Prescribing cholinesterase inhibitors in mild cognitive impairment—Observations from the Alzheimer's Disease Neuroimaging Initiative

INTRODUCTION: Analyses of off‐label use of acetylcholinesterase inhibitors (AChEIs) in mild cognitive impairment (MCI) has produced mixed results. Post hoc analyses of observational cohorts, such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), have reported deleterious effects in AChEI‐treated subjects (AChEI+). Here, we used neuroimaging biomarkers to determine whether AChEI+ subjects had a greater rate of neurodegeneration than untreated (AChEI–) subjects while accounting for baseline differences. METHODS: We selected 121 ADNI MCI AChEI+ subjects and 151 AChEI– subjects with a magnetic resonance imaging (MRI) scan; 82 AChEI+ and 110 AChEI– also had a fluorodeoxyglucose (FDG) scan. A subset (83 AChEI+ and 98 AChEI–) had cerebrospinal fluid (CSF) or amyloid positron emission tomography (PET) assessment for amyloid positivity. Linear regression models were used to compare the effect of treatment on changes in Mini‐Mental State Examination and Clinical Dementia Rating‐Sum of Boxes scores. We used standard regression in SPM (for baseline) and the SPM toolbox sandwich estimator, SwE (for longitudinal) for comparisons of AChEI+ and AChEI– FDG PET and MRI data. RESULTS: At baseline, the AChEI+ group had significantly reduced cortical gray matter density (GMD) and more hypometabolism than AChEI– subjects. The greater rate of atrophy and hypometabolic changes over time in AChEI+ compared to AChEI– subjects did not survive correction for baseline differences. AChEI+ participants were more likely to be amyloid‐positive and have lower GMD and FDG standardized uptake value ratio than AChEI– at baseline. AChEI+ subjects showed greater atrophy over time, which remained significant after controlling for amyloid status. DISCUSSION: Our data suggest that the observed differences in rates of cognitive decline, atrophy, and hypometabolism are likely the result of significant baseline differences between the groups. Furthermore, the data indicate no treatment effect of AChEI (positive of negative), rather that physicians prescribe AChEI to subjects who present with more severe clinical impairment. This alone may account for the negative effect seen previously in the ADNI population of AChEI use among MCI subjects.