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Comparative Study
. 2025 Apr;21(4):e70208.
doi: 10.1002/alz.70208.

A comparison of p-tau assays for the specificity to detect tau changes in Alzheimer's disease

Shorena Janelidze  1 , Nicholas J Ashton  2   3   4 , Anna Orduña Dolado  1 , Ulrika Nordström  5 , Divya Bali  1 , Karin M E Forsberg  5 , Isil Keskin  5 , Andrea Mastrangelo  6 , Veria Vacchiano  6   7 , Rocco Liguori  6   7 , Kaj Blennow  2   8   9   10 , Henrik Zetterberg  2   8   11   12   13   14 , Niklas Mattsson-Carlgren  1   15   16 , Fernando Gonzalez-Ortiz  2 , Piero Parchi  6   7 , Peter Munch Andersen  5 , Oskar Hansson  1
Affiliations
Comparative Study

A comparison of p-tau assays for the specificity to detect tau changes in Alzheimer's disease

Shorena Janelidze et al. Alzheimers Dement. 2025 Apr.

Abstract

Introduction: We evaluated differences in p-tau levels between Alzheimer's disease (AD), a condition with brain-specific changes in p-tau, and amyotrophic lateral sclerosis (ALS), a condition associated with increases in peripheral p-tau levels.

Methods: Cerebrospinal fluid and plasma from 668 participants were analyzed using immunoassays specific for the low-molecular-weight (LMW) tau isoforms present in the brain (i.e., p-tau217Lilly, p-tau181Lilly) and those that detect both LMW- and high-molecular-weight (HMW) tau expressed in the peripheral nervous system (i.e., p-tau217AlzPath, p-tau181UGOT).

Results: Increases in plasma p-tau in ALS versus controls were significantly smaller for the LMW-specific p-tau assays (15.9%-20.5%) compared with non-specific assays (92.0%-121.3%). The LMW-specific p-tau assays showed significantly larger plasma p-tau increases in AD versus ALS, discriminating AD from ALS with areas under the curve (AUCs; 0.890.93) higher than the AUCs of the non-specific assays (0.54-0.74).

Discussion: LMW-specific p-tau assays could be more useful in the diagnostic workup of AD, especially in population-based communities where conditions causing peripheral neuropathy are frequent.

Highlights: Increases in plasma phosphorylated tau (p-tau) in amyotrophic lateral sclerosis (ALS) versus controls were significantly smaller for low-molecular-weight (LMW)-specific p-tau assays (i.e., p-tau217Lilly, p-tau181Lilly) compared with p-tau assays that also detect high-molecular-weight (HMW) assays (i.e., p-tau217AlzPath, p-tau181UGOT). The LMW-specific p-tau assays showed significantly larger increases in plasma p-tau in AD versus ALS compared with the non-specific assays. The LMW-specific p-tau assays discriminated AD from ALS with higher precision, showing significantly better performance than the non-specific assays. LMW-specific p-tau assays could be more useful in the diagnostic workup of AD, especially in population-based communities where conditions causing peripheral neuropathy (such as ALS) are frequent.

Keywords: Alzheimer's disease; amyotrophic lateral sclerosis; biomarker; blood; low‐molecular‐weight tau; p‐tau.

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Conflict of interest statement

K.B. has served as a consultant and at advisory boards for Abbvie, AC Immune, ALZpath, AriBio, Beckman‐Coulter, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Quanterix, Roche Diagnostics, Sanofi, and Siemens Healthineers; has served on data‐monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials, and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai, and Roche Diagnostics; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). O.H. is a part‐time employee of Eli Lilly, and he has previously acquired research support (for Lund University) from AVID Radiopharmaceuticals, Biogen, C2N Diagnostics, Eli Lilly, Eisai, Fujirebio, GE Healthcare, and Roche. In the past 2 years, he has received consultancy/speaker fees from ALZpath, BioArctic, Biogen, Bristol Meyer Squibb, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi, and Siemens. N.M.C. has received consultancy/speaker fees from Biogen, Owkin, and Merck.

P.M.A.: Paid consultancies and serve/have served on advisory boards for Biogen, Roche, Arrowhead, Avrion, Regeneron, uniQure, Voyager, and Orphazyme A/S; and clinical trial site investigator for AB Science, AL‐S Pharma and Lilly, Amylyx, Alexion Pharmaceuticals, Biogen Idec, IBT‐Med, IONIS Pharmaceuticals, Mitsubishi Pharma, Novartis, Orion Pharma, PTC Pharmaceuticals, and Sanofi. Since 2021, a member of the ClinGen ALS Gene variant Curation Expert panel and an external advisor to the European Medicine Agency.

R.L.: Paid consultancies and serve/have served on advisory boards for Alexion Pharma Italy s.r.l., Sanofi Genzyme Corporation, and Argenx.

S.J., N.J.A., A.O.D., U.N., D.B., K.M.E.F., I.K., A.M., V.V., F.G.O., and P.P. report no conflicts of interest. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Cerebrospinal fluid (CSF) biomarker levels across diagnostic groups. Fold increases in CSF levels of Lilly phosphorylated tau (p‐tau)217 (A), Lilly p‐tau181 (B), brain‐derived tau (BD‐tau, C), ALZpath p‐tau217 (D), and UGOT p‐tau181 (E) in patients with Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) and control participants. Several outliers (Lilly p‐tau217, n = 13; ALZpath p‐tau217, n = 17; Lilly p‐tau181, n = 5; BD‐tau, n = 3) are not shown but were included in the statistical analysis. p‐values, adjusted for multiple comparison using the Bonferroni test (three comparisons per individual biomarker), are from the analysis of variance with log‐transformed biomarkers as dependent variables and diagnosis as independent variable adjusting for age. (F) Receiver‐operating characteristic for differentiating ALS from AD. FC, fold change; LMW, low‐molecular‐weight; UGOT, University of Gothenburg.
FIGURE 2
FIGURE 2
Plasma biomarker levels across diagnostic groups. Fold increases in plasma levels of Lilly phospho‐tau (p‐tau)217 (A), Lilly p‐tau181 (B), brain‐derived tau (BD‐tau, C), ALZpath p‐tau217 (D), and UGOT p‐tau181 (E) in patients with Alzheimer's Disease (AD) and amyotrophic lateral sclerosis (ALS) and control participants. Several outliers (Lilly p‐tau217, n = 5; ALZpath p‐tau217, n = 47; Lilly p‐tau181, n = 2; UGOT p‐tau181, n = 18; BD‐tau, n = 2) are not shown but were included in the statistical analysis. p‐values, adjusted for multiple comparison using the Bonferroni method (three comparisons per individual biomarker), are from the analysis of variance with log‐transformed biomarkers as dependent variables and diagnosis as independent variable adjusting for age. (F) Receiver operating characteristic for differentiating ALS from AD. FC, fold change; LMW, low‐molecular weight; UGOT, University of Gothenburg.
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