Proc. Natl. Acad. Sci. USA
Vol. 94, pp. 4526-4531, April 1997

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

Robert E. Davis, Scott Miller, Corinna Herrnstadt, Soumitra S. Ghosh,
Eoin Fahy, Leslie A. Shinobu, Douglas Galasko, Leon J. Thal,
M. Flint Beal, Neil Howell, and W. Davis Parker Jr.

MitoKor, 11494 Sorrento Valley Road, San Diego, CA 92121;  Department of
Neurosciences, University of California at San Diego, La Jolla, CA 92161;
 Department of Neurology, San Diego Veterans Affairs Medical Center, San
Diego, CA 92161;  Department of Neurology, Massachusetts General
Hospital, Boston, MA 02114; Biology Division, University of Texas
Medical Branch, Galveston, TX 77550; and  Department of Neurology and
Pediatrics, School of Medicine, University of Virginia, Charlottesville, VA

Communicated by Pedro M. Cuatrecasas, Warner-Lambert Company, Ann Arbor, MI,
February 20, 1997 (received for review November 6, 1996)

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.