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

Objective: Plasma phosphorylated-tau-181 (p-tau181) reliably detects clinical Alzheimer's disease (AD) as well as asymptomatic amyloid-beta (A beta) 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 A beta-PET. Simoa plasma A beta 42 measurements were available in a CU subset (N = 69). Receiver operating characteristics and A beta-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 A beta 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 A beta pathology more accurately than age, sex and APOE combined (AUC = 0.64). In asymptomatic elderly, correlations between plasma p-tau181 and A13 pathology were observed throughout the cerebral cortex (rho = 0.40, p < 0.0001), with focal associations within AD-vulnerable regions, particularly the precuneus. The plasma A beta 42/p-tau181 ratio did not reflect asymptomatic A beta 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.