Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer’s continuum when only subtle changes in Aβ pathology are detected

• Published in: EMBO molecular medicine Vol. 12; no. 12; pp. e12921 - n/a
• Main Authors: Suárez‐Calvet, Marc, Karikari, Thomas K, Ashton, Nicholas J, Lantero Rodríguez, Juan, Milà‐Alomà, Marta, Gispert, Juan Domingo, Salvadó, Gemma, Minguillon, Carolina, Fauria, Karine, Shekari, Mahnaz, Grau‐Rivera, Oriol, Arenaza‐Urquijo, Eider M, Sala‐Vila, Aleix, Sánchez‐Benavides, Gonzalo, González‐de‐Echávarri, José Maria, Kollmorgen, Gwendlyn, Stoops, Erik, Vanmechelen, Eugeen, Zetterberg, Henrik, Blennow, Kaj, Molinuevo, José Luis, Beteta, Annabella, Cacciaglia, Raffaele, Cañas, Alba, Deulofeu, Carme, Cumplido, Irene, Dominguez, Ruth, Emilio, Maria, Falcon, Carles, Fuentes, Sherezade, Hernandez, Laura, Huesa, Gema, Huguet, Jordi, Marne, Paula, Menchón, Tania, Operto, Grégory, Polo, Albina, Pradas, Sandra, Soteras, Anna, Vilanova, Marc, Vilor‐Tejedor, Natalia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.12.2020; EMBO Press; John Wiley and Sons Inc; Springer Nature
• Subjects: Alzheimer's disease; Amyloid; Antibodies; Asymptomatic; biomarker; Biomarkers; Cerebrospinal fluid; Cognitive ability; Dementia; Disease; Kinases; Neurodegenerative diseases; Neurosciences; Neurovetenskaper; Pathology; Phosphorylation; Plasma; tau; Tau protein; Threonine; tau; Alzheimer’s disease; biomarker; plasma; cerebrospinal fluid
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.15252/emmm.202012921

In Alzheimer’s disease (AD), tau phosphorylation in the brain and its subsequent release into cerebrospinal fluid (CSF) and blood is a dynamic process that changes during disease evolution. The main aim of our study was to characterize the pattern of changes in phosphorylated tau (p‐tau) in the preclinical stage of the Alzheimer’s continuum . We measured three novel CSF p‐tau biomarkers, phosphorylated at threonine‐181 and threonine‐217 with an N‐terminal partner antibody and at threonine‐231 with a mid‐region partner antibody. These were compared with an automated mid‐region p‐tau181 assay (Elecsys) as the gold standard p‐tau measure. We demonstrate that these novel p‐tau biomarkers increase more prominently in preclinical Alzheimer, when only subtle changes of amyloid‐β (Aβ) pathology are detected, and can accurately differentiate Aβ‐positive from Aβ‐negative cognitively unimpaired individuals. Moreover, we show that the novel plasma N‐terminal p‐tau181 biomarker is mildly but significantly increased in the preclinical stage. Our results support the idea that early changes in neuronal tau metabolism in preclinical Alzheimer, likely in response to Aβ exposure, can be detected with these novel p‐tau assays. SYNOPSIS This study investigated novel CSF and plasma p‐tau biomarkers in the preclinical stage of the Alzheimer’s continuum and compared them with the widely used CSF Mid‐ptau181. Novel p‐tau biomarkers CSF N‐p‐tau181, N‐p‐tau217 and Mid‐p‐tau231 increase early in the Alzheimer’s continuum, when only subtle changes in Aβ pathology are detected. CSF N‐p‐tau181, N‐p‐tau217 and Mid‐p‐tau231 can accurately differentiate Aβ‐positive, cognitively unimpaired individuals from those that are Aβ‐negative. Plasma N‐p‐tau181 biomarker is significantly increased in the preclinical stage of the Alzheimer’s continuum. These results suggest that there are early changes in tau metabolism in preclinical Alzheimer, probably in response to emerging Aβ pathology. Graphical Abstract This study investigated novel CSF and plasma p‐tau biomarkers in the preclinical stage of the Alzheimer’s continuum and compared them with the widely used CSF Mid‐ptau181.