Cholinesterase inhibitors in Alzheimer's disease and Lewy body spectrum disorders: the emerging pharmacogenetic story

Abstract

This review provides an update on the current state of pharmacogenetic research in the treatment of Alzheimer's disease (AD) and Lewy body disease (LBD) as it pertains to the use of cholinesterase inhibitors (ChEI). AD and LBD are first reviewed from clinical and pathophysiological perspectives. This is followed by a discussion of ChEIs used in the symptomatic treatment of these conditions, focusing on their unique and overlapping pharmacokinetic and pharmacodynamic profiles, which can be used to identify candidate genes for pharmacogenetics studies. The literature published to date is then reviewed and limitations are discussed. This is followed by a discussion of potential endophenotypes which may help to refine future pharmacogenetic studies of response and adverse effects to ChEIs.

Figure 1

Hypothetical genotype-phenotype correlations in response to cholinesterase inhibitor (ChEI) X in Alzheimer's disease. The CYP2D6 enzyme is the major metaboliser in the pharmacokinetics of ChEI X, while acetylcholinesterase is the main pharmacodynamic target. (A) Polymorphisms in CYP2D6 and acetylcholinesterase are weakly associated with response and adverse effects to drug X because there are many unknown steps linking the genotype to the phenotype. (B) Polymorphisms in CYP2D6 and acetylcholinesterase are strongly associated with endophenotypes, which are more closely linked to the drug response and adverse effect phenotype. The endophenotypes illustrated include: drug X-to-metabolite X ratio, which provides an index of CYP2D6 activity and varies depending on which CYP2D6 genotype/allele is possessed; and a single photon emission computed tomography (SPECT) scan showing reduced perfusion in biparietal areas (red arrows), which hypothetically improves after treatment with drug X, depending on which genotype/allele is present. Orange colours on SPECT indicate higher perfusion, while purple/blue colours indicate reduced perfusion. Abbreviations: PK = pharmacokinetic; PD = pharmacodynamic.