Plasma p‐tau181 concentration accurately predicts clinically diagnosed Alzheimer’s Disease cases

Abstract

AbstractBackgroundThe feasibility of detecting tau phosphorylated at threonine‐181(p‐tau181) in CSF makes it a valuable biomarker for diagnosis in the field of Alzheimer’s Disease (AD). Recently, the novel technologies accurately measuring biomarkers directly in blood offer a unique advantage for use in clinical testing and trials. This study describes the performance testing of a novel plasma p‐tau181 Simoa assay to predict clinical AD.MethodThe presented data were obtained after analysis of EDTA plasma from cases with clinical AD who had been referred to the UBC Hospital Clinic with complaint of cognitive impairment and were assessed for dementia and AD between 2008 – 2018.We also analysed serum of 50 random healthy donors and 50 aged ‐ matched controls with normal cognition. The samples were assayed using an ADx Neurosciences developed p‐tau181 specific Simoa assay. Analytical performance (precision, detection limit, parallelism) and analyte stability was evaluated using healthy‐donor samples. Finally, the p‐tau181 specificity was assessed using synthetic peptides.Result254 AD patients (female = 125) and 100 controls (female = 39) were included. The average of plasma p‐tau181 was 72.9 ±36.8 ng/L in AD cases and the average of serum p‐tau181 was 8.1± 10.5 ng/L in controls.The concentration of plasma p‐tau181 in patients with AD was significantly increased with at‐least 9‐fold versus controls (p=<0.001). ROC analysis demonstrated an AUC of 0.92 and a suitable clinical cut‐off of 34.3 ng/L. Analytical performance testing: 1 of the 254 AD samples tested were below the LLOQ of 1.38 ng/L. The intra‐ and inter‐ assay variability was 8.2% CV and 11.8 % CV, respectively. Sample dilution (df 2‐4‐5‐6) resulted in mean parallelism of 93.5 %. P‐tau181 levels were stable up to 5 Freeze/Thaw cycle (mean 98.9%) and up to 24h at 4°C or RT. The assay was found to be highly specific towards p‐tau181 and nonreactive to p‐tau175.ConclusionThe plasma p‐tau181 concentration in AD cases were significantly higher than controls with limited overlap and in line with published data. The specific measurement of plasma p‐tau181 shows good promise in offering a non‐biased measurement and help in the clinical assessment of AD patients and clinical trials.