THE TRNA(GLN)-4336 MITOCHONDRIAL-DNA VARIANT IS NOT A HIGH PENETRANCEMUTATION WHICH PREDISPOSES TO DEMENTIA BEFORE THE AGE OF 75 YEARS

The genetic factors that predispose to Alzheimer's disease (AD) are he terogeneous. Two recent reports have suggested that a mitochondrial DN A mutation within the tRNA(Gln) gene, located at position 4336, may be a risk factor for AD, as it was found in 10/256 (3.9%) cases with AD confirmed by necropsy. Although low prevalences of this mutation were detected in non-demented subjects in both of these studies, the contro ls were not carefully matched with the AD cases. We have investigated the frequency of this mutation in two community based elderly cohorts in Cambridgeshire, who have participated in longitudinal studies of co gnitive function. The 4336 mitochondrial mutation was detected in 8/44 3 people examined. These people were found to be non-demented at ages 74, 81, 84, 86, 89, 90, 91, and 102 years, in contrast to the previous ly described cases whose onset of dementia occurred between 60 and 76 years (mean 68). Accordingly, we believe that this mitochondrial varia nt is not a high penetrance mutation which predisposes to dementia bef ore the age of 76 years.