Liu_2025_Alzheimers.Dement_21_e70193

INTRODUCTION: This study examines whether cholinesterase inhibitors (ChEIs) influence the progression to Alzheimer's disease (AD) dementia and cognitive trajectories in amnestic mild cognitive impairment (MCI) patients, considering their amyloid beta (Abeta) status. METHODS: Kaplan-Meier and time-varying Cox models evaluated ChEI use and different Abeta status on MCI-to-AD progression. Linear mixed-effects models assessed cognitive trajectories. Locally estimated scatterplot smoothing regression analyzed cognitive changes before and after ChEI initiation. RESULTS: Among 558 amnestic MCI participants (168 ChEI users), ChEI users exhibited higher risk of progression to AD dementia (hazard ratio = 1.77, 95% confidence interval: 1.15 to 2.73, p = 0.001). Both ChEI use and Abeta burden independently accelerated MCI progression and cognitive decline. Cognitive trajectories demonstrated decline before ChEI initiation and continued to decline after treatment began. DISCUSSION: The association between ChEI treatment and accelerated progression to AD dementia and cognitive decline, independent of Abeta status, emphasized the need to reconsider optimal timing for ChEI initiation in MCI. HIGHLIGHTS: ChEI use in MCI was associated with increased risk of progression to AD dementia. ChEI use in MCI was associated with accelerated longitudinal cognitive decline. Cognitive decline persisted after ChEI initiation rather than reversing. ChEI effects on MCI progression to AD dementia were independent of Abeta status.