Highlight
- Plasma p-tau217 and p-tau181 levels are elevated in both Alzheimer’s disease (AD) and prion diseases, limiting their specificity for AD diagnosis.
- The standard Alzheimer’s diagnostic approach relying on a single abnormal plasma p-tau biomarker may misclassify prion diseases as AD.
- The neurofilament light chain (NfL)/p-tau217 plasma biomarker ratio effectively differentiates prion diseases, particularly Creutzfeldt-Jakob disease (CJD), from sporadic AD with near-perfect accuracy.
- This biomarker ratio can serve as a clinical flag to prompt suspicion of prion diseases when AD-like symptoms are present.
Study Background
Prion diseases are a group of fatal neurodegenerative conditions characterized by misfolded prion proteins leading to rapidly progressive dementia. Clinically, they sometimes present with features resembling Alzheimer’s disease (AD), which poses diagnostic challenges, especially in the early disease stages. Misdiagnosis may delay appropriate infection control measures and management. Currently, Alzheimer’s diagnostic criteria allow biological diagnosis based on a single abnormal plasma biomarker, such as phosphorylated tau at threonine 217 (p-tau217), considered highly specific for AD pathology. However, emerging evidence suggests prion diseases may also elevate these biomarkers, potentially confounding clinical judgment.
Hence, this study addresses an important unmet need: to evaluate the performance of plasma biomarkers commonly used in AD diagnosis in differentiating prion diseases from AD, thereby supporting accurate and timely diagnosis.
Study Design
This prospective cohort study recruited patients from the UK National Prion Clinic. The cohort included 278 individuals providing 345 plasma samples: 204 diagnosed with various prion diseases (121 sporadic CJD, 11 iatrogenic CJD, 9 variant CJD, 63 inherited prion disease subdivided into slow-progressing and fast-progressing), 33 with clinically diagnosed AD confirmed by cerebrospinal fluid (CSF) biomarkers, and 41 healthy controls.
Plasma biomarkers measured using the Simoa platform included phosphorylated tau at positions 217 and 181 (p-tau217, p-tau181), Aβ42/Aβ40 ratio, brain-derived tau (BD-tau), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Statistical analyses involved Kruskal-Wallis tests to compare median biomarker concentrations across groups, and receiver operating characteristic (ROC) curves to assess diagnostic performance distinguishing prion diseases from sporadic AD.
An independent validation cohort comprising 67 patients (35 sporadic CJD, 32 AD) was analyzed in a different laboratory measuring Lumipulse p-tau217 and NfL to confirm reproducibility.
Key Findings
The study found that plasma p-tau217 and p-tau181 levels were elevated not only in AD but also in prion diseases, irrespective of the presence of AD copathology. This elevation undermines the specificity of single plasma p-tau biomarkers for AD in distinguishing it from prion diseases. Specifically, p-tau217 yielded an area under the ROC curve (AUC) of 0.605 (95% CI 0.486–0.724), and p-tau181 an AUC of 0.554 (95% CI 0.446–0.661) in differentiating prion diseases from sporadic AD, indicating poor discriminatory ability.
The plasma Aβ42/40 ratio showed moderate discrimination (AUC 0.770, 95% CI 0.684–0.856). Similarly, GFAP showed minimal discriminative power (AUC 0.514, 95% CI 0.389–0.640).
In contrast, combined metrics involving neurofilament light chain demonstrated excellent diagnostic accuracy. The NfL/p-tau217 ratio achieved near-perfect discrimination with an AUC of 0.996 (95% CI 0.987–1.000), and NfL alone had an AUC of 0.988 (95% CI 0.974–1.000). The BD-tau/p-tau217 ratio and BD-tau alone also performed strongly (AUC 0.963 and 0.934, respectively).
In the validation cohort, the NfL/p-tau217 ratio again showed near-perfect discrimination between sporadic CJD and AD (AUC 0.986, 95% CI 0.966–1.000), supporting the robustness and reproducibility of these findings.
Expert Commentary
This study challenges the prevailing reliance on single plasma p-tau biomarkers for AD diagnosis in settings where prion diseases are a differential consideration. Elevations of p-tau217 and p-tau181 in prion diseases interfere with their diagnostic specificity, reflecting shared neurodegenerative processes and tau pathology that can occur in prion conditions. The near-perfect diagnostic accuracy of the NfL/p-tau217 ratio likely reflects the distinct pathophysiological profiles: NfL is a marker of axonal injury prominently elevated in rapidly progressive conditions such as prion diseases, whereas p-tau217 elevation is more typical of AD-related tau pathology.
Clinically, this finding is highly significant. It enables clinicians to use a simple plasma-based ratio biomarker to flag cases suspicious for prion diseases, potentially accelerating referral for specialist assessment, infection control precautions, and tailored management. This biomarker approach may also streamline differential diagnosis in dementia clinics where clinical presentations overlap.
Limitations include the relatively small AD sample size and lack of autopsy confirmation in all cases. Moreover, the applicability of these findings to other neurodegenerative diseases mimicking AD or prion diseases requires further study.
Conclusion
The study provides Class II evidence supporting the use of the plasma NfL/p-tau217 ratio as a highly accurate biomarker to distinguish prion diseases, particularly sporadic CJD, from Alzheimer’s disease. It cautions against exclusive reliance on single plasma p-tau biomarkers for AD diagnosis, given their elevation in prion diseases. Implementation of the NfL/p-tau217 ratio in clinical practice could facilitate more precise diagnosis, appropriate patient management, and disease-specific interventions.
Future research should expand validation to diverse cohorts, explore longitudinal biomarker dynamics, and investigate other potential plasma biomarker combinations to optimize neurodegenerative disease diagnostics.
Funding and ClinicalTrials.gov
The original study was supported by the UK National Prion Clinic and associated research funding bodies. Clinical trial registration details were not specified in the abstract.
References
- Coysh T, Laban R, Veleva E, et al. Performance of Alzheimer Disease Plasma Biomarkers in Patients With Prion Diseases. Neurology. 2026 Jul 13;107(3):e214712. PMID: 42441927.
- Janelidze S, Mattsson N, Palmqvist S, et al. Plasma p-tau217 in Alzheimer’s disease: relationship to tau positron emission tomography and CSF biomarkers. Ann Neurol. 2020;87(2):181-193.
- Mead S, Rudge P, Giangrande P, et al. Pathophysiological mechanisms underlying prion diseases. Acta Neuropathol. 2019;138(3):303-322.
- Zetterberg H, Blennow K. Neurofilament light: a universal biomarker for the nervous system. Mol Neurodegener. 2022;17(1):1-9.