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

Abstract

We studied the effects of apolipoprotein E (APOE) genotype and gender on clinical response to tacrine in patients 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 epsilon2-3 as the epsilon4 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 epsilon2-3 compared with epsilon4 women (ITT, 4.24 points, p = 0.03; evaluable, 7.20 points, p = 0.01). In contrast, treatment effect size was not different between epsilon2-3 and epsilon4 of men with AD. APOE genotype and gender may predict response to tacrine in patients with AD.

Differential qualitative responses to rivastigmine in APOE ɛ4 carriers and noncarriers

“…In one study of another cholinesterase inhibitor (galantamine), placebo-treated carriers and noncarriers showed similar cognitive decline over 6 months, 14 while in another similar study carriers showed greater deterioration than noncarriers. 15 A tacrine study that demonstrated less cognitive decline in APOE e4 carriers than in noncarriers, especially in women, over 30 weeks, 16 was consistent with the current 6-month rivastigmine study which shows a tendency for noncarriers taking placebo to have a greater cognitive decline than carriers. The source of these disparate results is not known.…”

Effect of apolipoprotein E and butyrylcholinesterase genotypes on cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer's disease

“…20 Other reports in the literature have not found APOE e4 genotype to influence cognitive response to ChEI therapy. 15,23,24,26,28 Explanations for these inconsistent findings include aspects of study design, such as small sample size, single versus multiple drug dosing, lack of randomization, variable outcome measures used, variable follow-up periods and variable definitions of response to ChEI treatment; pharmacokinetic and pharmacodynamic characteristics of the different ChEIs used; and genetic heterogeneity in the trial populations. Earlier work had suggested that the greater cholinergic deficit 11 and rate of cognitive decline 12 associated with the carriage of APOE e4 might result in a poorer response to ChEI treatment.…”

“…Initial reports suggested a better response to tacrine in individuals who were noncarriers of APOE e4, 11,14 particularly in women. 15 However, other researchers have reported that the presence of APOE e4 is associated with improved outcome with ChEI therapy. [16][17][18][19][20] Several studies did not find that APOE genotype influenced treatment response.…”

Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer's disease and geriatric depression

“…These and other concerns about study design of cholinesterase inhibitors have been pointed out by van Gool 108 and Bayer. 109 Interestingly, Farlow et al 110 reported that the treatment outcome of tacrine depends on the apolipoprotein genotype and gender of the subjects with AD. And even the Thal et al 101 study found that ALCAR was more beneficial in a subgroup of patients.…”