Deleterious Effect of Butyrylcholinesterase K-Variant in Donepezil Treatment of Mild Cognitive Impairment

Article type: Research Article

Authors: Sokolow, Sophie^{a; b; *} | Li, Xiaohui^{c; d} | Chen, Lucia^a | Taylor, Kent D.^{c; d} | Rotter, Jerome I.^{c; d} | Rissman, Robert A.^{e; f} | Aisen, Paul S.^g | Apostolova, Liana G.^h

Affiliations: [a] School of Nursing, University of California at Los Angeles, Los Angeles, CA, USA | [b] Brain Research Institute, University of California at Los Angeles, Los Angeles, CA, USA | [c] Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA | [d] Division of Genomic Outcomes, Departments of Pediatrics and Medicine, Harbor-UCLA Medical Center, Torrance, CA, USA | [e] Alzheimer’s Disease Cooperative Study, University of California San Diego, San Diego, CA, USA | [f] Department of Neuroscience, School of Medicine at UCSD, University of California San Diego, San Diego, CA, USA | [g] Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, CA, USA | [h] Indiana University School of Medicine, Indiana Alzheimer’s Disease Center, Indianapolis, IN, USA

Correspondence: [*] Correspondence to: Sophie Sokolow, MPharm, PhD, UCLA School of Nursing, 700 Tiverton Avenue, Factor Bldg 5-238, Los Angeles, CA 90095-6919, USA. E-mail: [email protected].

Abstract: Background: Donepezil is an acetylcholinesterase inhibitor frequently prescribed for the treatment of mild cognitive impairment (MCI) though not approved by the Food and Drug Administration for this indication. In Alzheimer’s disease, butyrylcholinesterase (BChE) activity increases with disease progression and may replace acetylcholinesterase function. The most frequent polymorphism of BChE is the K-variant, which is associated with lower acetylcholine-hydrolyzing activity. BChE-K polymorphism has been studied in Alzheimer’s disease progression and donepezil therapy, and has led to contradictory results. Objectives: To determine whether BChE-K genotype predicts response to donepezil in MCI. Methods: We examined the association between BChE-K genotype and changes in cognitive function using the data collected during the ADCS vitamin E/donepezil clinical trial in MCI. Results: We found significant interactions between BChE-K genotype and the duration of donepezil treatment, with increased changes in MMSE and CDR-SB scores compared to the common allele in MCI subjects treated during the 3-year trial. We found faster MMSE decline and CDR-SB rise in BChE-K homozygous individuals treated with donepezil compared to the untreated. We observed similar interactions between BChE-K genotype and steeper changes in MMSE and CDR-SB scores in APOE4 carriers treated with donepezil compared to controls. Conclusion: BChE-K polymorphisms are associated with deleterious changes in cognitive decline in MCI patients treated with donepezil for 3 years. This indicates that BChE-K genotyping should be performed to help identify subsets of subjects at risk for donepezil therapy, like those carrying APOE4. BChE-K and APOE4 carriers should not be prescribed off-label donepezil therapy for MCI management.

Keywords: Alzheimer’s disease, butyrylcholinesterase, clinical trial, donepezil, mild cognitive impairment, pharmacogenetics, therapeutics

DOI: 10.3233/JAD-160562

Journal: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 229-237, 2017