioFINDER cohort. They ranked each marker based on how well its level reflected progression of the person’s amyloid PET, tau PET in the medial temporal lobe and neocortex, cortical thickness, as well as their PACC and MMSE scores taken over the course of four years of study.

The team ultimately settled on three markers that best correlated with disease progression across the population. Two of them, p-tau217r and p-tau205r, represent ratios between phosphorylated and non-phosphorylated species. The former became positive with the onset of amyloid pathology, the latter with MCI symptoms. The third marker, an alternatively spliced isoform called 0N-tau, increased later still, when MCI progressed to dementia.

Blood Groups. Plasma p-tau217r, p-tau205r and 0N-tau scores change as people progressed from cognitive normality into amyloid positivity, MCI, then dementia. A new plasma staging model (below) proposes four phases of disease based on the amount or ratio of each marker. (Courtesy of Lund University.)

From these data, the researchers built a four-stage model (see image above) and validated it in 140 people from the TRIAD cohort based in Montreal. In both datasets, the model revealed four distinct stages of clinical and PET pathology that corresponded with plasma tau levels. People at higher stages had steeper tau accumulation and cognitive decline over the study period. It “shows that you can use changes in blood markers to accurately stage disease,” Salvadó said.

“It’s a great effort,” Bruna Bellaver, University of Pittsburgh, who chaired the session, told Alzforum. Bernard Hanseeuw, Cliniques Universitaires Saint-Luc, Brussels, who presented an alternative approach to tau plasma biomarker testing (see below), told Alzforum that Salvadó’s study convincingly showed that plasma can recapitulate PET stages of AD.

That said, the model was mostly verified in clear-cut stages rather than with the more difficult intermediate cases where PET and plasma results only partially overlap. “The percentage of mismatches makes it difficult to use in clinical practice where individual precision is needed, although it could work to enrich clinical trials,” Hanseeuw wrote.

Salvadó readily acknowledged that this plasma staging system is at the proof-of-concept stage, and far from ready for clinical use. “We need to validate it in a bigger and more diverse population,” she told Alzforum. At this point, it is difficult to even determine how precisely each biomarker reflects tau in the brain, she said. “We do not know whether the tau PET stages can be used as a gold standard yet.”

Although Bellaver considers the data promising, she was concerned about the finding that people in stage 1 had tau tangles in the neocortex. Neocortical tangles usually appear later in disease progression, years after p-tau217.

Salvadó said her group will next refine the model by incorporating additional biomarkers such as MTBR-243, which indicates tangles in the brain and can be measured both in CSF and plasma (Aug 2024 conference news). They also plan to determine how other co-pathologies, such as cerebrovascular disease and α-synuclein deposits, could affect the levels of various tau species in plasma.

An alternative approach, Hanseeuw said, is to avoid the question of biomarkers entirely by measuring tau’s aggregation capacity rather than its phosphorylation. In his talk, Hanseeuw presented early data from VeraBIND, a new assay by the Austin, Texas-based diagnostics company Veravas. The assay detects tau species with hyperphosphorylation at any location along the length of the protein. It involves multiple antibodies linked to beads and combines the tau isolated from a proband’s plasma sample with regular tau protein. The trick? By way of a luminescent readout, the assay reveals whether aggregation can occur—in other words, whether the donor’s blood contains species of tau that are actively able to aggregate “normal tau.”

Hanseeuw told Alzforum that this might be more clinically useful than simply knowing whether blood contains more of a certain form of tau. The approach is also free of known confounds such as chronic kidney disease and other comorbid conditions influencing p-tau217 plasma levels (Bornhorst, et al., 2025). Furthermore, only around 6 percent of people with amyloid but no tangles as measured by PET go on to develop cognitive impairment within the next three to five years (Ossenkoppele et al., 2022). “It’s important for [people] to know whether they have a significant short-term risk, and p-tau217 doesn’t give that information,” Hanseeuw said.

Hanseeuw and colleagues tested the new system in plasma samples from 58 cognitively unimpaired and 33 impaired people, along with plasma p-tau217 levels and MK6420 Tau PET scans from them. Compared with p-tau217 assays, the VeraBIND assay was less specific and less sensitive at predicting a person’s amyloid status, but it outperformed p-tau217 at predicting tau status. The VeraBIND assay was also more accurate than p-tau217 at detecting those cases who had tangles but no amyloid.

Bye-Bye p-Tau? The phosphorylation-agnostic VeraBIND assay predicts tangles in the brain more accurately than does plasma p-tau217, which is closely associated with amyloid status. (Courtesy of Bernard Hanseeuw.)

Bellaver called the VeraBIND data promising, despite the small sample size. “They saw more specificity for tau than for amyloid. That’s what we’re looking for,” she told Alzforum.

Suzanne Schindler, Washington University, St. Louis, agrees there’s a great need to keep improving plasma assays since few research centers—and even fewer clinics—can perform tau PET. “We know people with really high p-tau217 are likely to have high tau PET, but the prediction isn’t great,” she said. If a person’s plasma levels are already high, she said, it may not be worth enrolling them in a trial or starting them on a therapy that works best at earlier stages of pathology.

Right now, the quest for the best plasma biomarkers is hobbled by lingering uncertainty about how best to quantify tangles in the brain, which, after all, is the standard blood tests are supposed to be held against. Several tau PET tracers are competing in this regard, and the differences between them are significant (Jul 2024 news). Few direct comparison studies exist.

At HAI, Pamela Ferreira, University of Pittsburgh, showed results from one. Ferreira compared how well four tau PET tracers correlated with plasma p-tau217 using data from HEAD. In this head-to-head study, people at different disease stages or healthy controls receive PET scans with two to four different tracers. Ferreira and colleagues analyzed MK6240, flortaucipir, PI2620, and RO948 uptake across disease stages. At HAI, she reported that MK6240 most closely tracked with plasma p-tau217, especially during early disease stages, although all four tracers showed statistically significant associations.

6240 Wins This One. In HEAD, plasma p-tau217 levels correlate more closely with reads from MK6240 than three other tau PET tracers, especially during early tangle deposition.

“It looks like MK6420 is better across the board,” Schindler said of the Merck compound, which is still in clinical trials but is used by some research groups. Her group and many others primarily use flortaucipir, since it is the only FDA-approved tau tracer thus far, despite its known off-target binding in the hippocampus. Ferreira’s data, Schindler said, “is telling us that we're not doing the optimal test.”

MK6420 was originally developed as a research tool by Merck (Hostetler et al., 2016; Apr 2017 conference news) Merck, a pharmaceutical company, did not want to develop a commercial tau PET tracer, and it is now being moved through Phase 3 by Lantheus under the name florquinitau (Shuping et al., 2023; Rea Reyes et al., 2024; Bahr et al., 2025).—Sara Reardon

Sara Reardon is a freelance writer in Bozeman, Montana.

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References

News Citations

  1. A Plasma Test for Tangles?
  2. Tau PET Misses Early AD Pathology, Primary Age-Related Tauopathy
  3. Next-Generation Tau PET Tracers Strut Their Stuff

Paper Citations

  1. Bornhorst JA, Lundgreen CS, Weigand SD, Figdore DJ, Wiste H, Griswold M, Vemuri P, Graff-Radford J, Knopman DS, Cogswell P, Jack CR, Petersen RC, Algeciras-Schimnich A. Quantitative Assessment of the Effect of Chronic Kidney Disease on Plasma P-Tau217 Concentrations. Neurology. 2025 Feb 11;104(3):e210287. Epub 2025 Jan 17 PubMed.
  2. Ossenkoppele R, Pichet Binette A, Groot C, Smith R, Strandberg O, Palmqvist S, Stomrud E, Tideman P, Ohlsson T, Jögi J, Johnson K, Sperling R, Dore V, Masters CL, Rowe C, Visser D, van Berckel BN, van der Flier WM, Baker S, Jagust WJ, Wiste HJ, Petersen RC, Jack CR Jr, Hansson O. Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline. Nat Med. 2022 Nov;28(11):2381-2387. Epub 2022 Nov 10 PubMed.
  3. Hostetler ED, Walji AM, Zeng Z, Miller P, Bennacef I, Salinas C, Connolly B, Gantert L, Haley H, Holahan M, Purcell M, Riffel K, Lohith TG, Coleman P, Soriano A, Ogawa A, Xu S, Zhang X, Joshi E, Della Rocca J, Hesk D, Schenk DJ, Evelhoch JL. Preclinical Characterization of 18F-MK-6240, a Promising PET Tracer for In Vivo Quantification of Human Neurofibrillary Tangles. J Nucl Med. 2016 Oct;57(10):1599-1606. Epub 2016 May 26 PubMed.
  4. Shuping JL, Matthews DC, Adamczuk K, Scott D, Rowe CC, Kreisl WC, Johnson SC, Lukic AS, Johnson KA, Rosa-Neto P, Andrews RD, Van Laere K, Cordes L, Ward L, Wilde CL, Barakos J, Purcell DD, Devanand DP, Stern Y, Luchsinger JA, Sur C, Price JC, Brickman AM, Klunk WE, Boxer AL, Mathotaarachchi SS, Lao PJ, Evelhoch JL. Development, initial validation, and application of a visual read method for [18F]MK-6240 tau PET. Alzheimers Dement (N Y). 2023;9(1):e12372. Epub 2023 Feb 12 PubMed.
  5. Rea Reyes RE, Cody KA, Wilson RE, Zetterberg H, Chin NA, Jonaitis EM, Bahr M, Mandel O, Wintlend M, Bendlin BB, Okonkwo OC, Clark LR, Zammit M, Asthana S, Christian BT, Betthauser TJ, Eisenmenger L, Langhough RE, Johnson SC. Visual read of [F-18]florquinitau PET that includes and extends beyond the mesial temporal lobe is associated with increased plasma pTau217 and cognitive decline in a cohort that is enriched with risk for Alzheimer's disease. Alzheimers Dement. 2024 Nov 19; Epub 2024 Nov 19 PubMed.
  6. Bahr M, Wintlend M, Mandel OR, Studer RL, Jonaitis EM, Alberson SF, Meyering E, Ryther B, Hellenbrand T, Kaminski N, Chin NA, Betthauser TJ, Christian BT, Johnson SC. Cognitive outcomes with AD tauopathy characterized by florquinitau PET. Alzheimers Dement. 2025 Jan 9;20(Suppl 2):e092841. PMCID: PMC11714911. Alzheimer's & Dementia

External Citations

  1. HEAD

Further Reading

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