Abstract Food combinations have been associated with lower incidence of Alzheimer's disease. We hypothesized that a combination whole-food diet containing freeze-dried fish, vegetables, and fruits would improve cognitive function in TgCRND8 mice by modulating brain insulin signaling and neuroinflammation. Cognitive function was assessed by a comprehensive battery of tasks adapted to the Morris water maze. Unexpectedly, a “Diet × Transgene” interaction was observed in which transgenic animals fed the whole-food diet exhibited even worse cognitive function than their transgenic counterparts fed the control diet on tests of spatial memory (p < 0.01) and strategic rule learning (p = 0.034). These behavioral deficits coincided with higher hippocampal gene expression of tumor necrosis factor-α (p = 0.013). There were no differences in cortical amyloid-β peptide species according to diet. These results indicate that a dietary profile identified from epidemiologic studies exacerbated cognitive dysfunction and neuroinflammation in a mouse model of familial Alzheimer's disease. We suggest that normally adaptive cellular responses to dietary phytochemicals were impaired by amyloid-beta deposition leading to increased oxidative stress, neuroinflammation, and behavioral deficits.