Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer's disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study

Elisabeth H Thijssen, Renaud La Joie, Amelia Strom, Corrina Fonseca, Leonardo Iaccarino, Amy Wolf, Salvatore Spina, Isabel E Allen, Yann Cobigo, Hilary Heuer, Lawren VandeVrede, Nicholas K Proctor, Argentina Lario Lago, Suzanne Baker, Rajeev Sivasankaran, Agnieszka Kieloch, Arvind Kinhikar, Lili Yu, Marie-Anne Valentin, Andreas Jeromin, Henrik Zetterberg, Oskar Hansson, Niklas Mattsson-Carlgren, Danielle Graham, Kaj Blennow, Joel H Kramer, Lea T Grinberg, William W Seeley, Howard Rosen, Bradley F Boeve, Bruce L Miller, Charlotte E Teunissen, Gil D Rabinovici, Julio C Rojas, Jeffrey L Dage, Adam L Boxer, Advancing Research and Treatment for Frontotemporal Lobar Degeneration investigators, Elisabeth H Thijssen, Renaud La Joie, Amelia Strom, Corrina Fonseca, Leonardo Iaccarino, Amy Wolf, Salvatore Spina, Isabel E Allen, Yann Cobigo, Hilary Heuer, Lawren VandeVrede, Nicholas K Proctor, Argentina Lario Lago, Suzanne Baker, Rajeev Sivasankaran, Agnieszka Kieloch, Arvind Kinhikar, Lili Yu, Marie-Anne Valentin, Andreas Jeromin, Henrik Zetterberg, Oskar Hansson, Niklas Mattsson-Carlgren, Danielle Graham, Kaj Blennow, Joel H Kramer, Lea T Grinberg, William W Seeley, Howard Rosen, Bradley F Boeve, Bruce L Miller, Charlotte E Teunissen, Gil D Rabinovici, Julio C Rojas, Jeffrey L Dage, Adam L Boxer, Advancing Research and Treatment for Frontotemporal Lobar Degeneration investigators

Abstract

Background: Plasma tau phosphorylated at threonine 217 (p-tau217) and plasma tau phosphorylated at threonine 181 (p-tau181) are associated with Alzheimer's disease tau pathology. We compared the diagnostic value of both biomarkers in cognitively unimpaired participants and patients with a clinical diagnosis of mild cognitive impairment, Alzheimer's disease syndromes, or frontotemporal lobar degeneration (FTLD) syndromes.

Methods: In this retrospective multicohort diagnostic performance study, we analysed plasma samples, obtained from patients aged 18-99 years old who had been diagnosed with Alzheimer's disease syndromes (Alzheimer's disease dementia, logopenic variant primary progressive aphasia, or posterior cortical atrophy), FTLD syndromes (corticobasal syndrome, progressive supranuclear palsy, behavioural variant frontotemporal dementia, non-fluent variant primary progressive aphasia, or semantic variant primary progressive aphasia), or mild cognitive impairment; the participants were from the University of California San Francisco (UCSF) Memory and Aging Center, San Francisco, CA, USA, and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL; 17 sites in the USA and two in Canada). Participants from both cohorts were carefully characterised, including assessments of CSF p-tau181, amyloid-PET or tau-PET (or both), and clinical and cognitive evaluations. Plasma p-tau181 and p-tau217 were measured using electrochemiluminescence-based assays, which differed only in the biotinylated antibody epitope specificity. Receiver operating characteristic analyses were used to determine diagnostic accuracy of both plasma markers using clinical diagnosis, neuropathological findings, and amyloid-PET and tau-PET measures as gold standards. Difference between two area under the curve (AUC) analyses were tested with the Delong test.

Findings: Data were collected from 593 participants (443 from UCSF and 150 from ARTFL, mean age 64 years [SD 13], 294 [50%] women) between July 1 and Nov 30, 2020. Plasma p-tau217 and p-tau181 were correlated (r=0·90, p<0·0001). Both p-tau217 and p-tau181 concentrations were increased in people with Alzheimer's disease syndromes (n=75, mean age 65 years [SD 10]) relative to cognitively unimpaired controls (n=118, mean age 61 years [SD 18]; AUC=0·98 [95% CI 0·95-1·00] for p-tau217, AUC=0·97 [0·94-0·99] for p-tau181; pdiff=0·31) and in pathology-confirmed Alzheimer's disease (n=15, mean age 73 years [SD 12]) versus pathologically confirmed FTLD (n=68, mean age 67 years [SD 8]; AUC=0·96 [0·92-1·00] for p-tau217, AUC=0·91 [0·82-1·00] for p-tau181; pdiff=0·22). P-tau217 outperformed p-tau181 in differentiating patients with Alzheimer's disease syndromes (n=75) from those with FTLD syndromes (n=274, mean age 67 years [SD 9]; AUC=0·93 [0·91-0·96] for p-tau217, AUC=0·91 [0·88-0·94] for p-tau181; pdiff=0·01). P-tau217 was a stronger indicator of amyloid-PET positivity (n=146, AUC=0·91 [0·88-0·94]) than was p-tau181 (n=214, AUC=0·89 [0·86-0·93]; pdiff=0·049). Tau-PET binding in the temporal cortex was more strongly associated with p-tau217 than p-tau181 (r=0·80 vs r=0·72; pdiff<0·0001, n=230).

Interpretation: Both p-tau217 and p-tau181 had excellent diagnostic performance for differentiating patients with Alzheimer's disease syndromes from other neurodegenerative disorders. There was some evidence in favour of p-tau217 compared with p-tau181 for differential diagnosis of Alzheimer's disease syndromes versus FTLD syndromes, as an indication of amyloid-PET-positivity, and for stronger correlations with tau-PET signal. Pending replication in independent, diverse, and older cohorts, plasma p-tau217 and p-tau181 could be useful screening tools to identify individuals with underlying amyloid and Alzheimer's disease tau pathology.

Funding: US National Institutes of Health, State of California Department of Health Services, Rainwater Charitable Foundation, Michael J Fox foundation, Association for Frontotemporal Degeneration, Alzheimer's Association.

Conflict of interest statement

Declaration of interests JLD and NKP are employees of Eli Lilly and Company, which is exploring commercial development opportunities for p-tau assays. JLD is listed as an inventor on a patent related to reagents used in the p-tau assays. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure, and Biogen, and is a cofounder of Brain Biomarker Solutions (BBS) in Gothenburg AB, which is a part of the GU Ventures Incubator Program. OH has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy or speaker fees from AC Immune, Alzpath, Biogen, Cerveau, and Roche. KB served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a cofounder of BBS in Gothenburg AB, outside the submitted work. LTG receives research support from Avid Radiopharmaceuticals and Eli Lilly. She has received consulting fees from the Simon Foundation and Cura Sen, and serves as associate editor for Frontiers in Aging Neurosciences, Frontiers in Dementia, and the Journal of Alzheimer Disease. HR has received research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals, and receives research support from US National Institutes of Health (NIH). BFB receives research support from NIH, the Mangurian Foundation, and the Little Family Foundation. He is on the Scientific Advisory Board for the Tau Consortium, and has received grant support for clinical trials from Biogen, Alector, and EIP Pharma. GDR receives research support from NIH, Alzheimer's Association, American College of Radiology, Rainwater Charitable Foundation, Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare, and Life Molecular Imaging. He has served as a consultant for Eisai, Merck, Axon Neurosciences, and Johnson & Johnson, and has received speaking honoraria from GE Healthcare. He serves as Associate Editor for JAMA Neurology. JCR is a site principal investigator for clinical trials supported by Eli Lilly and receives support from NIH. ALB receives research support from the NIH, the Rainwater Charitable Foundation, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, the Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association. He has served as a consultant for Alector, AGTC, Arkuda, Arvinas, AZTherapies, GSK, Oligomerix, Ono, Regeneron, Roche, Samumed, Stealth, Third Rock, Transposon, and Wave, and received research support from Biogen, Eisai, and Regeneron. All other authors declare no competing interests.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1.. P-tau217 and P-tau181 concentrations per…
Figure 1.. P-tau217 and P-tau181 concentrations per clinical diagnosis.
A. P-tau217 was increased in the AD spectrum compared to all other diagnoses. B. P-tau18 was increased in the AD-spectrum compared to all other diagnoses. C. ROC curve analyses of the differentiation between the patients in the AD-spectrum and the normal controls. Brown represents P-tau217, pink represents P-tau181. D. ROC curve analyses of the differentiation between the patients in the AD-spectrum and patients in the FTLD-spectrum. Brown represents P-tau217, pink represents P-tau181. *Significant difference in AUC. For visualization, raw biomarker concentrations were used.
Figure 2.. P-tau217 and P-tau181 concentrations per…
Figure 2.. P-tau217 and P-tau181 concentrations per pathology confirmed diagnosis and MAPT genotype.
A. P-tau217 was increased in the pathology confirmed AD group compared to the FTLD-TDP and FTLD-tau groups. B. P-tau181 was increased in the pathology confirmed AD group compared to the FTLD-TDP and FTLD-tau groups. C. ROC curve analyses of the differentiation between the pathology-confirmed AD and FTLD-tau combined with the FTLD-TDP participants. Brown represents P-tau217, pink represents P-tau181. D. There was no difference in P-tau217 concentrations between 4R (n=33, 58% female, mean age=41.8), 3R/4R (n=11, 45% female, mean age=45.3) MAPT and age and sex matched amyloid-PET-negative controls (n=8, 50% female, mean age=50.7). E. There was no difference in P-tau181 concentrations between 4R, 3R/4R MAPT and age and sex matched controls. Three of the five MAPT mutation carriers with the highest P-tau values (P-tau217>0.5 pg/mL or P-tau181>2.0 pg/mL) had a known CSF P-tau concentration which was also high (>30 pg/mL).***p<0·0001, adjusted for sex, age, CDRsb (and time between plasma sample and death for pathology-confirmed participants). For visualization, raw biomarker concentrations were used, although natural log transformed data were used for ANCOVA.
Figure 3.. Association between P-tau217, P-tau181, amyloid-PET…
Figure 3.. Association between P-tau217, P-tau181, amyloid-PET and tau-PET.
A. The correlation between plasma P-tau217 and temporal tau-PET SUVR, shapes show clinical diagnosis and color shows amyloid-PET status. The dotted line is the cut-off value for tau-PET positivity of 1.27 SUVR. Correlation coefficient indicates Pearson’s correlation on raw plasma and PET values, but correlation strength was not impacted by log-transformation of P-tau217 values (r=0.80) or using rank correlation (Spearman ρ=0.79). B. The correlation between plasma P-tau181 and temporal tau-PET SUVR. Correlation strength was little impacted by log-transformation of P-tau181 (r=0.72) or rank correlation (Spearman ρ=0.72). C. Differentiation between amyloid-PET-positive and -negative, by boxplot and ROC AUC. Brown represents P-tau217, pink represents P-tau181. D. Differentiation between tau-PET-positive and -negative, by boxplot and ROC AUC. Brown represents P-tau217, pink represents P-tau181. *Significant difference in AUC, adjusted for sex, age. For visualization, raw biomarker concentrations were used, although natural log transformed data were used for ANCOVA.
Figure 4.. Voxelwise correlation between plasma P-tau217,…
Figure 4.. Voxelwise correlation between plasma P-tau217, P-tau181 and Tau-PET tracer binding or grey matter volume.
The density plots on top of the color bars show the distribution of Pearson’s r values across all voxels included in the GM cortex mask. The pink lines in the color bar indicate phttps://neurovault.org/collections/SDXLLPNR/

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