Pharmacogenetics in drug development: Alzheimer's Disease
Apolipoprotein E4 is associated with lowering the age of onset distribution of common, late-onset Alzheimer ’s disease [AD]. We initially studied the role of apoE4 in brain metabolism using APOE knock-out and humanized APOE-transgenic mice to determine which metabolic pathways were affected in brain. We found that enzymes involved in glucose utilization, particularly those involved in the Krebs cycle and those enzymes constituted by using mitochondria coded sub-units were either over- or under-expressed in proteomic experiments with APOE knock-out mice. Using glucose-stimulated thermogenesis we confirmed that brain homogenates of APOE KO and APOE4 transgenic mice had a decreased glucose utilization that could be stimulated by PPAR gamma agonists in a dose-dependent manner. The emergence of positron emission tomography data demonstrating that patients with AD had decreased brain-region-specific glucose utilization and that this same distribution was observed in normal APOE4 carriers decades before the age of onset of AD provided the impetus for studying PPARgamma agonists. Rosiglitazone was approved for the treatment of type 2 diabetes mellitus in 1999 and is now widely prescribed. Because of its well established safety profile, clinical trials were initiated. In a 24 week Phase IIB monotherapy trial of 511 patients, there was no demonstrated effect of rosiglitazone on the ADAS-cog or other clinical measures of cognitive improvement in mild to moderate AD patients. However, when these patient data were stratified by patients carrying one or two APOE4 alleles versus patients carrying no APOE4 allele, there was significant improvement in the cognitive scores in the patients who carried no APOE4 allele in all three doses tested. A possible dose effect was also observed in carriers of APOE4, with the lowest dose deteriorating and some positive effect at the higher doses, although not to the level of improvement observed in APOE4 non-carriers. Thus, what would have been a negative clinical trial became a Phase III registration program based on the inheritance of a confirmed susceptibility biomarker.