Cerebrospinal Fluid beta-Amyloid Turnover in the Mouse, Dog, Monkey and Human Evaluated by Systematic Quantitative Analyses

Background: Reducing brain beta-amyloid (A beta) via inhibition of beta-secretase, or inhibition/modulation of gamma-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 A beta lowering in the brain and/or cerebrospinal fluid (CSF) as the primary pharmacological end point. Interpretation and translation of the pharmacokinetic (PK)/pharrnacodynamic (PD) relationship for these compounds is complicated by the relatively slow A beta turnover process in these compartments. Objective: To understand A beta turnover kinetics in preclinical species and humans. Methods: We collected CSF A beta dynamic data after beta- or gamma-secretase inhibitor treatment from in-house experiments and the public domain, and analyzed the data using PK/PD modeling to obtain CSF A beta turnover rates (k(out)) in the mouse, dog, monkey and human. Results:The k(out) for CSF A beta 40 follows allometry (k(out) = 0.395 x body weight(-351)). The kout for CSF A beta 40 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 A beta 40 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 A beta in rodents may be different from those in the higher species. The understanding of A beta turnover has considerable implications for the discovery and development of A beta-lowering therapeutics, as illustrated from the perspectives of preclinical PK/PD characterization and preclinical-to-clinical translation. Copyright (C) 2012 S. Karger AG, Basel