Highlights
- Plasma p-tau217 acts as a high-sensitivity ‘Core 1’ biomarker for identifying amyloid-β (Aβ) pathology, whereas eMTBR-tau243 serves as a ‘Core 2’ biomarker reflecting tau tangle burden and clinical symptom onset.
- Integrating eMTBR-tau243 in p-tau217-positive patients increases the positive predictive value (PPV) for established Alzheimer’s disease (AD) from 57% to 84%, significantly reducing diagnostic uncertainty.
- Plasma eMTBR-tau243 concentrations correlate strongly with tau-PET load and are predictive of longitudinal cognitive decline and future tau accumulation.
- The implementation of sequential blood-based biomarker (BBM) algorithms could reduce the requirement for expensive PET imaging by 58%–80% in clinical trial and specialist settings.
Background
The diagnostic landscape for Alzheimer’s disease (AD) is undergoing a fundamental shift from clinical symptom-based assessment to a biological definition centered on amyloid-β (Aβ) plaques and tau neurofibrillary tangles. While cerebrospinal fluid (CSF) analysis and positron emission tomography (PET) remain the gold standards, their cost, invasiveness, and limited availability hinder widespread use. Blood-based biomarkers (BBMs) offer a scalable alternative. Specifically, phosphorylated tau at residue 217 (p-tau217) has emerged as an exceptionally accurate marker of brain amyloidosis.
However, a clinical challenge remains: p-tau217 often becomes positive early in the disease course, during the preclinical stage when individuals may be cognitively unimpaired. Clinicians require additional markers that confirm whether AD pathology is the actual driver of a patient’s current cognitive symptoms. Recently, the endogenously cleaved microtubule-binding region of tau (eMTBR-tau243) has been identified as a marker that specifically reflects the transition from soluble tau to insoluble tau tangles. This synthesis evaluates the clinical utility of integrating these two markers for diagnosis, stratification, and prognosis.
Key Content
Characterizing Core 1 and Core 2 Biomarkers
Current research categorizes AD biomarkers into two functional groups. Core 1 biomarkers (e.g., p-tau217, Aβ42/40 ratio) change early and accurately identify the presence of Aβ pathology. Core 2 biomarkers (e.g., eMTBR-tau243, p-tau205) change later, correlating more closely with the spread of tau tangles and the onset of cognitive impairment. A seminal study published in Nature Medicine (2025) demonstrated that plasma eMTBR-tau243 is significantly elevated at the mild cognitive impairment (MCI) stage and rises further in dementia, outperforming other markers like %p-tau205 in reflecting the actual tauopathy load (β = 0.72 vs tau-PET).
Evidence from the Swedish BioFINDER-2 Study
The most robust evidence for the integration of these markers comes from a prospective cohort study published in The Lancet Neurology (2026), which followed 572 patients with cognitive symptoms. The study utilized mass spectrometry to measure %p-tau217 (ratio to non-phosphorylated peptide) and eMTBR-tau243 concentrations.
The results highlighted a clear sequential utility:
- Aβ Confirmation: Of the 350 patients positive for plasma %p-tau217, 97% were confirmed Aβ-positive via CSF or PET. However, only 57% of these p-tau217-positive individuals had ‘established AD’ (defined as both pathology-positive and symptomatic).
- Symptom Attribution: Among the p-tau217-positive group, the addition of eMTBR-tau243 positivity increased the diagnostic accuracy for established AD to 81%, with a PPV of 84%.
- Negative Predictive Value (NPV): Patients who were p-tau217 positive but eMTBR-tau243 negative were unlikely to have high tau-PET loads (NPV 90%), suggesting their symptoms might be driven by co-pathologies or that they are in a very early, pre-tangle stage of AD.
Refining Diagnostic Algorithms: The GRAD Framework
To address the ‘gray zone’ of indeterminate biomarker results (which affects 30–50% of patients), researchers developed the GRAD (Gatekeeper & Reflex for Alzheimer’s Disease) algorithm. In this model, p-tau217 acts as the ‘Gatekeeper.’ Cases falling into the intermediate probability range are then subjected to ‘Reflex’ testing. While the original GRAD study (medRxiv 2026) utilized multi-marker panels (NfL, GFAP), the integration of eMTBR-tau243 into such frameworks is now considered the next step in optimizing health economic outcomes, potentially reducing spending by 67% compared to universal PET testing.
The Role of Normalization and Regional Prediction
Methodological advances have further refined the accuracy of these BBMs. Research in Brain (2025) suggests that normalizing eMTBR-tau243 to reference proteins like Aβ40 or non-phosphorylated mid-region tau (np-tau) reduces inter-individual variability. For instance, the association with tau-PET improved from R² = 0.60 to 0.72 when using the eMTBR-tau243/np-tau ratio. Furthermore, combining plasma p-tau217 with CSF-based eMTBR-tau243 has been shown to predict regional tau PET burden with an AUROC of 0.94, facilitating precision staging without the immediate need for imaging (Alzheimer’s & Dementia, 2025).
Expert Commentary
The integration of p-tau217 and eMTBR-tau243 represents a major milestone in clinical neurology. For years, the lack of a ‘tangle-specific’ blood marker meant that clinicians could identify amyloid but could not easily confirm if a patient had progressed to the neurodegenerative stage of tau spreading. The evidence from the BioFINDER-2 and Knight ADRC cohorts suggests that eMTBR-tau243 fills this gap.
Clinical Applicability: In a primary or secondary care setting, a sequential approach is most logical. A p-tau217 test should be the first line to confirm AD pathology. If positive, eMTBR-tau243 can then be used to stage the disease. This is particularly relevant given the emergence of anti-amyloid therapies (e.g., lecanemab, donanemab), where treatment eligibility and response monitoring may depend heavily on the baseline tau burden.
Controversies and Limitations: While mass spectrometry provides high precision for these measurements, its throughput is lower than immunoassay platforms. Widespread clinical adoption will require the development of automated, high-sensitivity immunoassays for eMTBR-tau243. Additionally, while these markers are highly specific for AD, they do not account for non-AD co-pathologies (such as TDP-43 or vascular changes) which frequently contribute to cognitive decline in older populations.
Conclusion
The combination of plasma %p-tau217 and eMTBR-tau243 provides a comprehensive biological snapshot of Alzheimer’s disease progression. By distinguishing between amyloid-positivity (Core 1) and symptomatic tau-aggregation (Core 2), this dual-biomarker strategy enhances diagnostic confidence, improves prognostic accuracy for cognitive decline, and offers a cost-effective pathway for patient selection in clinical trials. Future research should focus on the standardization of eMTBR-tau243 assays and the validation of these markers in more diverse, real-world clinical populations.
References
- Mattsson-Carlgren N, et al. Integration of plasma eMTBR-tau243 and p-tau217 in the diagnosis and stratification of Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 2026;25(4):357-367. PMID: 41864233.
- Horie K, et al. Plasma MTBR-tau243 biomarker identifies tau tangle pathology in Alzheimer’s disease. Nat Med. 2025;31(6):2044-2053. PMID: 40164726.
- Salvadó G, et al. Reference proteins to improve Core 1 and Core 2 Alzheimer’s disease CSF and plasma biomarkers. Brain. 2025;awaf375. PMID: 41051312.
- Janelidze S, et al. Combining CSF MTBR-tau243 and plasma pTau217 ratio enhances the prediction of continuous regional tau PET burden in early Alzheimer’s disease. Alzheimers Dement. 2025;21(11):e70881. PMID: 41170658.
- Anonymous. GRAD: A Two-Stage Algorithm for Resolving Diagnostic Uncertainty in the Plasma p-tau217 Gray Zone. medRxiv. 2026. PMID: 41728312.
