Evaluation of the performance of novel Aβ isoforms as theragnostic markers in Alzheimer's disease: from the cell to the patient

Abstract

Background: Alzheimer's disease (AD) is the most common neurodegenerative disorder in the aging population and is characterized by extracellular plaques in the brain. The last decades have witnessed an explosion in studies of the role of amyloid-β (Aβ) metabolism and aggregation in the pathogenesis of AD which has been translated into novel promising therapies with putative disease-modifying effects.

Objective: The aim is to investigate the performance of truncated Aβ isoforms as theragnostic markers in clinical trials.

Methods: Aβ isoforms were immunoprecipitated from human, mouse and dog cerebrospinal fluid (CSF) or cell media and analyzed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Results: Aβ1-14, Aβ1-15, and Aβ1-16 are elevated in cell media and in CSF in response to γ-secretase inhibitor treatment. In a clinical trial including AD patients, Aβ1-14, Aβ1-15, and Aβ1-16 increased dose-dependently in response to treatment with the γ-secretase inhibitor LY450139. In dogs, Aβ1-37 was significantly increased in response to treatment with the γ-secretase modulator E2012.

Conclusions: The results presented add to the current knowledge on APP processing and that Aβ isoforms can be used as novel biomarkers to monitor anti-Aβ treatments in clinical trials and may be valuable for making a go/no go decision for large and expensive phase 2 or 3 clinical trials.