Studies in this laboratory have shown that DNA extracted from the brains of victims of Alzheimer's Disease (AD) exhibit triplication of chromosome 21 at the molecular level near to or within the Down syndrome (DS) location. These results support a unitary genetic hypothesis for AD and DS, explaining the multiple occurrence of AD in some families (familial AD or FAD) by inheritance and its sporadic appearance in others (non-FAD) by de novo formation in somatic cells. The same has been found in the blood of a FAD member diagnosed clinically as having AD. This implies that the chromosome 21 triplication is systemic for FAD and has pre-symptomatic diagnostic potential. Results were obtained using an improved system for quantification of Southern blots. This requires preimaging of a step-wedge gradient on film to provide a control for insuring that the radioactive signals produced by the 'hot' probe attachment lie within the linear range of response of the film. Two probes are simultaneously applied to genomic DNA digests - one control and one from chromosome 21. With this control of exposure, single densitometric tracings of single gel lanes provide accurate area ratios subsumed by the two peaks; these can be meaningfully compared to ratios found for samples in other lanes on the same gel. For chromosome 21, a unique sequence was subcloned from one extreme end of the gene for superoxide dismutase (the closet known to DS); an epsilon-globin subclone from chromosome 16 was used as control. Test with fibroblasts of monosomy, disomy, and trisomy 21 cell lines (chromosomal ratios of 1/2, 2/2, and 3/2) showed the system provided discriminatory capability. Test on coded samples indicated predictive distinction between normal and DS DNA from blood. For AD tests brain samples with autopsy verification were used. Area ratios of chromosome 21 to chromosome 16 hybridization amounts in AD were found to correspond to those of DS, not to those of normal samples run at the same time. We propose to test a wide variety of blood and brain samples. The questions to be addressed are whether triplication is characteristic of AD or occurs in other age-induced dementias; whether it occurs and to what extent in non-FAD; and its potential for presymptomatic diagnosis. Other chromosome 21 clones will be employed to map the extent of triplications found, correlating to AD parameters where possible. Clarification of the relationship of AD and aging in DS could provide insights into both conditions as well as an improved understanding of normal aging processes.
| Schweber, M S (1989) Alzheimer's disease and Down syndrome. Prog Clin Biol Res 317:247-67 |
