Moderation of Amyloid-β Deposition on the Effect of Cholinesterase Inhibitors on Cognition in Mild Cognitive Impairment

Abstract

Background: Clinical trial findings on cholinesterase inhibitors (ChEIs) for mild cognitive impairment (MCI) are inconclusive, offering limited support for their MCI treatment. Given that nearly half of amnestic MCI cases lack cerebral amyloid-β (Aβ) deposition, a hallmark of Alzheimer’s disease; this Aβ heterogeneity may explain inconsistent results. Objective: This study aimed to assess whether Aβ deposition moderates ChEI effects on amnestic MCI cognition. Methods: We examined 118 individuals with amnestic MCI (ages 55–90) in a longitudinal cohort study. Baseline and 2-year follow-up assessments included clinical evaluations, neuropsychological testing, and multimodal neuroimaging. Generalized linear models were primarily analyzed to test amyloid positivity’s moderation of ChEI effects on cognitive change over 2 years. Cognitive outcomes included Mini-Mental Status Examination score, the total score of the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery, and Clinical Dementia Rating-sum of boxes. Results: The analysis found no significant ChEI use x amyloid positivity interaction for all cognitive outcomes. ChEI use, irrespective of Aβ status, was associated with more cognitive decline over the 2-year period. Conclusions: Aβ pathology does not appear to moderate ChEI effects on cognitive decline in MCI.