Plasma tau phosphorylation at T217 predicts amyloid deposition in dominantly inherited and late onset Alzheimer disease participants without clinical symptoms

Abstract

AbstractBackgroundProgressive amyloid plaque accumulation in the brain precedes the emergence of clinical symptoms in Alzheimer disease (AD). This asymptomatic phase, referred to as preclinical AD, induces significant modification of tau phosphorylation in the cerebrospinal fluid (CSF). CSF tau phosphorylation occupancy at Threonine 217 (T217) becomes abnormal more than 20 years before cognitive decline in dominantly inherited AD (DIAD). CSF hyperphosphorylation at T217 also associates with amyloid pathology in late‐onset AD (LOAD) individuals with preclinical AD. In this study, we examined the performance of plasma T217 phosphorylation to detect amyloid plaques deposition measured by amyloid‐PET in asymptomatic participants with DIAD or late‐onset AD (LOAD).MethodWe measured plasma T217 phosphorylation using tau immunoprecipitation and high‐resolution mass spectrometry. Phosphorylation abundance at T217 was expressed as p‐tau217 ratio defined using the level of T217 phosphorylated tau peptide normalized to total tau level. The DIAD cohort included 355 samples from 176 CDR0 and 51 CDR>0 participants in the DIAN Observational study with 62% mutation carriers, all collected in relation to the estimated years to symptom onset (EYO). The LOAD cohort included 321 cross‐sectional samples from BioFINDER‐2 study. Amyloid positivity was determined using cross sectional amyloid‐PET scan available for each participant.ResultWe observed abnormal plasma p‐tau217 ratio in DIAD mutation carriers more than 15 years before EYO (Figure 1). Plasma p‐tau217 ratio accurately predicted amyloid PET positivity for individuals across multiple preclinical stages (Table 1, AUC respectively 0.89 and 0.98 for EYO brackets ‐20 to ‐10 and ‐10 to 0). The plasma test had similar performance in distinguishing amyloid status in the DIAD and the LOAD cohorts (AUC respectively 0.96 and 0.97, Table 1). In LOAD, plasma p‐tau217 ratio identified amyloid positivity independently of the cognitive status (AUC respectively 0.96 and 0.97 for asymptomatic and symptomatic).ConclusionOur results support the use of plasma p‐tau217 ratio to screen cognitively normal populations at risk of developing AD dementia. This blood‐based biomarker can support the recruitment of asymptomatic participants for prevention trials and help identifying patients who might benefit from early care using future AD drugs more than a decade before the detection of cognitive symptoms.