Plasma phospho-tau217 for Alzheimer’s disease diagnosis in primary and secondary care using a fully automated platform | Sebastian Palmqvist et al. | ResearchPod

Transcript: Plasma phospho-tau217 for Alzheimer’s disease diagnosis in primary and secondary care using a fully automated platform

Alex: Welcome to another episode of ResearchPod. Today, we're looking at a study published in *Nature Medicine* that explores a more accessible way to diagnose Alzheimer's disease.

Sam: So this paper is asking whether we can move Alzheimer's testing out of specialist clinics and into regular doctor's offices?

Alex: Exactly. The current gold-standard tests—spinal taps, specialised brain scans—are invasive, expensive, and often hard to access. This study asks whether a simple blood draw can provide the same diagnostic answers.

Sam: That would be a meaningful shift. If a family doctor can just order a blood test, patients stop waiting months for a referral to a specialist. What exactly are they measuring in the blood?

Alex: So when Alzheimer's disease is developing, the brain starts accumulating abnormal protein deposits. That process leaves a kind of chemical trace in the bloodstream—a small protein fragment called p-tau217. Think of it like a biological fingerprint: it shows up in the blood precisely when the brain is experiencing the kind of damage associated with Alzheimer's.

Sam: So it's a biological indicator—a biomarker—that acts as a window into what's happening in the brain, without having to go near the brain directly. How do they know it's accurate enough to actually rely on?

Alex: They compared blood test results directly against the traditional spinal fluid tests, which are considered the reference standard. They ran everything through a fully automated machine called Lumipulse—the kind already common in hospital labs for routine blood work. The fact that it's already widely available matters, because hospitals wouldn't need to buy new equipment to use this approach.

Sam: That's a practical advantage. But is a blood test ever going to be as precise as a spinal tap? Those are measuring fluid that's much closer to the brain itself.

Alex: That's the right question to ask. The study found the blood test was highly accurate—but the researchers were honest about the fact that some results will always sit in a grey zone. So they introduced what they call a "two-cutoff" strategy to handle those ambiguous cases responsibly.

Sam: Two cutoffs—that sounds like a traffic light system. Green, amber, red.

Alex: That's a good way to picture it. Instead of one threshold that sorts everyone into simply positive or negative, they set two thresholds. Results clearly above the upper threshold are flagged as positive. Results clearly below the lower threshold are flagged as negative. And anything in between is classified as "intermediate"—meaning the test is essentially saying: I'm not certain enough to give you a firm answer here; this patient needs further investigation. It's a way of building honesty about uncertainty directly into the test's design.

Plasma phospho-tau217 for Alzheimer’s disease diagnosis in primary and secondary care using a fully automated platform

Sebastian Palmqvist, Noëlle Warmenhoven, Federica Anastasi, Andrea Pilotto, Shorena Janelidze, Pontus Tideman, Erik Stomrud, Niklas Mattsson-Carlgren, Ruben Smith, Rik Ossenkoppele, Kübra Tan, Anna Dittrich, Ingmar Skoog, Henrik Zetterberg, Virginia Quaresima, Chiara Tolassi

Apr 9, 2025·5:10·pmc·Original Paper

Neurodegenerative DiseasesClinical Memory ResearchBiological MarkersBiomarkersClinical NeurologyPlasma phospho-tau217 (p-tau217)

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5 min

Briefing

Abstract

Global implementation of blood tests for Alzheimer's disease (AD) would be facilitated by easily scalable, cost-effective and accurate tests. In the present study, we evaluated plasma phospho-tau217 (p-tau217) using predefined biomarker cutoffs. The study included 1,767 participants with cognitive symptoms from 4 independent secondary care cohorts in Malmö (Sweden, n = 337), Gothenburg (Sweden, n = 165), Barcelona (Spain, n = 487) and Brescia (Italy, n = 230), and a primary care cohort in Sweden (n = 548). Plasma p-tau217 was primarily measured using the fully automated, commercially available, Lumipulse immunoassay. The primary outcome was AD pathology defined as abnormal cerebrospinal fluid Aβ42:p-tau181. Plasma p-tau217 detected AD pathology with areas under the receiver operating characteristic curves of 0.93-0.96. In secondary care, the accuracies were 89-91%, the positive predictive values 89-95% and the negative predictive values 77-90%. In primary care, the accuracy was 85%, the positive predictive values 82% and the negative predictive values 88%. Accuracy was lower in participants aged ≥80 years (83%), but was unaffected by chronic kidney disease, diabetes, sex, APOE genotype or cognitive stage. Using a two-cutoff approach, accuracies increased to 92-94% in secondary and primary care, excluding 12-17% with intermediate results. Using the plasma p-tau217:Aβ42 ratio did not improve accuracy but reduced intermediate test results (≤10%). Compared with a high-performing mass-spectrometry-based assay for percentage p-tau217, accuracies were comparable in secondary care. However, percentage p-tau217 had higher accuracy in primary care and was unaffected by age. In conclusion, this fully automated p-tau217 test demonstrates high accuracy for identifying AD pathology. A two-cutoff approach might be necessary to optimize performance across diverse settings and subpopulations.

Research Objective

The researchers aimed to validate a fully automated, commercially available blood test for Alzheimer’s disease (AD)—specifically, the plasma phospho-tau217 (p-tau217) immunoassay on the Lumipulse platform. Because current diagnostic methods like cerebrospinal fluid (CSF) analysis and PET scans are invasive or expensive, there is a critical need for scalable, accurate, and accessible blood-based biomarkers (BBMs) that can be used in both primary and secondary clinical care settings.

Approach

The study evaluated 1,767 participants across four secondary care cohorts (Sweden, Spain, and Italy) and one primary care cohort in Sweden. The researchers defined "AD pathology" as abnormal levels of Aβ42:p-tau181 in the CSF or a positive amyloid PET scan. They tested two diagnostic strategies:

Single-cutoff approach: A fixed threshold to classify patients as either AD-positive or AD-negative.
Two-cutoff approach: A strategy that creates an "intermediate" zone between a low and high threshold, intended to increase diagnostic confidence by excluding cases that fall into the uncertain range.

They also assessed how demographic factors (age, sex), comorbidities (kidney disease, diabetes), and genetic markers (APOE genotype) influenced the test's performance.

Main Findings

The study found that the fully automated p-tau217 test is highly accurate for identifying AD pathology.

High Accuracy: The test achieved high areas under the receiver operating characteristic (ROC) curves (0.93–0.96). In secondary care, accuracy reached 89–91%, and in primary care, it was 85%.
Optimized Performance: Using a two-cutoff approach improved accuracy to 92–94% across all settings, though it left 12–17% of patients in an "intermediate" category requiring further testing.
Robustness: The test’s performance was generally unaffected by common comorbidities like diabetes or chronic kidney disease, as well as sex or APOE genotype. However, accuracy was slightly lower in participants aged 80 and older.

Why It Matters

This research provides evidence that a standardized, automated blood test can reliably identify Alzheimer’s pathology in routine clinical settings. By moving diagnostic capability from specialized research labs to standard hospital platforms, this test could significantly increase access to early diagnosis. This is particularly important as new anti-amyloid treatments become available, which require early and accurate confirmation of AD pathology to be effective.

Key Terms and Definitions

Plasma phospho-tau217 (p-tau217) — A specific protein fragment in the blood that serves as a biomarker for the presence of amyloid-beta plaques in the brain, which are a hallmark of Alzheimer's disease.
Lumipulse — A fully automated, commercially available immunoassay platform used in clinical laboratories to measure protein concentrations in patient samples.
AD Pathology — The biological presence of Alzheimer’s disease, defined in this study by specific abnormal ratios of proteins (Aβ42:p-tau181) in the cerebrospinal fluid or positive amyloid PET imaging.
Two-cutoff approach — A diagnostic method that uses two thresholds to categorize patients into three groups (positive, negative, or intermediate), designed to increase the accuracy of the positive and negative classifications by isolating uncertain results.
Biomarker (BBM) — A measurable substance in the blood that indicates the presence or progression of a specific disease state.

Plasma phospho-tau217 for Alzheimer’s disease diagnosis in primary and secondary care using a fully automated platform: Research Paper Podcast