Plasma p217+tau vs NAV4694 amyloid and MK6240 tau PET across the Alzheimer continuum

ABSTRACT INTRODUCTION We evaluated a new Simoa plasma assay for phosphorylated tau at aa217 enhanced by additional ptau sites (p217+tau). METHODS Plasma p217+tau levels were compared to 18 F-NAV4694 amyloid-beta (Aβ) PET and 18 F-MK6240 tau PET in 174 cognitively impaired (CI) and 223 cognitively unimpaired (CU) participants. RESULTS Compared to Aβ-CU, the plasma levels of p217+tau increased two-fold in Aβ+ CU and 3.5-fold in Aβ+ CI. In Aβ-the p217+tau levels did not significantly differ between CU, MCI or dementia. P217+tau correlated with Aβ centiloids ρ=0.67 (CI 0.64; CU 0.45) and tau SUVR MT ρ=0.63 (CI 0.69; CU 0.34). Area under curve (AUC) for AD vs Aβ-CU was 0.94, for AD vs other dementia was 0.93, for Aβ+ vs Aβ– PET was 0.89 and for tau+ vs tau-PET was 0.89. DISCUSSION Plasma p217+tau levels elevate early in the AD continuum and correlate well with Aβ and tau PET. Research in Context Systematic review: The authors reviewed the literature using PubMed, meeting abstracts and presentations. Plasma phospho-tau measures compare well to PET and post-mortem across the continuum of AD but accuracy varies across ptau target sites and assay methods. There are no reports comparing PET to plasma assays targeting multiple sites of tau phosphorylation as typically found in AD. The p217+tau assay targets p217 with binding enhanced by phosphorylation at additional sites such as aa212. Interpretation: Plasma p217+tau elevates early and correlates with both Aβ and tau as measured by PET indicating that tau phosphorylation is an early event in AD and occurs with Aβ deposition. Plasma p217+tau measurement should assist both selection for trials and diagnosis of AD. Future directions: Further validation studies, head-to-head comparison to other assays, assessing the influence of co-morbidities and the ability to measure change in brain Aβ and tau levels are required.