A MITOCHONDRIAL-DNA CLONE IS ASSOCIATED WITH INCREASED RISK FOR ALZHEIMER-DISEASE

Severe mitochondrial genetic mutations lead to early degeneration of s pecific human tissues; milder mitochondrial mutations may cause degene ration at a later point in life. A mutation at position 4336 was repor ted to occur at increased frequency in individuals with Alzheimer dise ase (AD) and Parkinson disease [Shoffner, J. M., Brown, M. D., Torroni , A, Lott, M. T., Cabell, M. F., Mirra, S. S., Beal, M. F., Yang, C.-C ., Gearing, M., Salvo, R, Watts, R. L., Juncos, J. L., Hansen, L. A., Crain, B. J., Fayad, M., Reckord, C. L. and Wallace, D. C. (1993) Geno mics 17, 171-184]. We have investigated the notion that this mutation leads to excess risk of AD by using a case-control study design of 72 AD autopsies and 296 race- and age-matched controls. The 4336G mutatio n occurred at higher frequency in AD autopsies than age-matched contro ls, a statistically significant difference. Evolutionary analysis of m tDNAs bearing the 4336G mutation indicated they were more closely rela ted to each other than to other mtDNAs, consistent with the model of a single origin for this mutation. The tight evolutionary relatedness a nd homoplasmy of mtDNAs that confer elevated risk for a late-onset dis ease contrast strikingly with the distant relatedness and heteroplasmy of mitochondrial genomes that cause early onset disease. The dichotom y can be explained by a lack of selection against mutations that confe r a phenotppe at advanced age during most of the evolution of humans. We estimate that approximate to 1.5 million Caucasians in the United S tates bear the 4336G mutation and are at significantly increased risk of developing mitochondrial AD in their lifetime. A mechanism for 4336 G-mediated cell death is proposed.