ALS or Alzheimer’s? Blood Phospho-Tau Could Mean Either

For years, the Alzheimer’s disease field has been on a quest for the perfect blood marker. Such a test could spare patients from invasive lumbar punctures, broaden care access, and allow AD cases to be identified sooner. But a new study in the March 5 Nature Communications highlights a complication for two of the most promising candidates, p-tau181 and p-tau217. These phosphorylated tau species are elevated in the serum not only of AD patients, but also in people with ALS, who likely produce it in their muscles, according to the authors’ findings.

  • Serum p-tau217 ticks up in ALS, but less so than in AD.
  • Levels of p-tau181 are similar in both diseases, confirming past findings.
  • Damaged muscle fibers from ALS patients contain both forms of p-tau.

“Phospho-tau in blood is not as specific as everyone would like to think. … And for ALS patients, it is actually an additional new biomarker,” said Markus Otto of Martin-Luther-University Halle-Wittenberg, Germany, who led the study.

P-tau181 and p-tau217 are considered early markers of Aβ and tau pathology. Previously, scientists had reported an association between serum p-tau181 and ALS (Cousins et al., 2022; Vacchiano et al., 2023). But in the AD field, attention has been shifting to p-tau217, which is a more specific marker for AD (Dec 2023 conference news; Aug 2024 conference news). The new study is the first to look for it in people with ALS.

“This is an amazing and very important study,” wrote Henrik Zetterberg, University of Gothenburg, Sweden, who was not involved in the work. “The p-tau increase in ALS is only seen in blood and not in CSF. This speaks strongly for phosphorylation of peripheral tau in ALS,” he wrote to Alzforum (comment below.)

First authors Samir Abu-Rumeileh, Leila Scholle, and colleagues tested the blood and CSF of participants at four health care centers in Germany and Italy. Of the 362 volunteers, 152 had ALS, 111 had AD, and 99 were controls who did not have neurodegenerative or muscular diseases.

The serum p-tau181 findings matched those of prior studies, with high levels in both AD and ALS and no difference between the two. Serum p-tau217 was also elevated in the serum of AD and ALS patients, but it was higher in AD. The scientists were able to distinguish between AD and ALS and between ALS and controls based on serum p-tau217, but with only moderate accuracy. In contrast, p-tau217 was so consistently high in AD that it reliably distinguished AD patients from controls (image below).

AD or ALS? Serum p-tau181 (left) was higher in people with ALS than in controls (DCo), whether they did (A+), or did not (A-), have AD pathology as judged by CSF analysis. Serum p-tau181 did not distinguish ALS from AD. Serum p-tau217 (right) distinguished AD from ALS, ALS-A-, and controls, but not ALS-A+.  [Courtesy of Abu-Rumeileh et al., Nature Communications, 2025.]

“P-tau217 is much better than p-tau181 in AD. And here we find that there's even a distinction between AD and ALS. So, I think it's still a very good marker,” said Katheryn Cousins at the University of Pennsylvania. But she thinks on its own, even p-tau217 is not accurate enough to be called a diagnostic. Cousins was not involved in the work, although she was one of the scientists who first discovered high serum p-tau181 in ALS patients.

Why would these p-tau species show up in in ALS, even when there is no AD pathology? That’s still unclear, but clues may come from where the p-tau is produced. In AD, p-tau181 and p-tau217 appear to come from the brain, since these markers rise in the CSF as well as blood. Neither p-tau showed up in ALS CSF. However, immunostaining identified p-tau181 and p-tau217 in muscle biopsies from 13 ALS patients, but not in 14 controls.

“We were very surprised how much phospho-tau is in these muscle cells. It was a clear yes or no, if you compare ALS patients with control,” said Otto.

P-tau in Muscle. Immunohistochemistry suggests abundant p-tau181 (left) and p-tau217 (right) in the muscle of a person with ALS (top), but not in muscle of a control (bottom). [Courtesy of Abu-Rumeileh et al., 2025.]

Strikingly, people with ALS had far more of both p-tau isoforms in muscle fibers that showed signs of atrophy than in fibers that still appeared healthy. Moreover, their serum p-tau correlated with troponin T, a marker of muscle damage. Does this mean wasting muscle fibers release p-tau181 and 217 into the blood? Otto is not ready to jump to conclusions. Before scientists get too confident that damaged muscle is the source, they should look at paired muscle and serum from the same individuals, he said. Serum was only available from two of the patients who provided muscle biopsies for the current study.

As p-tau181 and 217 make their way into routine practice, clinicians will need to take these new data into account. Typically, such tests are run for people who show symptoms, at which point it is hard to confuse ALS with AD. But on rare occasions people have both diseases at once, and there could be other conditions that cause p-tau to rise as well, noted Otto. “[ALS] is an example that p-tau can also come from other sources,” he said.

Many scientists hope that blood biomarkers can someday serve as population screening tools for AD, helping to catch and treat people before symptoms appear, or for screening for prevention trials. Since the people in this study all had symptoms, it’s not clear how the findings might apply to people in earlier, asymptomatic disease stages, said Cousins. Perhaps there would be more potential for confusion between diagnoses, or perhaps preclinical ALS cases would show no changes in p-tau at all, she suggested. Otto concurred.

Other biomarkers could help clarify what a patient’s blood p-tau levels mean. For example, Abu-Rumeileh and colleagues found that serum NfL is higher in ALS than in AD, so if a blood test shows very high p-tau181 and NfL, the person likely has ALS.

Zetterberg noted there are already tests that can distinguish tau produced in the brain from tau produced elsewhere in the body, based on portions of the protein that are spliced out in the brain (see Dec 2022 conference news).

Otto and colleagues identified several new tau phosphorylation sites in muscle biopsies using mass spectrometry. Two of them, S437 and S438, are in regions that are spliced out of tau in the brain, hinting at the possibility of muscle-specific markers. Comparing these new p-tau isoforms in diseased versus healthy muscle “is the next project” Otto wrote. —Nala Rogers

Nala Rogers is a freelance science writer based in Silver Spring, Maryland.

Comments

  1. This is an amazing and very important study. There are many informative aspects to it. The p-tau increase in ALS is only seen in blood and not in CSF. This speaks strongly for phosphorylation of peripheral tau in ALS, whilst the phosphorylation in AD happens on brain-derived (short) tau, with increases in both CSF and blood.

    The ALS effect is stronger for p-tau181 than p-tau217. This speaks for tau phosphorylation at amino acid 217 being a more CNS-related event; maybe this explains why p-tau217 often turns up as a slightly better biomarker for AD than p-tau181 when measured in blood.

    In ALS, patients often undergo both CSF and blood biomarker analysis. The ALS pattern would be high CSF and plasma NfL concentrations, normal CSF p-tau181 concentration, and high plasma p-tau181 concentration. The study also underscores that plasma p-tau biomarkers need to be interpreted in a complete clinical context.

    Phosphorylation of peripheral tau in ALS is both a problem and a possibility. Assays that combine antibodies specific against brain-derived tau with antibodies against phosphorylated tau epitopes will likely solve the problem. At the same time, blood p-tau181, especially together with NfL, may be an excellent biomarker for ALS. 

    View all comments by Henrik Zetterberg

  2. This study represents an important advance in our understanding of elevated blood but not CSF p-tau in persons with amyotrophic lateral ALS. While CSF and blood p-tau isoforms 181 and 217 are most commonly used for detecting tau pathology in association with AD pathology, this multi-cohort study adds to the growing body of evidence that blood (plasma and serum) p-tau181 is also elevated in ALS, particularly lower motor neuron (LMN) predominant ALS.

    Abu-Rumeileh and colleagues also provide new evidence that serum p-tau217 is elevated in ALS, while serum total-tau is not. Importantly, the study uses CSF biomarkers to classify ALS with and without AD co-pathology, showing elevated serum p-tau181 and p-tau217 in both AD-positive and -negative ALS.

    Given that ALS is not a tauopathy, but is most commonly associated with TDP-43 pathology, there are still open questions about why blood p-tau 181 and p-tau217 are elevated in ALS and other LMN diseases. Muscle biopsies showed p-tau181 and p-tau217 immunoreactivity in the myonuclei of both ALS (n=13) and non-neurogenerative disease controls (n=14). They also found increased sarcoplasmic reactivity to p-tau181 and p-tau217 in atrophic muscle fibers, and I agree with the authors that future work will need to correlate these with blood levels to test muscle as a potential source of elevated blood p-tau levels in ALS.

    These findings also raise important questions about use of blood p-tau to detect AD. While serum p-tau217 is elevated in ALS compared to disease controls, levels were still highest in AD, whereas p-tau181 levels were comparable in AD and ALS. The authors note that this finding further supports the superior accuracy of p-tau217 compared to 181 in AD, and that, moreover, the distinct clinical differences between AD and ALS (and other LMN diseases) will provide the important interpretive context in symptomatic stages of disease. Still, future work is needed to test blood p-tau in pre-symptomatic ALS to inform application and interpretation of blood biomarkers in people without symptoms.

    View all comments by Katheryn Cousins

  3. This important and interesting work by Drs. Abu-Rumeileh, Otto, and colleagues examines changes in serum p-tau biomarkers in ALS. The study robustly replicated two previous papers showing higher levels of plasma p-tau181 in ALS than in controls (Cousins et al., 2022; Vacchiano et al., 2023). Furthermore, the authors report for the first time that serum p-tau217 levels were also elevated in ALS, albeit to a lesser extent than in AD. This was not the case for p-tau181, further supporting the superiority of p-tau217 as AD biomarker.

    One very exiting aspect of this study is that it explored potential mechanisms underlying increased blood levels of p-tau in ALS. Specifically, p-tau181 and p-tau217 were detected in muscle biopsies, with atrophic muscle fibers showing higher immunoreactivity for both p-tau variants. These findings suggest that the increases in blood p-tau levels in ALS may, at least in part, be caused by their release from atrophic muscle tissue.

    One critical issue to consider is that the Simoa p-tau181 and p-tau217 assays used in this paper do not differentiate between high-molecular-weight tau isoforms expressed in the peripheral nervous system and low-molecular-weight (LMW) tau predominant in the central nervous system (Fischer et al., 2020; Buchholz and Zempel, 2024). Therefore, it would be very important to perform similar studies with assays that specifically detect the LMW brain-derived tau that might be less affected by peripheral tau sources, such as those developed by Lilly Research Laboratories (Palmqvist et al., 2020; Janelidze et al., 2020) or total tau assay designed at the University of Gothenburg (Gonzalez-Ortiz et al., 2024).

    References:

    Cousins KA, Shaw LM, Shellikeri S, Dratch L, Rosario L, Elman LB, Quinn C, Amado DA, Wolk DA, Tropea TF, Chen-Plotkin A, Irwin DJ, Grossman M, Lee EB, Trojanowski JQ, McMillan CT. Elevated Plasma Phosphorylated Tau 181 in Amyotrophic Lateral Sclerosis. Ann Neurol. 2022 Nov;92(5):807-818. Epub 2022 Aug 17 PubMed.

    Vacchiano V, Mastrangelo A, Zenesini C, Baiardi S, Avoni P, Polischi B, Capellari S, Salvi F, Liguori R, Parchi P, BoReALS group. Elevated plasma p-tau181 levels unrelated to Alzheimer's disease pathology in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2023 Jun;94(6):428-435. Epub 2023 Apr 3 PubMed.

    Fischer I, Baas PW. Resurrecting the Mysteries of Big Tau. Trends Neurosci. 2020 Jul;43(7):493-504. Epub 2020 May 17 PubMed.

    Buchholz S, Zempel H. The six brain-specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes. Alzheimers Dement. 2024 May;20(5):3606-3628. Epub 2024 Mar 31 PubMed.

    Palmqvist S, Janelidze S, Quiroz YT, Zetterberg H, Lopera F, Stomrud E, Su Y, Chen Y, Serrano GE, Leuzy A, Mattsson-Carlgren N, Strandberg O, Smith R, Villegas A, Sepulveda-Falla D, Chai X, Proctor NK, Beach TG, Blennow K, Dage JL, Reiman EM, Hansson O. Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA. 2020 Aug 25;324(8):772-781. PubMed.

    Janelidze S, Stomrud E, Smith R, Palmqvist S, Mattsson N, Airey DC, Proctor NK, Chai X, Shcherbinin S, Sims JR, Triana-Baltzer G, Theunis C, Slemmon R, Mercken M, Kolb H, Dage JL, Hansson O. Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer's disease. Nat Commun. 2020 Apr 3;11(1):1683. PubMed.

    Gonzalez-Ortiz F, Ferreira PC, González-Escalante A, Montoliu-Gaya L, Ortiz-Romero P, Kac PR, Turton M, Kvartsberg H, Ashton NJ, Zetterberg H, Harrison P, Bellaver B, Povala G, Villemagne VL, Pascoal TA, Ganguli M, Cohen AD, Minguillon C, Contador J, Suárez-Calvet M, Karikari TK, Blennow K. A novel ultrasensitive assay for plasma p-tau217: Performance in individuals with subjective cognitive decline and early Alzheimer's disease. Alzheimers Dement. 2024 Feb;20(2):1239-1249. Epub 2023 Nov 17 PubMed.

    View all comments by Shorena Janelidze

  4. My interpretation of this paper is that it accurately acknowledges the inherent complexities in interpreting blood p-tau biomarker data. Tau undergoes normal phosphorylation in both the central nervous system (CNS) and peripheral nervous system (PNS), with phosphorylated forms entering the bloodstream at low concentrations. Our previous research, comparing tau phosphorylation status in CSF and blood across multiple residues, indicated potential differences in site-specific tau phosphorylation abundance between CSF and blood plasma (Barthélemy et al., 2020). We proposed that these differences may explain the observed variations in p-tau relative abundance between CNS and PNS.

    We and others have observed that brain amyloid deposition, and to a lesser extent tau aggregation, contribute to a sensitive increase in p-tau217 abnormalities detectable in both CSF and blood (Barthélemy et al., 2023; Barthélemy et al., 2024). Notably, p-tau217 is significantly more accurate in blood than p-tau181 for detecting amyloid deposition (Janelidze et al., 2023). Consequently, p-tau217 is now recognized as the leading blood-based biomarker candidate for measuring amyloid deposition.

    While numerous studies suggest p-tau217 and other p-tau forms possess enhanced specificity for CNS amyloid pathology, it remains crucial to consider the potential influence of other biological processes in both the CNS and PNS, which can modulate the activity of kinases and phosphatases on tau and, consequently, p-tau relative abundance and levels, as well as factors affecting overall blood tau concentration (Janelidze et al., 2022). 

    Blood p-tau generally does not appear to be responsive to non-AD tauopathies in most amyloid-negative individuals (Thijssen et al., 2021), with potential exceptions observed in symptomatic MAPT mutation carriers (Sato et al., 2011). However, recent findings demonstrating elevated blood p-tau in Niemann-Pick disease (Gonzalez-Ortiz et al., 2024), and now in response to tau phosphorylation detected in atrophic muscle fibers in ALS as reported here by Abu-Rumeileh et al., emphasize that it is important to be cautious when interpreting plasma p-tau as a sole marker of amyloid deposition.

    This underscores the critical need to integrate clinical diagnostics with comprehensive biomarker measurements if only blood biomarkers are available. I anticipate that future research should focus on investigating how the combination of established blood biomarkers (p-tau, tau, NfL) and potentially more disease-specific markers (eMTBR-tau243, exosomal TDP-43, or a hypothetical accurate Aβ derived measure) could enhance the differentiation of ALS and AD individuals. Further research should include strategies to precisely delineate CNS and PNS contributions to blood tau in individual samples, such as exploring potential differences in tau isoform distribution (small tau, brain-specific versus big tau, more PNS-specific) and specific post-translational modifications between these systems.

    References:

    Barthélemy NR, Horie K, Sato C, Bateman RJ. Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer's disease. J Exp Med. 2020 Nov 2;217(11) PubMed.

    Barthélemy NR, Saef B, Li Y, Gordon BA, He Y, Horie K, Stomrud E, Salvadó G, Janelidze S, Sato C, Ovod V, Henson RL, Fagan AM, Benzinger TL, Xiong C, Morris JC, Hansson O, Bateman RJ, Schindler SE. CSF tau phosphorylation occupancies at T217 and T205 represent improved biomarkers of amyloid and tau pathology in Alzheimer's disease. https://doi.org/10.1038/s43587-023-00380-7 PubMed. Nature Aging

    Barthélemy NR, Salvadó G, Schindler SE, He Y, Janelidze S, Collij LE, Saef B, Henson RL, Chen CD, Gordon BA, Li Y, La Joie R, Benzinger TL, Morris JC, Mattsson-Carlgren N, Palmqvist S, Ossenkoppele R, Rabinovici GD, Stomrud E, Bateman RJ, Hansson O. Highly accurate blood test for Alzheimer's disease is similar or superior to clinical cerebrospinal fluid tests. Nat Med. 2024 Apr;30(4):1085-1095. Epub 2024 Feb 21 PubMed.

    Janelidze S, Bali D, Ashton NJ, Barthélemy NR, Vanbrabant J, Stoops E, Vanmechelen E, He Y, Dolado AO, Triana-Baltzer G, Pontecorvo MJ, Zetterberg H, Kolb H, Vandijck M, Blennow K, Bateman RJ, Hansson O. Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer's disease. Brain. 2022 Sep 10; PubMed.

    Thijssen EH, La Joie R, Strom A, Fonseca C, Iaccarino L, Wolf A, Spina S, Allen IE, Cobigo Y, Heuer H, VandeVrede L, Proctor NK, Lago AL, Baker S, Sivasankaran R, Kieloch A, Kinhikar A, Yu L, Valentin MA, Jeromin A, Zetterberg H, Hansson O, Mattsson-Carlgren N, Graham D, Blennow K, Kramer JH, Grinberg LT, Seeley WW, Rosen H, Boeve BF, Miller BL, Teunissen CE, Rabinovici GD, Rojas JC, Dage JL, Boxer AL, Advancing Research and Treatment for Frontotemporal Lobar Degeneration investigators. Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer's disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study. Lancet Neurol. 2021 Sep;20(9):739-752. PubMed.

    Sato C, Mallipeddi N, Ghoshal N, Wright BA, Day GS, Davis AA, Kim AH, Zipfel GJ, Bateman RJ, Gabelle A, Barthélemy NR. MAPT R406W increases tau T217 phosphorylation in absence of amyloid pathology. Ann Clin Transl Neurol. 2021 Sep;8(9):1817-1830. Epub 2021 Aug 2 PubMed.

    Gonzalez-Ortiz F, Karikari TK, Taylor-Te Vruchte D, Shepherd D, Kirsebom BE, Fladby T, Platt F, Blennow K. Plasma phosphorylated-tau217 is increased in Niemann-Pick disease type C. Brain Commun. 2024;6(6):fcae375. Epub 2024 Oct 25 PubMed.

    View all comments by Nicolas Barthélemy

  5. Interesting result. p-tau181 is in fact modified in ALS but from a clinical point of view, the measurement of p-tau181 is not very informative when compared to NfL. See our latest article in Neurology (Mondesert et al., 2025), which provides Class II evidence that serum NfL levels are useful in identifying over 80 percent of patients with ALS and predicting survival in patients with ALS compared with pTau181 and GFAP levels.

    References:

    Mondesert E, Delaby C, De La Cruz E, Kuhle J, Benkert P, Pradeilles N, Duchiron M, Morchikh M, Camu W, Cristol JP, Hirtz C, Esselin F, Lehmann S. Comparative Performances of 4 Serum NfL Assays, pTau181, and GFAP in Patients With Amyotrophic Lateral Sclerosis. Neurology. 2025 Mar 25;104(6):e213400. Epub 2025 Feb 26 PubMed.

    View all comments by Sylvain Lehmann

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References

News Citations

  1. Two New p-Tau217 Blood Tests Join a Crowded Field
  2. In Head-to-Head Testing, P-Tau217/Tau217 Comes Out on Top. By a Hair.
  3. Better Diagnosis with Blood Test Detecting Only Tau Made in Brain

Paper Citations

  1. Cousins KA, Shaw LM, Shellikeri S, Dratch L, Rosario L, Elman LB, Quinn C, Amado DA, Wolk DA, Tropea TF, Chen-Plotkin A, Irwin DJ, Grossman M, Lee EB, Trojanowski JQ, McMillan CT. Elevated Plasma Phosphorylated Tau 181 in Amyotrophic Lateral Sclerosis. Ann Neurol. 2022 Nov;92(5):807-818. Epub 2022 Aug 17 PubMed.
  2. Vacchiano V, Mastrangelo A, Zenesini C, Baiardi S, Avoni P, Polischi B, Capellari S, Salvi F, Liguori R, Parchi P, BoReALS group. Elevated plasma p-tau181 levels unrelated to Alzheimer's disease pathology in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2023 Jun;94(6):428-435. Epub 2023 Apr 3 PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. Abu-Rumeileh S, Scholle L, Mensch A, Großkopf H, Ratti A, Kölsch A, Stoltenburg-Didinger G, Conrad J, De Gobbi A, Barba L, Steinacker P, Klafki HW, Oeckl P, Halbgebauer S, Stapf C, Posa A, Kendzierski T, Silani V, Hausner L, Ticozzi N, Froelich L, Weishaupt JH, Verde F, Otto M. Phosphorylated tau 181 and 217 are elevated in serum and muscle of patients with amyotrophic lateral sclerosis. Nat Commun. 2025 Mar 5;16(1):2019. PubMed.

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