JAMA Neurol. 2020 Nov 9:e204201.
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-β (Aβ)-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 Aβ-PET but normal tau-PET in the entorhinal cortex (Aβ-PET+/ tau-PET- group vs Aβ-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 Aβ load in nonlinear spline models, both plasma and CSF P-tau217 were increased at lower Aβ-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.
Conflict of interest statement
Conflict of Interest Disclosures: Dr Berron reported being a cofounder of neotiv GmbH outside the submitted work. Mr Proctor reported being an employee and stockholder of Eli Lilly and Company. Dr Dage reported being an employee and stockholder of Eli Lilly and Company. Dr Hansson reported receiving grants from the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Roche, and Biogen; receiving financial support from GE Healthcare outside the submitted work; receiving research support from Roche, Pfizer, GE Healthcare, Biogen, Eli Lilly and Company, and AVID Radiopharmaceuticals; and receiving consultancy and speaker fees (paid to the institution) from Biogen and Roche. No other disclosures were reported.