Butyrylcholinesterase K and Apolipoprotein E-ɛ4 Reduce the Age of Onset of Alzheimer’s Disease, Accelerate Cognitive Decline, and Modulate Donepezil Response in Mild Cognitively Impaired Subjects
Affiliations: [a]
Douglas Mental Health University Institute, McGill University, Verdun, Montreal, Canada
| [b] Center for Studies in the Prevention of Alzheimer’s Disease, McGill University, Verdun, Montreal, Canada
Correspondence:
[*]
Correspondence to: Dr. Judes Poirier, C.Q., Director, Research Program on Aging, Cognition and Alzheimer’s Disease, Douglas Mental Health University Institute, 6875 Lasalle, Verdun, Quebec H4H 1R3, Canada. Tel.: +1 514 761 6131; Ext. 6153; Fax: +1 514 888 4094; E-mail: [email protected].
Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Cooperative Study (ADCS) database. As such, the investigators within the ADCS contributed to the design and implementation of ADCS and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADCS investigators can be found at: http://www.adcs.org/Resource/studyResources.aspx
Abstract: Background: Genetic heterogeneity in amnestic mild cognitively impaired (aMCI) subjects could lead to variations in progression rates and response to cholinomimetic agents. Together with the apolipoprotein E4 (APOE-ɛ4) gene, butyrylcholinesterase (BCHE) has become recently one of the few Alzheimer’s disease (AD) susceptibility genes with distinct pharmacogenomic properties. Objective: To validate candidate genes (APOE/BCHE) which display associations with age of onset of AD and donepezil efficacy in aMCI subjects. Methods: Using the Petersen et al. (2005) study on vitamin E and donepezil efficacy in aMCI, we contrasted the effects of BCHE and APOE variants on donepezil drug response using the Alzheimer’s Disease Assessment Score-Cognition (ADAS-Cog) scale. Independently, we assessed the effects of APOE/BCHE genotypes on age of onset and cortical choline acetyltransferase activity in autopsy-confirmed AD and age-matched control subjects. Results: Statistical analyses revealed a significant earlier age of onset in AD for APOE-ɛ4, BCHE-K*, and APOE-ɛ4/BCHE-K* carriers. Among the carriers of APOE-ɛ4 and BCHE-K*, the benefit of donepezil was evident at the end of the three-year follow-up. The responder’s pharmacogenomic profile is consistent with reduced brain cholinergic activity measured in APOE-ɛ4 and BCHE-K* positive subjects. Conclusions: APOE-ɛ4 and BCHE-K* positive subjects display an earlier age of onset of AD, an accelerated cognitive decline and a greater cognitive benefits to donepezil therapy. These results clearly emphasize the necessity of monitoring potential pharmacogenomic effects in this population of subjects, and suggest enrichment strategies for secondary prevention trials involving prodromal AD subjects.
