Association of [¹⁸F]Flortaucipir-PET and Plasma p-Tau217 With Tau Neuropathology in Alzheimer Disease and Other Neurodegenerative Disorders.

Abstract

Evaluating tau biomarkers in patients with autopsy data is critical for validating their sensitivity and specificity to Alzheimer disease (AD) neuropathologic changes (ADNCs). We examined associations between [¹⁸F]flortaucipir tau PET, plasma phosphorylated-tau 217 (p-tau217), and AD neuropathology in a cohort of clinically impaired participants from a tertiary dementia center. This was a retrospective study conducted at the University of California San Francisco Neurodegenerative Disease Brain Bank that included all participants with a clinical diagnosis of neurodegenerative disease who underwent antemortem flortaucipir-PET and autopsy from 2013 to 2024. Flortaucipir-PET was acquired 80-100 minutes after injection and normalized to the inferior cerebellar cortex; standardized uptake value ratios (SUVRs) were extracted from the entorhinal cortex (early tau region) and the temporal meta-regions of interest (ROIs) (AD-signature region). Plasma p-tau217 was quantified using Simoa (Janssen) in 56 participants (median [interquartile range, IQR] PET-to-plasma duration: 1.6 months [0.24-3.7]). Semiquantitative rating of AD neurofibrillary tangle (NFT) burden in cortical areas was available for 56 participants. The diagnostic performance of tau PET and plasma p-tau217 was assessed using receiver operating characteristic analysis with cross-validation. We analyzed 73 participants (median [IQR] age: 67 [59-73] years, 60% male, median [IQR] PET-to-autopsy duration: 3.9 [2.1-5.1] years) with primary neuropathologic diagnosis of AD (n = 39), frontotemporal lobar degeneration (tauopathies, n = 26; nontauopathies, n = 4), chronic traumatic encephalopathy (n = 2), and Lewy body disease (n = 2). Flortaucipir SUVRs were elevated in participants with a neuropathologic diagnosis of AD compared with non-AD participants. Consistently elevated PET signal was detected in both the entorhinal cortex and temporal meta-ROIs at NFT Braak stage VI and high ADNC levels. No PET signal elevation was observed at intermediate ADNC levels. AD NFT burden correlated with local flortaucipir SUVRs and plasma p-tau217 concentrations across cortical brain regions. Plasma p-tau217 concentrations increased at Braak stages V and VI and correlated with flortaucipir SUVRs (<i>r</i>'s ≥ 0.75). Both markers identified Braak stage V-VI levels with similarly high performance (entorhinal SUVR, area under the curve [AUC] = 0.92 [95% CI 0.91-0.93]; temporal meta-ROI SUVR, AUC = 0.91 [95% CI 0.90-0.92]; plasma p-tau217, AUC = 0.90 [95% CI 0.89-0.91]), but PET outperformed plasma p-tau217 in identifying high/intermediate ADNCs (entorhinal ROI, AUC = 0.94 [95% CI 0.94-0.95]; temporal meta-ROI AUC = 0.94 [95% CI 0.94-0.95]; plasma p-tau217, AUC = 0.89 [95% CI 0.88-0.90]). Flortaucipir-PET and plasma p-tau217 both displayed strong specificity for primary AD neuropathologic diagnosis but limited sensitivity for early tau co-pathology in non-AD diagnoses.