Disruption of cholinergic neurotransmission exacerbates Aβ-related cognitive impairment in preclinical Alzheimer's disease

Abstract

Disruption in cholinergic neurotransmission is one of the earliest neuropathological changes in preclinical Alzheimer's disease (AD) and may be associated with abnormal beta-amyloid (Aβ) accumulation. Therefore, disruption of cholinergic neurotransmission with scopolamine may unmask otherwise undetectable cognitive deficits in preclinical AD. To compare the effects of low-dose (0.20 mg s.c.) scopolamine on cognition between Aβ+ and Aβ− cognitively normal (CN) older adults using the Groton Maze Learning Test (GMLT). CN older adults completed the GMLT predose and then received scopolamine (0.20 mg) subcutaneously. Participants were reassessed 1-, 3-, 5-, 7-, and 8-hours post dose. All participants underwent positron emission tomography neuroimaging for Aβ using 18F-florbetapir within 6 weeks of their baseline visit. Rhode Island Hospital Clinical Research Center, Providence, USA. CN older adults (n = 63), with a family history of AD and subjective memory complaints were enrolled (15 were classified as Aβ+ and 48 were classified as Aβ−). Cognition was assessed using the computerized GMLT at all predose and post-dose time points. At 5-hours post dose, the Aβ+ group performed significantly worse than the Aβ− group on all measures of learning efficiency and working memory and/or executive function (Cohen's d = 1.13–1.56). When participants were classified as having an abnormal response to scopolamine (based on change score at 5-hours post dose >0), 100% were correctly classified as Aβ+ and 67% as Aβ−. The results of this study suggest that diminished cholinergic tone likely occurs in preclinical AD, and as such, the use of a cholinergic stress test to perturb an already compromised neurotransmitter system may be an effective way of identifying CN older adults who are in this preclinical stage of AD.