Biomarkers.

Area of Science:

• Neurology
• Biomarker Discovery
• Clinical Diagnostics

Background:

• Emerging blood-based biomarkers for Alzheimer's disease (AD) require validation for clinical practice.
• Significant knowledge gaps exist regarding the performance of novel AD diagnostic assays.

Purpose of the Study:

• To evaluate fully automated immunoassays and mass spectrometry-based assays for plasma phospho-tau217 (p-tau217), Aβ42, and Aβ40.
• To assess the diagnostic performance of these biomarkers in diverse clinical cohorts.

Main Methods:

• Included 1,767 participants with cognitive symptoms from four secondary care cohorts and one primary care cohort.
• Measured plasma p-tau217 and Aβ42 using Lumipulse immunoassays (Fujirebio).
• Measured %p-tau217 and Aβ42/40 ratios using mass spectrometry (PrecivityAD2; C2N Diagnostics).
• Defined primary outcome as AD pathology via cerebrospinal fluid Aβ42/p-tau181 ratio.

Main Results:

• Plasma p-tau217 (Lumipulse) showed high accuracy (AUCs 0.93-0.96) for detecting AD pathology.
• Accuracies in secondary care were 89-91%, with positive predictive values (PPV) of 89-95% and negative predictive values (NPV) of 77-90%.
• Primary care accuracy was 85% (PPV 82%, NPV 88%), with performance unaffected by comorbidities or APOE genotype.
• Mass spectrometry-based %p-tau217 showed similar secondary care accuracy and higher primary care accuracy, unaffected by age.

Conclusions:

• Both automated and mass spectrometry assays show promise for clinical implementation in Alzheimer's disease diagnostics.
• A two-cutoff approach may be necessary for specific settings and subpopulations, particularly with automated assays.
• Further studies will explore clinician attitudes, clinical utility, and comparisons with CSF biomarkers and amyloid PET imaging.