In this study, we investigated the effects of long-term (9-month) treatment with pioglitazone (PIO; 20 mg/kg/d) in two animal models of Alzheimer's disease (AD)-related neural dysfunction and pathology: the PS1-KI(M146V) (human presenilin-1 (M146V) knock-in mouse) and 3xTg-AD (triple transgenic mouse carrying AD-linked mutations) mice. We also investigated the effects on wild-type (WT) mice. Mice were monitored for body mass changes, fasting glycemia, glucose tolerance, and studied for changes in brain mitochondrial enzyme activity (complexes I and IV) as well as energy metabolism (lactate dehydrogenase (LDH)). Cognitive effects were investigated with the Morris water maze (MWM) test and the object recognition task (ORT). Behavioral analysis revealed that PIO treatment promoted positive cognitive effects in PS1-KI female mice. These effects were associated with normalization of peripheral gluco-regulatory abnormalities that were found in untreated PS1-KI females. PIO-treated PS1-KI females also showed no statistically significant alterations in brain mitochondrial enzyme activity but significantly increased reverse LDH activity.PIO treatment produced no effects on cognition, glucose metabolism, or mitochondrial functioning in 3xTg-AD mice. Finally, PIO treatment promoted enhanced short-term memory performance in WT male mice, a group that did not show deregulation of glucose metabolism but that showed decreased activity of complex I in hippocampal and cortical mitochondria. Overall, these results indicate metabolically driven cognitive-enhancing effects of PIO that are differentially gender-related among specific genotypes.