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
4 min
As Alzheimer's disease (AD) therapies emerge, there is an urgent need for non-invasive, cost-effective screening tools to identify patients with underlying AD pathology. While cerebrospinal fluid (CSF) and PET imaging are the current gold standards, they are expensive and invasive. This study aimed to compare the diagnostic accuracy of two blood-based biomarkers—plasma p-tau217 and p-tau181—to determine if one is superior for identifying AD pathology and differentiating it from frontotemporal lobar degeneration (FTLD) syndromes.
Researchers analyzed plasma samples from 593 participants across two major research cohorts (UCSF and the ARTFL consortium). A critical strength of this study was the use of electrochemiluminescence-based assays that were nearly identical in design, differing only in the specific antibody epitope targeted. This minimized technical variability that has plagued previous comparative studies. The team evaluated diagnostic performance against clinical diagnoses, neuropathological findings, and amyloid/tau PET imaging results.
Both p-tau217 and p-tau181 demonstrated excellent diagnostic performance, with high accuracy in distinguishing AD patients from cognitively unimpaired controls and those with FTLD. However, p-tau217 consistently outperformed p-tau181 in several key metrics: it was more effective at differentiating AD syndromes from the FTLD spectrum, served as a stronger indicator of amyloid-PET positivity, and showed a significantly stronger correlation with tau-PET binding in the temporal cortex. Despite these differences, the two markers were highly correlated with each other, suggesting they both capture similar underlying pathological processes.
These results suggest that blood-based p-tau tests are nearing the level of reliability required for clinical screening. By providing a less invasive way to identify patients who should undergo more definitive diagnostic testing (like PET or CSF analysis), these biomarkers could significantly streamline the diagnostic pathway for AD. While p-tau217 appears to offer a slight diagnostic edge, both markers represent a major step forward in the shift toward accessible, blood-based diagnostics for neurodegenerative disease.
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.
Sam: So the blood test isn't just a rough approximation—it's tracking something real about what's happening in the brain.
Alex: That's the key point. It's not a guess. The proteins are a direct biological consequence of the disease process, which is why the blood signal correlates so closely with what the imaging shows.
Sam: Are there limitations the researchers flag?
Alex: Yes, and they're worth taking seriously. The study notes that these results, while promising, need to be validated across larger and more diverse populations before this becomes routine clinical care. A test that works well in one group of patients doesn't automatically work equally well for everyone, so that broader validation is an essential next step.
Sam: So it's a meaningful step forward, but not a finished product yet.
Alex: That's a fair way to put it. What the study does establish is that blood-based diagnostics are a scientifically viable path. The researchers also note that the work benefited from large collaborative networks—multiple institutions pooling data and expertise. That kind of cooperation is often what allows a tool to be refined to the level of precision needed for clinical use.
Sam: And the next phase is making sure these tests hold up across different backgrounds and populations.
Alex: Exactly. Reliability across all populations is what separates a promising research finding from a tool that can actually be deployed in a clinic. That work is still ahead. But the foundation this study lays is a solid one—and for patients and families navigating an Alzheimer's diagnosis, a blood draw is a much more accessible starting point than a brain scan or a spinal tap. Thanks for listening to ResearchPod.