Plasma p-tau217 Validation
(2025)Objective
To validate the accuracy of the fully automated Lumipulse plasma p-tau217 assay for detecting AD pathology in symptomatic patients across diverse clinical settings using predefined biomarker cutoffs.
Study Summary
• A two-cutoff approach (<0.22 and >0.34 pg/ml) increased accuracy to 92-94% in both settings, with 12-17% intermediate results, and all PPVs/NPVs ≥90% except NPV in Brescia (84%)
• Accuracy was lower in participants aged ≥80 years (83% vs 91% in <73 years, P=0.003) with single cutoff, but this was resolved with two-cutoff approach
• MS-based %p-tau217 showed higher accuracy than Lumipulse p-tau217 in primary care (90% vs 85%, P=0.003) but comparable performance in secondary care
• Performance was unaffected by chronic kidney disease, diabetes, sex, APOE genotype, or cognitive stage
Intervention
Plasma p-tau217 measurement using fully automated Lumipulse immunoassay platform compared to cerebrospinal fluid Aβ42:p-tau181 ratio as reference standard
Inclusion Criteria
Patients with cognitive symptoms presenting to primary or secondary care
Study Design
Arms: Diagnostic accuracy study with multiple cohorts: Malmö (n=337), Gothenburg (n=165), Barcelona (n=487), Brescia (n=230), Swedish primary care (n=548)
Patients per Arm: 165-548 per cohort
Outcome
• Two-cutoff approach: Accuracy 92-94% across all settings; PPV and NPV ≥90% in most cohorts
• P-tau217:Aβ42 ratio provided similar accuracy but reduced intermediate results to 7-10% (vs 15-16% for p-tau217 alone)
• MS-based %p-tau217 had superior performance in primary care (accuracy 90%, AUC 0.96) and was unaffected by age
• Cost savings estimated at 60% vs CSF testing and 81% vs amyloid PET
Clinical Question
Can a fully automated plasma p-tau217 assay accurately identify Alzheimer's disease pathology in primary and secondary care settings using predefined cutoffs?
Bottom Line
The fully automated Lumipulse plasma p-tau217 assay demonstrates high accuracy (89-91% in secondary care, 85% in primary care) for identifying AD pathology using a single cutoff, with accuracy improving to 92-94% using a two-cutoff approach. A two-cutoff strategy may be necessary to optimize performance across diverse settings and subpopulations, particularly in older individuals (≥80 years) and primary care.
Major Points
- Plasma p-tau217 detected AD pathology with AUCs of 0.93-0.96 across five independent cohorts from Sweden, Spain, and Italy
- Single cutoff (>0.27 pg/ml) yielded 89-91% accuracy in secondary care and 85% in primary care
- Two-cutoff approach (<0.22 and >0.34 pg/ml) increased accuracy to 92-94% across all settings, excluding 12-17% with intermediate results
- Accuracy was significantly lower in participants ≥80 years (83%) versus <73 years (91%, P=0.003) with single cutoff but not with two-cutoff approach
- Performance was unaffected by chronic kidney disease, diabetes, sex, APOE genotype, or cognitive stage
- MS-based %p-tau217 showed superior accuracy in primary care (90% vs 85%, P=0.003) and was unaffected by age
- P-tau217:Aβ42 ratio did not improve accuracy but reduced intermediate results to 7-10%
- Cost-effectiveness analysis estimated 60% savings versus CSF testing and 81% versus amyloid PET
Study Design
- Study Type
- Multicenter diagnostic accuracy study
- Randomization
- No
- Blinding
- Laboratory personnel blinded to clinical diagnosis
- Sample Size
- 1767
- Follow-up
- Cross-sectional
- Centers
- 5
- Countries
- Sweden, Spain, Italy
Primary Outcome
Definition: AD pathology defined as abnormal CSF Aβ42:p-tau181 (<11.94) or positive amyloid PET
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - |
Limitations & Criticisms
- Lower accuracy in primary care (85%) with single cutoff compared to secondary care (89-91%)
- Reduced accuracy in participants ≥80 years (83%) requiring two-cutoff approach
- Two-cutoff approach excludes 12-17% of participants with intermediate results, requiring further testing
- MS-based %p-tau217 showed superior performance in primary care and was unaffected by age, suggesting Lumipulse may have limitations in certain populations
- Missing lumbar puncture data in 87 primary care participants (amyloid PET used instead)
- Cross-sectional design limits assessment of longitudinal performance
- Predominantly European population may limit generalizability to other ethnicities
- Cost-effectiveness analysis based on approximated US costs may not reflect costs in other healthcare systems
- No correction for multiple comparisons in subgroup analyses
Citation
Palmqvist S, et al. Plasma phospho-tau217 for Alzheimer's disease diagnosis in primary and secondary care using a fully automated platform. Nat Med. 2025;31:2036-2043.