Elsevier

The Lancet Neurology

Volume 20, Issue 9, September 2021, Pages 739-752
The Lancet Neurology

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

https://doi.org/10.1016/S1474-4422(21)00214-3Get rights and content

Summary

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.

Introduction

Tau pathology has an essential role in Alzheimer's disease and in about half of the patients with frontotemporal lobar degeneration (FTLD).1 The clinical syndromes associated with Alzheimer's pathology or FTLD pathology are heterogeneous and frequently overlap, particularly in individuals younger than 65 years at symptom onset. Established biomarkers for Alzheimer's disease, including β amyloid and tau measurements in CSF, or amyloid or tau PET imaging, have been of limited use for screening because of the invasiveness, high costs, and need for specialised personnel for the techniques. Blood-based biomarkers generally have lower costs, are less invasive, and have the potential to be deployed widely throughout the community, allowing for early and repeated testing.

With the development of potentially disease-modifying Alzheimer's disease therapies, a blood test could be used to identify patients with underlying Alzheimer's disease pathology to undergo more established CSF or PET diagnostic testing before initiating therapy. This approach might be particularly valuable in clinical syndromes that are not strongly predictive of a specific neuropathology but where Alzheimer's disease pathology or copathology is a possibility, such as mild cognitive impairment (MCI),2, 3 corticobasal syndrome,4 and dementia with Lewy bodies.5

Phosphorylated tau (p-tau) is a key component of neurofibrillary tangles in patients with Alzheimer's disease pathology. Plasma p-tau at threonine 181 (p-tau181) is a valuable differential diagnostic marker with concentrations 1·5–3·5 times higher in in patients with Alzheimer's disease compared with cognitively unimpaired controls,6, 7, 8 and 1·8–3·7 times higher in Alzheimer's disease compared with clinical and pathology-confirmed FTLD.6 P-tau181 is a strong indicator of both amyloid-PET (receiver operating characteristic [ROC] area under the curve [AUC] 0·76–0·91)6, 9 and tau-PET-positivity (AUC 0·83–0·93),8, 9 and can be used for individualised prediction of Alzheimer's disease dementia in patients with MCI.10, 11

Tau has over 40 phosphorylation sites, although little research has been done on their comparative diagnostic value, especially in plasma. A recent autopsy study indicated that p-tau at threonine 217 (p-tau217) was the most important phosphorylation site in the differentiation between Alzheimer's disease and control brain tissue, outperforming p-tau181.12 Several studies have shown an advantage of p-tau217 over p-tau181 when measured in CSF using mass spectrometry13, 14 or immunoassays.15, 16 When measured simultaneously in CSF using mass spectrometry, p-tau217 had higher accuracy for differentiating amyloid-PET-positive from amyloid-PET-negative participants (AUC 0·96 vs 0·79, n=82).14 In an immunoassay study using similar assays for p-tau217 and p-tau181, CSF p-tau217 was consistently more strongly correlated with amyloid-PET and tau-PET binding than was p-tau181. P-tau217 also differentiated Alzheimer's disease dementia from other neurodegenerative diseases with somewhat higher accuracy than p-tau181.15 A comparative mass-spectrometry study (n=92) in plasma also showed that p-tau217 outperformed p-tau181 for detecting amyloid-PET positivity (AUC 0·92 vs 0·75).17 Similarly, an immunoassay study in larger cohorts reported that plasma p-tau217 performed similarly to CSF p-tau217 and tau-PET and outperformed plasma p-tau181 in identifying Alzheimer's disease in a clinical cohort (AUC of 0·96 for p-tau217 vs 0·81 for p-tau181, n=220).9 However, the p-tau217 and p-tau181 plasma assays used different platforms, detector antibodies, buffers, and calibrators. As pointed out by the authors,9 these important technical differences complicated the interpretation of which p-tau epitope might be superior for differential diagnosis and other purposes. A more recent study using assays with more similar antibodies and the same technology did not find such large differences in performance.18 Additional work is therefore needed to confirm the diagnostic superiority of p-tau217 since previously observed differences could be attributable to assay characteristics unrelated to which p-tau residue was measured.

As plasma p-tau measurements become more widely available and are increasingly planned for use in research and clinical care, it will be important to understand the relative merits of different epitopes and assays. In this study we compared plasma p-tau217 and p-tau181, measured using a novel p-tau181 assay with the same electrochemiluminescence-based technology, antibody, and buffers as the p-tau217 assay. We analysed samples from patients with a wide range of neurodegenerative diseases, including the full spectrum of Alzheimer's disease syndromes (Alzheimer's disease dementia, logopenic variant primary progressive aphasia, posterior cortical atrophy), MCI, FTLD syndromes, and other dementias, as well as from age-matched controls.

Section snippets

Participants

Data for this diagnostic performance study were retrospectively collected between July 1 and Nov 30, 2020. Participants were included from University of California San Francisco (UCSF, CA, USA) and Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL) from 19 consortium sites (17 in the USA and two in Canada). Blood samples had been collected between June 11, 2008, and May 14, 2019. Participants from both cohorts were carefully characterised, including

Results

1489 individuals enrolled in ARTFL were initially assessed for eligibility. 593 participants were included in this study; 443 from the UCSF and Aging Center, and 150 from the ARTFL Consortium. The selected cohort included 118 cognitively unimpaired controls (appendix p 16) and participants with a broad range of neuro_degenerative syndromes: 75 patients with an Alzheimer's disease syndrome (58 Alzheimer's disease dementia,30 15 logopenic variant primary progressive aphasia, and two posterior

Discussion

We compared the diagnostic performance of plasma p-tau217 with a novel p-tau181 assay, designed to match the assay characteristics of the p-tau217 assay, in a large cohort of patients with various neurodegenerative diseases. Both plasma biomarkers could distinguish Alzheimer's disease syndromes from non-Alzheimer's disease disorders, defined either clinically or neuropathologically, with high accuracy (AUCs>0·90), and both plasma biomarkers were associated with in-vivo presence of amyloid and

Data sharing

Data and informed consent form are available upon request after publication from the University of California, San Francisco Memory and Aging Center at http://memory.ucsf.edu/research-trials/professional/open-science and ARTFL consortium at https://www.allftd.org/data. Requests will be considered by study investigators based on the information provided by the requester regarding the study and analysis plan. If the use is appropriate, a data sharing agreement will be put in place before a fully

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

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