Beyond p-tau217: A Multi-Biomarker Strategy for Advanced Tau Pathology Assessment

Plasma phosphorylated tau 217 (p-tau217) is currently recognized as one of the most promising blood-based biomarkers for Alzheimer's disease (AD). It demonstrates excellent performance in identifying cerebral amyloid-β (Aβ) pathology and has become an important tool in AD biomarker research.

However, among Aβ-positive individuals, p-tau217 alone shows limited accuracy in determining whether patients have progressed to advanced tau pathology characterized by neurofibrillary tangle (NFT) accumulation (Braak stages V--VI).

With the clinical development and application of anti-Aβ monoclonal antibody therapies, accurately assessing tau burden has become increasingly important. Patients with low-to-moderate tau burden are more likely to benefit from treatment, while individuals with high tau burden may experience relatively limited therapeutic benefits.

A multi-cohort study published on August 10, 2026, in JAMA Neurology, titled "Plasma Biomarkers for Neocortical Tau Burden", investigated an improved strategy to address this challenge by combining multiple plasma biomarkers with p-tau217.

Using high-throughput plasma proteomics, researchers screened 125 plasma proteins to identify biomarkers associated with advanced tau pathology.

The study analyzed plasma samples from 560 Aβ-positive participants across different disease stages, ranging from cognitively unimpaired individuals to patients with dementia. Using the NULISAseq platform, researchers performed biomarker selection through Elastic Net regression and 1,000 bootstrap stability analyses.

The final biomarker panel consisted of seven proteins:

• p-tau217
• NPTXR (Neuronal Pentraxin Receptor)
• GDNF (Glial Cell Line-Derived Neurotrophic Factor)
• KLK6 (Kallikrein-6)
• IL-13 (Interleukin-13)
• Aβ40 (Amyloid-β 40)
• SFRP1 (Secreted Frizzled Related Protein 1)

These seven biomarkers represent multiple biological pathways associated with AD progression, including:

• Tau phosphorylation: p-tau217
• Synaptic function: NPTXR
• Neurotrophic support: GDNF
• Inflammatory response: IL-13
• Amyloid metabolism: Aβ40 and SFRP1
• Disease-associated processes: KLK6

Compared with a single biomarker approach, this multi-dimensional panel provides additional biological information and enables a more comprehensive assessment of advanced tau pathology.

To evaluate the performance and generalizability of the 7-protein panel, the researchers conducted independent validation using two separate cohorts.

The discovery cohort, from the BioFINDER study in Sweden, included 431 participants and was used for biomarker screening and model development.

The validation cohort, from the TRIAD study in Canada, included 129 participants. The predefined seven-protein panel identified from the discovery cohort was applied in this cohort without additional biomarker selection.

The two cohorts differed in several aspects, including tau PET imaging tracers:

• BioFINDER cohort: ¹⁸F-R0948 tau PET
• TRIAD cohort: ¹⁸F-MK6240 tau PET

Despite differences in imaging tracers and sample processing procedures, the 7-protein panel consistently demonstrated improved performance, suggesting that it captures common biological signals associated with advanced tau pathology.

The primary goal of the study was to distinguish individuals with advanced neocortical tau pathology (Braak V--VI) from those with earlier tau pathology stages.

The 7-protein panel significantly improved diagnostic performance compared with p-tau217 alone.

Discovery cohort (BioFINDER)

• p-tau217 alone: AUC = 0.86
• 7-protein panel: AUC = 0.92

Validation cohort (TRIAD)

• p-tau217 alone: AUC = 0.88
• 7-protein panel: AUC = 0.94

In the validation cohort, the panel also reduced the proportion of individuals classified within the intermediate-risk range by 14.7%–21.0%, improving clinical decision-making.

At the optimal cutoff determined by the Youden index, the 7-protein panel achieved:

• Sensitivity: 0.92
• Specificity: 0.85
• Accuracy: 0.88

Compared with p-tau217 alone:

• Sensitivity increased from 0.66 to 0.92
• Accuracy improved from 0.84 to 0.88

The improved performance of the 7-protein panel is mainly attributed to the additional information provided by complementary biomarkers.

During advanced tau pathology progression, p-tau217 levels may gradually reach a plateau, limiting its ability to differentiate early and late disease stages when used alone.

In contrast, several additional proteins in the panel, including NPTXR and GDNF, showed significant differences between early and advanced tau pathology groups in both cohorts.

These findings suggest that changes related to synaptic function, neurotrophic support, inflammation, and other disease-associated processes provide additional information beyond tau phosphorylation status.

By integrating multiple biological signals, the 7-protein panel helps overcome the limitations of a single biomarker and provides a more comprehensive evaluation of neocortical tau burden.

This study demonstrates that a plasma-based multi-protein panel can improve the assessment of advanced tau pathology compared with p-tau217 alone.

In the era of anti-Aβ therapies, such biomarker strategies may support clinical trial design and patient stratification by:

• Identifying individuals with different tau burden levels
• Improving selection of patients more likely to benefit from therapy
• Reducing inclusion of individuals with limited expected treatment response
• Supporting more precise disease staging

The study also highlights an important trend in AD biomarker development: moving from identifying a single optimal biomarker toward integrated multi-marker approaches.

The seven core targets investigated in this study — p-tau217, NPTXR, GDNF, KLK6, IL-13, Aβ40, and SFRP1 — are important targets for Alzheimer's disease biomarker validation and mechanism studies.

AntibodySystem provides research-grade antibodies and recombinant proteins to support studies in neurodegeneration, biomarker development, and disease-related research.

NPTXR

KLK6

GDNF

IL-13

SFRP1

Tau / p-tau217

AntibodySystem provides high-quality antibodies and recombinant proteins to support Alzheimer's disease research, biomarker validation, and neurodegeneration studies.