Cerebrospinal fluid β-Amyloid turnover in the mouse, dog, monkey and human evaluated by systematic quantitative analyses

Abstract

Background: Reducing brain β-amyloid (Aβ) via inhibition of β-secretase, or inhibition/modulation of γ-secretase, has been widely pursued as a potential disease-modifying treatment for Alzheimer's disease. Compounds that act through these mechanisms have been screened and characterized with Aβ lowering in the brain and/or cerebrospinal fluid (CSF) as the primary pharmacological end point. Interpretation and translation of the pharmacokinetic (PK)/pharmacodynamic (PD) relationship for these compounds is complicated by the relatively slow Aβ turnover process in these compartments.

Objective: To understand Aβ turnover kinetics in preclinical species and humans.

Methods: We collected CSF Aβ dynamic data after β- or γ-secretase inhibitor treatment from in-house experiments and the public domain, and analyzed the data using PK/PD modeling to obtain CSF Aβ turnover rates (kout) in the mouse, dog, monkey and human.

Results: The kout for CSF Aβ40 follows allometry (kout = 0.395 × body weight(-0.351)). The kout for CSF Aβ40 is approximately 2-fold higher than the turnover of CSF in rodents, but in higher species, the two are comparable.

Conclusion: The turnover of CSF Aβ40 was systematically examined, for the first time, in multiple species through quantitative modeling of multiple data sets. Our result suggests that the clearance mechanisms for CSF Aβ in rodents may be different from those in the higher species. The understanding of Aβ turnover has considerable implications for the discovery and development of Aβ-lowering therapeutics, as illustrated from the perspectives of preclinical PK/PD characterization and preclinical-to-clinical translation.