The study set out to determine (a) whether DNA damage is elevated in mice that carry mutations in the amyloid precursor protein (APP695swe) and presenilin 1 (PSEN1-dE9) that predispose to Alzheimer’s disease (AD) relative to non-transgenic control mice, and (b) whether increasing the intake of dietary polyphenols from curcumin or grape seed extract could reduce genomic instability events in a transgenic mouse model for AD. DNA damage was measured using the micronucleus (MN) assay in both buccal mucosa and erythrocytes and an absolute telomere length assay for both buccal mucosa and olfactory bulb tissue. MN frequency tended to be higher in AD mice in both buccal mucosa (1.7-fold) and polychromatic erythrocytes (1.3-fold) relative to controls. Telomere length was significantly reduced by 91% (p = 0.04) and non-significantly reduced by 50% in buccal mucosa and olfactory bulbs respectively in AD mice relative to controls. A significant 10-fold decrease in buccal MN frequency (p = 0.01) was found for AD mice fed diets containing curcumin (CUR) or micro-encapsulated grape seed extract (MGSE) and a 7-fold decrease (p = 0.02) for AD mice fed unencapsulated grape seed extract (GSE) compared to the AD group on control diet. Similarly, in polychromatic erythrocytes a significant reduction in MN frequency was found for the MGSE cohort (65.3%) (p < 0.05), whereas the AD CUR and AD GSE groups were non-significantly reduced by 39.2 and 34.8% respectively compared to the AD Control. A non-significant 2-fold increase in buccal cell telomere length was evident for the CUR, GSE and MGSE groups compared to the AD control group. Olfactory bulb telomere length was found to be non-significantly 2-fold longer in mice fed on the CUR diet compared to controls. These results suggest potential protective effects of polyphenols against genomic instability events in different somatic tissues of a transgenic mouse model for AD.