ACETYLCHOLINESTERASE INHIBITOR THERAPY IN MILD COGNITIVE IMPAIRMENT: YES OR NO?

Abstract

Acetylcholinesterase inhibitors (AChEI) are frequently prescribed for the symptomatic treatment of mild cognitive impairment (MCI) though not approved by the Food and Drug Administration for this indication. AChEIs use, genetic, biological and neurological outcomes data were collected during the three phases of the Alzheimer Disease Neuroimaging Initiative (ADNI1, ADNIGO, ADNI2). Linear regression models were used to compare the treatment effect - on changes in MMSE and CDR-SB scores during a time course of 2 years. MCI subjects treated with AChEIs showed a greater decline in MMSE and a greater rise in CDR-SB after 2-year compared to non-treated ones. Examining the data further, we found a significant association between treatment duration and AChEIs on MMSE decline in the treated group. A similar association between duration of therapy and increased CDR-SB was observed. Our findings thus indicate a faster decline in MMSE and faster rise CDR-SB scores in subjects treated with AChEIs compared to the untreated group. We then stratified by APOE4 genotypes and found a trend for steeper cognitive changes in treated APOE4 carriers compared to treated non-carriers. In a sub-group of MCI treated subjects, we also found that cerebrospinal fluid AD biomarkers (i.e. amyloid-beta and p-tau) were significantly different at baseline compared to the non-treated MCIs. This indicates that the worsening in cognitive decline observed in the treatment group may not be only associated with the use of AChEIs but also due to the natural history of the disease progression. Our findings have an important implication for MCI management. Thus, it opens up the discussion of the off-label use of AChEIs in MCI and the evaluation of the risks versus the benefits of such treatment approach if there is no alternative to AChEIs.