Abstract: The peroxisome proliferator-activated receptor-? (PPAR-\gama) is a ligand-inducible transcription factor that suppresses microglial inflammatory responses and inhibits amyloid beta (A\beta) production through promoting cholesterol efflux from glial cells. PPAR-\gamma agonists have been advanced as a new disease altering approach to Alzheimer's disease (AD), with rosiglitazone therapy having improved cognition in those AD patients that did not possess an Apolipoprotein E (APOE)\uspilon4 allele. The current study was designed to explore the effect of interactions between PPAR-\gamma and APOE gene polymorphisms on the AD risk. We examined genetic variations of PPAR-\gamma by genotyping 7 haplotype tagging SNPs (htSNPs) (rs10510412, rs17793951, rs1801282, rs4135263, rs1151999, rs709149, and rs709154) in a group of 352 Spanish late-onset AD cases and 438 controls. The PPAR-\gamma TCCA haplotype derived from SNPs in introns 4 (rs4135263), 5 (rs1151999), and 6 (rs709149 and rs709154) showed a strong protective effect against AD in APOE \epsilon4 allele noncarriers (p = 0.001, permutation p = 0.006, Bonferroni corrected p = 0.021), with a frequency of 39% in cases and 50% in controls. Our data suggest that PPAR-\gamma genetic variants may modify the risk of AD in an APOE \epsilon4 allele-dependent fashion.

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