Bioenergetic failure is a feature of Alzheimer’s disease (AD). We examined mitochondrial function in the amyloidprotein precursor transgenic ‘TgCRND8’mouse model of AD. Activities of NADH: cytochrome c reductase (complex I+ III) and cytochrome oxidase (complex IV) of the electron transport chain, as well as those of-ketoglutarate dehydrogenase (-KGDH) and pyruvate dehydrogenase (PDH) were assessed in brains of 45 week-old mice. Complex I+ III activity was reduced by almost 50%, whereas complex IV,-KGDH, and PDH activities were unaffected. Reduced activity coincided with decreased expression of NDUFB8, a nuclear-DNA encoded subunit integral to the assembly of complex I. The composition and availability of cardiolipin, a major phospholipid in inner mitochondrial membranes, was not altered. To determine whether mitochondrial output is affected by the selective reduction in complex I+ III activity, we examined tissue levels of high-energy phosphates. ATP was maintained whereas creatine increased in the cortex and hippocampus. These results suggest disruption of complex I function and the likely role of creatine in sustaining ATP at late stages of dysfunction in TgCRND8 mice.