Associations of Plasma Phospho-Tau217 Levels With Tau Positron Emission Tomography in Early Alzheimer Disease | Dementia and Cognitive Impairment | JAMA Neurology | JAMA Network
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    Original Investigation
    November 9, 2020

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

    Author Affiliations
    • 1Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Sölvegatan, Sweden
    • 2Department of Neurology, Skåne University Hospital, Lund, Sweden
    • 3Eli Lilly and Company, Indianapolis, Indiana
    • 4Memory Clinic, Skåne University Hospital, Malmö, Sweden
    • 5Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
    JAMA Neurol. 2021;78(2):149-156. doi:10.1001/jamaneurol.2020.4201
    Key Points

    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-β–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.


    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.