Abstract for presentation at 11th International Congress of Human Genetics

Alzheimer's disease (AD) is characterized by decreased cerebral glucose utilization. Rosiglitazone (RSG), a PPARg agonist, is an insulin-sensitizing agent that promotes more efficient use of endogenous insulin. APOE4, which confers an increased risk and younger age-of-onset of AD, is also associated with lowered cerebral glucose metabolism in younger, unaffected subjects. We investigated whether RSG would provide clinical improvement as a function of APOE4 status in 511 AD patients receiving placebo or RSG 2, 4 or 8 mg. Primary endpoints were mean change from baseline to Week 24 in ADAS-Cog and CIBIC-Plus global scores. No statistically significant differences between placebo and RSG were detected in the overall ITT population. Samples from 323 patients were obtained for genotyping. Using the prospectively designated biomarker of APOE4 status, patients were segregated to examine therapeutic response. There was significant interaction between APOE4 allele status and ADAS-Cog (P=0.014). Further exploratory analyses demonstrated significant improvement in ADAS-Cog in APOE4-negative patients on 8 mg RSG (P=0.024; not corrected for multiple comparisons). APOE4-positive patients did not show improvement and showed a decline at the lowest dose (P=0.012; not corrected for multiple comparisons). These preliminary findings require confirmation in appropriate clinical studies. Experimental evidence supports a direct role of PPARg agonists on mitochondrial metabolism and dynamics. These pharmacogenetic data fit with a hypothesis that apoE4 protein and its C-terminal degradation fragment have a greater inhibitory effect of mitochondrial dysfunction than observed with apoE3. RSG may be increasing the efficiency and number of brain mitochondria, thereby increasing glucose utilization and improving cognition in AD patients. The possible lack of benefit in APOE4-positive AD patients may be due to sustained excessive mitochondrial toxicity.