Microdosing of scopolamine as a cognitive stress test: Rationale and test of a very low dose in an at-risk cohort of older adults

Background: Abnormal beta-amyloid (A beta) is associated with deleterious changes in central acetylcholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist. We aimed to establish an optimal microdose of scopolamine for the development of a cognitive stress test. Methods: Healthy older adults (n = 26, aged 55-75 years) with two risk factors for AD, but with low cortical A beta burden, completed the Groton Maze Learning Test (GMLT) at baseline and then received scopolamine (0.20 mg subcutaneously). Participants were reassessed at 1, 3, 5, 7, and 8 hours postinjection. Results: There were significant differences, of a moderate magnitude, in performance between baseline and 3 hours postinjection for total errors, rule break errors, and the GMLT composite (d approximate to 0.50) that were all unrelated to body mass. Conclusions: A very low dose of scopolamine leads to reliable cognitive impairment at 3 hours postdose (T-max) and full cognitive recovery within 5 hours, supporting its use as a prognostic test paradigm to identify individuals with potential preclinical AD. This paradigm is being implemented in a larger cohort of healthy adults, with high or low A beta, to identify pharmacodynamic differences between groups. (C) 2014 The Alzheimer's Association. All rights reserved.