Clinical validation of the Eli Lilly SPX P‐tau217 blood‐based immunoassay as a laboratory‐developed test (LDT)

Abstract Background Blood‐based biomarkers have significant potential to aid in the diagnosis of Alzheimer’s disease (AD), providing a more accessible option than cerebrospinal fluid testing or positron emission tomography (PET). This study evaluated performance of a plasma P‐tau217 immunoassay for identifying AD pathology as detected by amyloid or tau PET. Method Plasma samples from screened participants from the donanemab Phase 3 trial (NCT04437511) were analyzed using a chemiluminescent immunoassay for plasma P‐tau217 on the Quanterix SP‐X platform. A Receiver Operating Characteristic (ROC) curve explored the relationship between plasma P‐tau217 values and positive amyloid PET (Aβ+), defined as 24.1 Centiloid (CL). A two‐threshold approach was used to propose P‐tau217 cut‐points that result in sensitivity and specificity each ≥90%; <20% of cases falling between the two cut‐off values (classified as indeterminate). Similar evaluation was performed for P‐tau217 against tau PET in a subset of participants. Result Plasma samples from 2071 participants (mean age 73.1 [SD = 6.4 years], Mini Mental State Examination mean 24.8 [SD = 2.5], 53.3% female, 50.7% APOE ε4 carriers, 65% Aβ+) were examined. The area under the curve (AUC) for the ROC of plasma P‐tau217 identifying Aβ+ participants was 0.915 (Figure 1). Stratification of P‐tau217 concentrations into three levels using two P‐tau217 cut‐points resulted in an upper‐level group with 95% positive predictive value (PPV) for Aβ+ and a low‐ level group with 84% negative predictive value (NPV) for Aβ‐, with a false positive rate of 7.5% and a false negative rate of 7.3% (Table 1). The remaining indeterminate group represented 18% of participant samples, of which 60% were Aβ+. Within this cohort, 359 participants had available tau PET results. Preliminary analysis revealed 93% ROC AUC for P‐tau217 against tau PET visual read (Figure 2). Conclusion The presented plasma P‐tau217 assay has high concordance with amyloid PET for identification of amyloid pathology, indicating its potential utility in the diagnostic workup of AD. Preliminary analysis demonstrated a relationship between plasma P‐tau217 and tau PET; however, additional work is needed to establish the assay’s diagnostic performance for tau pathology.