Defects in mitochondrial oxidative phosphorylation have frequently been associated with
Alzheimer's disease (AD), and both inherited and somatic
mtDNA mutations have been reported in certain AD cases. To determine whether
mtDNA mutations contribute more generally to the etiology of AD, we have investigated the sequence of the
mtDNA control region (CR) from AD brains for possible disease-causing mutations. Sixty-five percent of the AD brains harbored the T414G mutation, whereas this mutation was absent from all controls. Moreover, cloning and sequencing of the
mtDNA CR from patient and control brains revealed that all AD brains had an average 63% increase in heteroplasmic
mtDNA CR mutations and that AD brains from patients 80 years and older had
a 130% increase in heteroplasmic CR mutations. In addition, these mutations preferentially altered known
mtDNA regulatory elements. Certain AD brains harbored the disease-specific CR mutations T414C and T477C, and several AD brains between 74 and 83 years of age harbored the CR mutations T477C, T146C, and T195C, at levels up to 70-80% heteroplasmy. AD patient brains also had an average 50% reduction in the
mtDNA L-strand ND6 transcript and in the
mtDNA/nuclear
DNA ratio. Because reduced ND6
mRNA and
mtDNA copy numbers would reduce brain oxidative phosphorylation, these CR mutations could account for some of the
mitochondrial defects observed in AD.