Phospho‐specific plasma p‐tau181 assay detects clinical as well as asymptomatic Alzheimer's disease

Abstract

Objective Plasma phosphorylated‐tau‐181 (p‐tau181) reliably detects clinical Alzheimer's disease (AD) as well as asymptomatic amyloid‐β (Aβ) pathology, but is consistently quantified with assays using antibody AT270, which cross‐reacts with p‐tau175. This study investigates two novel phospho‐specific assays for plasma p‐tau181 and p‐tau231 in clinical and asymptomatic AD. Methods Plasma p‐tau species were quantified with Simoa in 44 AD patients, 40 spouse controls and an independent cohort of 151 cognitively unimpaired (CU) elderly who underwent Aβ‐PET. Simoa plasma Aβ42 measurements were available in a CU subset (N = 69). Receiver operating characteristics and Aβ‐PET associations were used to evaluate biomarker validity. Results The novel plasma p‐tau181 and p‐tau231 assays did not show cross‐reactivity. Plasma p‐tau181 accurately detected clinical AD (area under the curve (AUC) = 0.98, 95% CI 0.95–1.00) as well as asymptomatic Aβ pathology (AUC = 0.84, 95% CI 0.76–0.92), while plasma p‐tau231 did not (AUC = 0.74, 95% CI 0.63–0.85 and 0.61, 95% CI 0.52–0.71, respectively). Plasma p‐tau181, but not p‐tau231, detected asymptomatic Aβ pathology more accurately than age, sex and APOE combined (AUC = 0.64). In asymptomatic elderly, correlations between plasma p‐tau181 and Aβ pathology were observed throughout the cerebral cortex (ρ = 0.40, p < 0.0001), with focal associations within AD‐vulnerable regions, particularly the precuneus. The plasma Aβ42/p‐tau181 ratio did not reflect asymptomatic Aβ pathology better than p‐tau181 alone. Interpretation The novel plasma p‐tau181 assay is an accurate tool to detect clinical as well as asymptomatic AD and provides a phospho‐specific alternative to currently employed immunoassays.

Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer’s disease

“…P-tau217 was measured as phosphorylation occupancy at Thr217 using MS assay developed at Washington University (p-tau217 WashU ), 7 Meso Scale Discovery (MSD) immunoassay developed by Lilly Research Laboratories (p-tau217 Lilly ) 10 , 27 and Single molecule arrays (Simoa) immunoassay developed by Janssen Research and Development (p-tau217 Janss ). 19 , 28 , 29 P-tau181 was measured as phosphorylation occupancy at Thr181 using MS-WashU assays (p-tau181 WashU ), 7 MSD immunoassay developed by Lilly Research Laboratories (p-tau181 Lilly ), 8 , 30 Simoa immunoassay developed at the University of Gothenburg (p-tau181 UGOT ), 9 Simoa immunoassay developed by ADx Neurosciences (p-tau181 ADx ), 20 , 31 Lumipulse immunoassay developed by Fujirebio (p-tau181 Fuji ) and Splex immunoassay from MSD (p-tau181 Splex ). P-tau231 was measured using in-house Simoa immunoassay developed at the University of Gothenburg (p-tau231 UGOT ).…”

“…phosphorylation occupancy at Thr181 using MS-WashU assays (p-tau181 WashU ), 7 MSD immunoassay developed by Lilly Research Laboratories (p-tau181 Lilly ), 8,30 Simoa immunoassay developed at the University of Gothenburg (p-tau181 UGOT ), 9 Simoa immunoassay developed by ADx Neurosciences (p-tau181 ADx ), 20,31 Lumipulse immunoassay developed by Fujirebio (p-tau181 Fuji ) and Splex immunoassay from MSD (p-tau181 Splex ). P-tau231 was measured using inhouse Simoa immunoassay developed at the University of Gothenburg (p-tau231 UGOT ).…”

Plasma phosphorylated tau181 predicts cognitive and functional decline

“…Plasma tau phosphorylated at threonine 181, 217, or 231 can discriminate clinically diagnosed AD dementia from both other neurodegenerative diseases and cognitively normal individuals. 12 , 13 , 14 , 15 , 16 Additionally, levels of plasma p‐tau181 associated with AD disease severity, predict brain amyloid and tau pathology captured by PET imaging, and predict AD pathology on autopsy. 17 , 18 In cognitively normal and MCI individuals, higher plasma p‐tau181 is associated with progression to dementia.…”

Alzheimer Disease Biomarkers in Clinical Practice: A Blood-Based Diagnostic Revolution

“…Since 2018, studies have shown that blood-based measures of phosphorylated-tau (p-tau) correlate with cerebrospinal fluid and PET measures of amyloid and tau neuropathology, and with symptomatic disease progression. 40 - 48 From a diagnostic perspective, measures of p-tau 217 isomers appear to hold the greatest promise. Independent studies support its sensitivity and specificity for AD, 40 , 42 , 43 , 45 while a head-to-head study established superiority of p-tau 217 measured by mass spectrometry for the diagnosis of symptomatic AD over 9 other immunoassays, with near-perfect ability to discriminate participants with AD (area under the curve of 0.95).…”

“…Increases in plasma p-tau 217 levels may precede changes in tau-PET, and even amyloid-PET. 42 , 43 , 46 Thus, elevations in plasma p-tau 217 may mark the earliest stages of “preclinical” or “asymptomatic” AD. Although the ability to identify asymptomatic patients at-risk of developing cognitive impairment offers little-to-no clinical benefit at the present time, the prospect of effective disease-modifying therapies for AD justifies continued research in this area.…”