eBioMedicine | February 11, 2022

Ashton NJ, Benedet AL, Pascoal TA, Karikari TK, Lantero-Rodriguez J, Brum WS, Mathotaarachchi S, Therriault J, Savard M, Chamoun M, Stoops E, Francois C, Vanmechelen E, Gauthier S, Zimmer ER, Zetterberg H, Blennow K and Rosa-Neto P

EBioMedicine. 2022;76:103836

https://doi.org/10.1016/j.ebiom.2022.103836

This study was performed using Simoa Homebrew assay(s).

Abstract

Background

Phosphorylated tau (p-tau) epitopes in cerebrospinal fluid (CSF) are accurate biomarkers for a pathological and clinical diagnosis of Alzheimer’s disease (AD) and are seen to be increased in preclinical stage of the disease. However, it is unknown if these increases transpire earlier, prior to amyloid-beta (Aβ) positivity as determined by position emission tomography (PET), and if an ordinal sequence of p-tau epitopes occurs at this incipient phase

Methods

We measured CSF concentrations of p-tau181, p-tau217 and p-tau231 in 171 participants across the AD continuum who had undergone Aβ ([¹⁸F]AZD4694) and tau ([¹⁸F]MK6240) position emission tomography (PET) and clinical assessment

Findings

All CSF p-tau biomarkers were accurate predictors of cognitive impairment but CSF p-tau217 demonstrated the largest fold-changes in AD patients in comparison to non-AD dementias and cognitively unimpaired individuals. CSF p-tau231 and p-tau217 predicted Aβ and tau to a similar degree but p-tau231 attained abnormal levels first. P-tau231 was sensitive to the earliest changes of Aβ in the medial orbitofrontal, precuneus and posterior cingulate before global Aβ PET positivity was reached

Interpretation

We demonstrate that CSF p-tau231 increases early in development of AD pathology and is a principal candidate for detecting incipient Aβ pathology for therapeutic trial application