This study investigated effects of rosiglitazone (RTZ) on cognitive impairment and peripheral gluco-regulatory status in Tg2576 mice. In recent years, epidemiological studies suggest that there is a link between peripheral gluco-regulatory abnormalities and AD. Patients who suffer from severe peripheral insulin resistance and hyperinsulinemia experienced in type 2 diabetes mellitus (T2DM), have an approximately 65% increased risk of developing AD. Given the converging evidence associating peripheral glucoregulatory abnormalities and cognitive function in AD, insulin-sensitizing drugs have been proposed as a possible treatment for AD. RTZ is a member of the class of insulin-sensitizing drugs called thiazolidinediones. RTZ increases insulin sensitivity by functioning as a ligand to activate the nuclear receptor PPARγ. This study assessed cognition and peripheral gluco-regulatory status of Tg2576 mice following one-month treatment with RTZ initiated prior to, coincident with, or after, the onset of peripheral gluco-regulatory abnormalities (4, 8, and 12-months of age, respectively). Whereas 5-months-old (MO) and 13 MO Tg2576 did not gain cognitive improvement after one-month treatment with RTZ, 9 MO Tg2576 mice exhibited reversal of associative learning and memory deficits. Peripheral gluco-regulatory abnormalities were improved in 9 and 13 MO Tg2576 with RTZ treatment; RTZ treatment had no effect on the normal glucose status of 5 MO Tg2576 mice. These findings suggest that RTZ-mediated cognitive improvement does not correlate with peripheral glucoregulatory abnormalities per se, but reflects the age-dependent mechanistic differences that underlie cognitive decline in this mouse model.