To test whether
chromosomal instability is associated with familial
Alzheimer's disease, we examined breakage on X chromosomes of fibroblasts derived from patients with familial
Alzheimer's disease, using gene cotransfer methodology. The X chromosome is a convenient target for analyzing
DNA breakage because of its numerous markers and ease of selection in rodent-human hybrid cells. Patients with familial
Alzheimer's disease, including the large Nova Scotia Alzheimer's kindred, show a significantly lower cotransfer of the X-linked
glucose-6-phosphate dehydrogenase (G6PD) gene with the selected
HPRT gene in hybrid cells, indicating breakage between the markers. Lower cotransfer of the more distant X-linked gene, MIC-2, was statistically significant in this kindred, but not in other patients with familial
Alzheimer's disease. The distance between MIC2 and
HPRT is sixfold to ninefold greater than that between
HPRT and G6PD, suggesting that there may be a "hot spot" for breakage in the latter interval on the X chromosome of patients with familial
Alzheimer's disease. The somatic cell hybrid model provides insights into underlying mechanisms for
chromosomal breakage induced by the Alzheimer defect. A hypothesis implicating a candidate gene,
C1-THF synthase, in the generation of
chromosome instability in the pathogenesis of familial
Alzheimer's disease, is presented.