Comparative diagnostic performance of plasma P‐tau217 and P‐tau181 in Alzheimer’s disease and frontotemporal lobar degeneration and correlations with [18F]Flortaucipir‐PET uptake

Background Plasma P‐tau181 has previously been shown to be associated with tau pathology in Alzheimer’s disease (AD). P‐tau217 is a novel blood‐based biomarker. We assessed the diagnostic value of plasma P‐tau181 and P‐tau217 in the same cohort of patients across the AD and frontotemporal lobar degeneration (FTLD) spectrum. Method This retrospective study of 617 participants included 119 healthy controls, 74 cases in the clinical AD spectrum (57 amnestic, 15 lvPPA, 2 PCA; all biomarker‐confirmed) and 294 in the FTLD spectrum. The cohort included 15 AD and 67 FTLD autopsy‐confirmed cases and 66 Microtubule‐Associated Protein Tau ( MAPT ) mutation carriers. P‐tau concentrations were measured using custom electrochemiluminiscence‐based assays at Lilly. P‐tau217 was available in 513 cases, P‐tau181 in 614 cases, and both in 509. Amyloid‐PET was available in 352 cases and [18F]Flortaucipir (FTP)‐PET in 227 cases. The differentiating power of P‐tau181 and P‐tau217 was assessed across clinical and autopsy‐confirmed phenotypes, amyloid‐ and FTP‐PET status, and type of tau pathology in MAPT mutation carriers. Result Plasma P‐tau217 concentrations were increased 5.2‐fold in clinical AD (n=74) relative to controls (AUC=97%, p <0.001) and 3.8 fold relative to clinical FTLD (AUC=93%, p <0.001). P‐tau217 was increased 4.9 fold in autopsy‐confirmed AD compared to autopsy‐confirmed FTLD (AUC=92%, p <0.001). Plasma P‐tau181 was increased 2.6 fold in clinical AD compared to controls (AUC=93%, p<0.001) and 2.4 fold relative to clinical FTLD (AUC=89%, p <0.001). P‐tau181 was increased 2.5 fold in autopsy‐confirmed AD compared to autopsy‐confirmed FTLD (AUC=87%, p <0.001). There was no change in P‐tau217 concentrations in MAPT mutation carriers with mixed 3R/4R tau pathology compared to 4R tau pathology, whereas P‐tau181 was 1.4 fold increased ( p <0.01). FTP‐PET SUVR was associated with P‐tau217 ( ρ =0.78, p <0.001) and P‐tau181 ( ρ =0.64, p <0.001). P‐tau217 could identify amyloid‐PET positive cases (n=317, AUC= 86%, p <0.001), and FTP‐PET positive cases (AUC= 96%, p <0.001, n=213) across diagnoses, with similar accuracy to P‐tau181 (amyloid‐PET AUC=81%, n=351, FTP‐PET AUC=90%, p <0.001, n=227). Conclusion Plasma P‐tau217 is comparable to P‐tau181 for differential diagnosis of AD and potentially superior for identifying FTP‐PET positivity. Additional investigations are necessary to explain potential differences in assay performance in MAPT mutation carriers that produce mixed 3R/4R tau, whose pathology is similar to AD.