Treatment outcome of tacrine therapy depends on apolipoprotein genotype and gender of the subjects with Alzheimer's disease

We studied the effects of apolipoprotein E (APOE) genotype and gender on clinical response to tacrine inpatients with mild to moderate Alzheimer's disease (AD). We analyzed data from a previously reported 30-week, double-blind, placebo-controlled trial of tacrine, in which APOE genotypes were determined from previously collected plasma samples. Patients were assigned to placebo or tacrine with daily dosages of 80, 120, or 160 mg/day. The outcome measures were Alzheimer's Disease Assessment Scale-Cognitive Component, Clinician Interview Based Impression, Mini-Mental State Examination, and the Caregiver-rated Clinical Global Impression of Change. An intent-to-treat (ITT) analysis of patients with available genotypes (n = 528) did not reveal response differences by genotype, although the effect size was twice as large in the epsilon 2-3 as the epsilon 4 group (-2.62 versus -1.25). The association of treatment effect with APOE genotype varied significantly according to gender (p < 0.002 for ITT; p < 0.05 for evaluables). The treatment effect was larger in the epsilon 2-3 compared with epsilon 4 women (ITT, 4.24 points, p = 0.03; evaluable, 7.20 points, p = 0.01). In contrast, treatment effect size was not different between epsilon 2-3 and epsilon 4 of men with AD. APOE genotype and gender may predict response to tacrine in patients with AD.