In a recent study published in Nature Medicine, researchers investigated phosphorylated tau217 (p-tau217) protein as a blood-based biomarker (BBB) for Alzheimer’s disease (AD). Detecting AD pathologies in the blood (serum) could facilitate early identification and prompt treatment.
A fully automated serological assay could increase detection rates at primary care centers where current AD diagnostic methods, i.e., cerebrospinal fluid (CSF) analysis or amyloid positron emission tomography (PET), may not be feasible. Such assays could improve health accessibility and lower AD burden across the globe.
Image Credit: PeopleImages.com - Yuri A/Shutterstock.com
Introduction
In recent years, the scientific community has made significant advancements in identifying blood-based biomarkers (BBMs) for diagnosing AD in symptomatic individuals.
Phosphorylated tau217 (p-tau217) outperformed non-phosphorylated tau217 (np-tau217) or Aβ42 in multiple methodologies, including immunoassays and mass spectrometry (MS)-based tests.
Despite encouraging outcomes, few barriers limit the incorporation of BBB into routine clinical practice. MS analysis requires sophisticated facilities, and fully automated immunoassays need validation in diverse clinical contexts across multiple centers using specific thresholds.
About the study
In the present study, researchers validated the ability of the Lumipulse serum p-tau217 assay to detect Alzheimer’s disease as a blood test in clinical settings. Specifically, they developed biomarker thresholds, applied them to patients from various nations, and investigated the effect of comorbidities and demographic variables on plasma p-tau217 performance.
The study comprised 1,767 individuals (mean age, 73 years; 53% female) with cognitive symptomatology from primary and secondary care settings.
The primary care cohort comprised 548 Swedish individuals. Secondary care recipients included individuals hospitalized in Sweden (165 at the Gothenburg Hospital and 337 at the Malmö Hospital), Italy (230 at the Brescia Hospital), and Spain (487 at Hospital del Mar).
The primary study outcome was Alzheimer's disease pathology, reflected as abnormal Aβ42:p-tau181 values in cerebrospinal fluid. Researchers measured serum p-tau217 using the fully automatic Lumipulse assay, with a predefined threshold of 0.27 pg/ml.
They also considered two thresholds (lower threshold: 0.22 pg/ml and upper threshold: 0.34 pg/ml) to identify AD.
The team performed a secondary analysis, comparing serum p-tau217 results with the p-tau217:Aβ42 ratio, currently under evaluation by the United States Food and Drug Administration (US FDA). They also compared the results to those obtained using a percentage p-tau217 method (p-tau217:np-tau217 × 100) derived from MS analyses in US clinics.
Additional analyses included a cost-effectiveness analysis, comparing the Lumipulse serological p-tau217 assay with CSF analysis and amyloid PET imaging. To confirm robustness, the team performed sensitivity analyses using the CSF Aβ42:40 ratio, with the FDA-approved threshold of ≤0.072 pg/ml for positive findings. They also repeated the analysis among 87 primary care recipients based on CSF Aβ42:p-tau181 values, excluding PET findings.
Results
Fifty-five percent of the study participants demonstrated AD pathologies. The team noted higher serum p-tau217 concentrations among individuals with AD pathologies. In particular, females and younger (aged below 73 years vs. above 73 years) individuals with chronic kidney disease showed higher serum p-tau217 levels than their counterparts.
The Lumipulse p-tau217 assay identified AD pathologies with area under the receiver operating characteristic curve (AUC) values ranging between 0.93 and 0.96. For primary care recipients, the serological assay demonstrated 85% accuracy, 82% positive predictive value, and 88% negative predictive value.
At secondary care centers, the values were 89%-91%, 89%-95%, and 77%-90%, respectively. The team observed lower accuracy among elderly individuals aged 80 years and above (83%); however, accuracy remained unaffected by sex, diabetes, chronic renal disease, apolipoprotein E (APOE) status, and cognitive stage.
The two-threshold approach increased accuracies to 92%-94%, excluding 12% to 17% of participants with intermediate findings. Using the ratio between serum p-tau217 and Aβ42 reduced intermediate results to ≤10% but did not alter accuracy.
The p-tau217 assay results were comparable to the high-performing MS-based p-tau217 percentage assay in hospital care settings but were less accurate for primary care recipients.
The study showed that the double-threshold Lumipulse assay was 60%-81% cheaper than CSF analysis and PET imaging in the US. Sensitivity analyses yielded similar results, indicating the robustness of the primary analysis findings.
Conclusion
To conclude, based on the study findings, the fully automated serum p-tau217 assay accurately identifies Alzheimer’s disease in primary and secondary care settings, with over 90% accuracy in hospital patients, comparable to that of a lumbar puncture. The Lumipulse assay is economical, user-friendly, reproducible, and scalable.
These features could help make AD diagnosis from a simple blood test a reality. Such assays could particularly benefit low-resource areas and facilitate equitable access to healthcare. Future studies should include non-European individuals to increase the generalizability of the findings.
“This development may allow us to determine who needs to undergo further tests, such as a lumbar puncture or a PET scan, and who doesn’t, as it enables the detection of Alzheimer’s in its early stages with great accuracy. We have been able to establish two cut-off points that help us determine this risk. People whose p-tau217 biomarker levels fall between these two thresholds are the ones who need further testing."
Dr. Marc Suárez-Calvet, a neurologist at Hospital del Mar and researcher at its research institute and the Barcelonaβeta Brain Research Center
Study Reveals Limits of Epigenetic Clocks in Predicting Biological Age