Publication date: Available online 9 November 2018
Source: Alzheimer’s & Dementia: Translational Research & Clinical Interventions
Author(s): Brian A. Willis, Karen Sundell, D Richard Lachno, Lisa R. Ferguson-Sells, Michael G. Case, Karen Holdridge, Ronald B. DeMattos, Joel Raskin, Eric R. Siemers, Robert A. Dean
Abstract
Introduction
Solanezumab treatment was previously shown to significantly increase total (bound + unbound) cerebrospinal fluid (CSF) levels of amyloid β (Aβ)1–40 and Aβ1–42 in patients with mild to moderate Alzheimer’s disease dementia yet did not produce meaningful cognitive effects. This analysis assessed solanezumab’s central nervous system target engagement by evaluating changes in CSF total and free Aβ isoforms and their relationship with solanezumab exposure.
Methods
CSF Aβ isoform concentrations were measured in patients with mild Alzheimer’s disease dementia from a pooled EXPEDITION + EXPEDITION2 population and from EXPEDITION3. CSF solanezumab concentrations were determined from EXPEDITION3.
Results
Solanezumab produced statistically significant increases in CSF total Aβ isoforms versus placebo, which correlated with CSF solanezumab concentration. Inconsistent effects on free Aβ isoforms were observed. Solanezumab penetration into the central nervous system was low.
Discussion
Solanezumab administration engaged the central molecular target, and molar ratio analyses demonstrated that higher exposures may further increase CSF total Aβ concentrations.