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.