Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease.

Mounting evidence suggests that defects in energy metabolism contribute to the pathogenesis of Alzheimer disease (AD). Cytochrome c oxidase (CO) is kinetically abnormal, and its activity is decreased in brain and peripheral tissue in late-onset AD. CO is encoded by both the mitochondrial and the nuclear genomes. Its catalytic centers, however, are encoded exclusively by two mitochondrial genes, CO1 and CO2 (encoding CO subunits I and II, respectively). We searched these genes, as well as other mitochondrial genes, for mutations that might alter CO activity and cosegregate with AD. In the present study, specific missense mutations in the mitochondrial CO1 and CO2 genes but not the CO3 gene were found to segregate at a higher frequency with AD compared with other neurodegenerative or metabolic diseases. These mutations appear together in the same mitochondrial DNA molecule and define a unique mutant mitochondrial genome. Asymptomatic offspring of AD mothers had higher levels of these mutations than offspring of AD fathers, suggesting that these mutations can be maternally inherited. Cell lines expressing these mutant mitochondrial DNA molecules exhibited a specific decrease in CO activity and increased production of reactive oxygen species. We suggest that specific point mutations in the CO1 and CO2 genes cause the CO defect in AD. A CO defect may represent a primary etiologic event, directly participating in a cascade of events that results in AD.