Associations of Plasma Phospho-Tau217 Levels With Tau Positron Emission Tomography in Early Alzheimer Disease

Importance There is an urgent need for inexpensive and minimally invasive blood biomarkers for Alzheimer disease (AD) that could be used to detect early disease changes. Objective To assess how early in the course of AD plasma levels of tau phosphorylated at threonine 217 (P-tau217) start to change compared with levels of established cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of AD pathology. Design, Setting, and Participants This cohort study included cognitively healthy control individuals (n = 225) and participants with subjective cognitive decline (n = 89) or mild cognitive impairment (n = 176) from the BioFINDER-2 study. Participants were enrolled at 2 different hospitals in Sweden from January 2017 to October 2019. All study participants underwent plasma P-tau217 assessments and tau- and amyloid-beta (A beta)-PET imaging. A subcohort of 111 participants had 2 or 3 tau-PET scans. Main Outcomes and Measures Changes in plasma P-tau217 levels in preclinical and prodromal AD compared with changes in CSF P-tau217 and PET measures. Results Of 490 participants, 251 were women (51.2%) and the mean (SD) age was 65.9 (13.1) years. Plasma P-tau217 levels were increased in cognitively unimpaired participants with abnormal A beta-PET but normal tau-PET in the entorhinal cortex (A beta-PET+/ tau-PET- group vs A beta-PET-/ tau-PET- group: median, 2.2 pg/mL [interquartile range (IQR), 1.5-2.9 pg/mL] vs 0.7 pg/mL [IQR, 0.3-1.4 pg/mL]). Most cognitively unimpaired participants who were discordant for plasma P-tau217 and tau-PET were positive for plasma P-tau217 and negative for tau-PET (P-tau217(+)/tau-PET-: 36 [94.7%]; P-tau217(-)/tau-PET+: 2 [5.3%]). Event-based modeling of cross-sectional data predicted that in cognitively unimpaired participants and in those with mild cognitive impairment, both plasma and CSF P-tau217 would change before the tau-PET signal in the entorhinal cortex, followed by more widespread cortical tau-PET changes. When testing the association with global A beta load in nonlinear spline models, both plasma and CSF P-tau217 were increased at lower A beta-PET values compared with tau-PET measures. Among participants with normal baseline tau-PET, the rates of longitudinal increase in tau-PET in the entorhinal cortex were higher in those with abnormal plasma P-tau217 at baseline (median standardized uptake value ratio, 0.029 [IQR, -0.006 to 0.041] vs -0.001 [IQR, -0.021 to 0.020]; Mann-Whitney U, P = .02). Conclusions and Relevance In this cohort study, plasma P-tau217 levels were increased during the early preclinical stages of AD when insoluble tau aggregates were not yet detectable by tau-PET. Plasma P-tau217 may hold promise as a biomarker for early AD brain pathology. This cohort study compares plasma levels of phosphorylated tau at threonine 217 with established cerebrospinal fluid and positron emission tomography (PET) tau biomarkers in early Alzheimer disease. Question How early in the course of Alzheimer disease do plasma levels of tau phosphorylated at threonine 217 (P-tau217) start to change compared with levels of established cerebrospinal fluid and positron emission tomography (PET) tau biomarkers? Findings In this cohort study of 490 individuals without dementia, plasma P-tau217 levels were elevated in amyloid-beta-positive cognitively unimpaired participants before insoluble tau aggregates became detectable by tau-PET; modeling approaches predicted that both plasma and cerebrospinal fluid P-tau217 increased before tau-PET in the entorhinal cortex followed by more widespread cortical tau-PET changes. Meaning The study results suggest that in Alzheimer disease, plasma P-tau217 becomes abnormal before tau-PET and that plasma P-tau217 may be considered as an early Alzheimer disease biomarker.

Automated summary

This study highlights the potential of plasma P-tau217 as an early biomarker for Alzheimer's disease, showing elevated levels before tau-PET detected insoluble tau aggregates. Modeling suggests that changes in plasma and CSF P-tau217 precede tau-PET signals, indicating its usefulness in detecting early AD brain pathology.