New blood biomarker may detect Alzheimer’s pathology more accurately

By Tarun Sai LomteReviewed by Susha Cheriyedath, M.Sc.Mar 3 2026

Scientists directly compared two leading pTau217 blood tests and found that a brain-derived version may detect Alzheimer’s-related brain pathology more accurately while avoiding confounding signals from kidney dysfunction.

Study: Head-to-head comparison of brain-derived pTau217 and total pTau217 for brain amyloid and tau pathology classification. Image Crredit: Inna Kot / Shutterstock

In a recent study published in the journal Proceedings of the National Academy of Sciences, researchers evaluated total and brain-derived phosphorylated tau-217 (pTau217) in classifying brain amyloid and tau pathology.

Blood-based biomarkers have become increasingly valuable tools for AD diagnosis and prognosis, due to their accessibility, non-invasiveness, accuracy, and cost-effectiveness. pTau217 is among the most promising biomarkers of AD. Studies report that elevated plasma or cerebrospinal fluid pTau217 levels strongly reflect AD-related brain tau and Aβ pathologies.

Nevertheless, the specificity of plasma pTau217 remains a significant challenge for detecting brain-derived pathology. The nervous system">CNS and PNS express structurally distinct forms of tau: the CNS expresses six low-molecular-weight (LMW) isoforms, whereas the PNS expresses only one high-molecular-weight (HMW) isoform.

Most existing immunoassays measure total pTau217 and do not differentiate between the isoforms. As such, the lack of specificity could confound measurement in conditions involving peripheral tau release, reducing the accuracy of pTau217 in AD. Therefore, assays that selectively measure brain-derived pTau217 can increase the reliability of plasma-based AD biomarkers.

The study and findings

In the present study, researchers compared the Simoa ALZpath total p-Tau217 assay and the NULISAqpcr BD-pTau217 assay in classifying brain amyloid and tau pathology. Both assays use pTau217-specific capturing antibodies but different detection antibodies. The detector antibody in the Simoa assay recognizes a broader spectrum of HMW and LMW tau species, whereas the NULISAqpcr assay is specific for brain-derived LMW tau.

Two independent Hong Kong–based Chinese cohorts (discovery and validation) with amyloid positron emission tomography (PET) imaging data were included. These cohorts included participants recruited from both community settings and memory clinics. The discovery cohort included 283 participants with a mean age of 73.8 years. The validation cohort comprised 146 individuals, with an average age of 70.6 years. Participants were classified into low/no Aβ, intermediate Aβ, or high Aβ groups based on amyloid-PET Centiloid thresholds reflecting underlying AD-related amyloid pathology.

First, the researchers confirmed that total and brain-derived pTau217 levels in plasma measured by both assays were strongly correlated across both cohorts. Previous studies have reported that patients with chronic kidney disease exhibit higher plasma pTau217 levels, irrespective of underlying AD pathology, likely reflecting impaired renal clearance of tau or dysregulation of peripheral tau metabolism.

As such, the team assessed whether kidney dysfunction could interfere with assays targeting brain-derived pTau217. To this end, they analyzed the correlation between plasma pTau217 (measured by both assays) and kidney function markers. Reduced kidney function was associated with elevated total pTau217, while little to no association was observed for brain-derived pTau217, in the discovery cohort.

This finding was replicated in the validation cohort, suggesting that renal impairments impact total pTau217 measurements but have minimal effect on brain-derived pTau217. Next, the team examined dysregulation of plasma pTau217 in people with brain Aβ pathology. In both cohorts, total and brain-derived pTau217 levels were upregulated in those with intermediate or high Aβ burden.

The median fold change of brain-derived pTau217 was higher than that of total pTau217 in both intermediate and high Aβ burden groups in both cohorts. Further, receiver operating characteristic curve analyses revealed numerically greater discriminative ability of brain-derived pTau217 in differentiating Aβ+ individuals from Aβ− subjects, than total pTau217. Moreover, it tended to show improved performance in distinguishing high- or intermediate-Aβ individuals from the low-Aβ group relative to total pTau217. Importantly, both assays demonstrated high overall classification performance for amyloid pathology, and several comparisons between assays were not statistically significant due to the smaller validation cohort.

Further, tau positron emission tomography (tau-PET) imaging was available for the validation cohort, and tau-staging analyses were conducted in a subsample of participants after excluding Aβ−/tau+ individuals. In this subgroup, total and brain-derived pTau217 levels increased progressively with growing tau burden and were higher in Aβ+tau+ individuals than in Aβ+tau– individuals. Similarly, brain-derived pTau217 generally showed stronger performance in identifying tau+ individuals than total pTau217. Finally, the researchers established reference cutoffs for brain-derived pTau217 based on amyloid-PET imaging data.

The optimal cutoff was estimated to be > 0.66 pg/mL, derived using the Youden index in the discovery cohort. This cutoff showed 87% sensitivity and 95.6% specificity in the discovery cohort, while validation analyses confirmed high specificity but somewhat lower sensitivity using the same threshold. The lower cutoff was < 0.36 pg/mL. People with brain-derived pTau217 levels > 0.66 pg/mL or < 0.36 pg/mL would be classified as positive or negative, respectively. Those with values between these upper and lower cutoffs would be classified as intermediate and require confirmatory testing.

Conclusions

The findings show that brain-derived pTau217 is less susceptible to peripheral changes, including kidney dysfunction, and demonstrates numerically higher diagnostic performance for classifying AD-related brain pathology compared with total pTau217 in several analyses, while both assays show strong overall accuracy.

Overall, these results highlight brain-derived pTau217 as a highly promising blood-based biomarker for AD, with significant potential for early detection, disease staging, and patient management.