The purpose of this study was to examine the antioxidant, anti-inflammatory and anti-amyloidogenic properties of dietary curcumin, and its metabolite tetrahydrocurcumin (TC). Curcumin was administered chronically to aged Tg2576 mice, or acutely LPS treated wild type mice. Despite dramatically higher drug plasma levels after TC dosing, compared with curcumin gavage, the resulting brain levels of the two compounds were similar. Treatment with either drug or TC resulted in a reduction in LPS-stimulated inducible nitric-oxide synthase, nitro tyrosine, F2 isoprostanes, and carbonyls. In both the acute (LPS) and chronic inflammation model (Tg2576), TC and curcumin similarly reduced interleukin-1β. Both drugs reduced Tris-buffered saline soluble Aβ and phospho-c-Jun NH2-terminal kinase (JNK). However, despite these similarities, only curcumin was effective in reducing amyloid plaque burden, insoluble β-amyloid peptide (Aβ). These data indicate that the dienone bridge present in curcumin, but not in TC, is necessary to reduce plaque deposition and protein oxidation in an Alzheimer’s model.