CHROMOSOMAL FRAGILITY ASSOCIATED WITH FAMILIAL ALZHEIMERS-DISEASE

To test whether chromosomal instability is associated with familial Al zheimer's disease, we examined breakage on X chromosomes of fibroblast s derived from patients with familial Alzheimer's disease, using gene cotransfer methodology. The X chromosome is a convenient target for an alyzing DNA breakage because of its numerous markers and ease of selec tion in rodent-human hybrid cells. Patients with familial Alzheimer's disease, including the large Nova Scotia Alzheimer's kindred, show a s ignificantly lower cotransfer of the X-linked glucose-6-phosphate dehy drogenase (G6PD) gene with the selected HPRT gene in hybrid cells, ind icating breakage between the markers, Lower cotransfer of the more dis tant X-linked gene, MIC-2, was statistically significant in this kindr ed, but not in other patients with familial Alzheimer's disease. The d istance between MIC2 and HPRT is sixfold to ninefold greater than that between HPRT and G6PD, suggesting that there may be a ''hot spot'' fo r breakage in the latter interval on the X chromosome of patients with familial Alzheimer's disease. The somatic sell hybrid model provides insights into underlying mechanisms for chromosomal breakage induced b y the Alzheimer defect. A hypothesis implicating a candidate gene, C-1 -THF synthase, in the generation of chromosome instability in the path ogenesis of familial Alzheimer's disease, is presented.