Failure of familial Alzheimer's disease to segregate with the A4-amyloid gene in several European families

Abstract

The gene coding for the amyloid protein, a component of neuritic plaques found in brain tissue from patients with Alzheimer's disease, has been localized to chromosome 21, and neighbouring polymorphic DNA markers segregate with Alzheimer's disease in several large families. These data, and the association of Alzheimer's disease with Down's syndrome, suggest that overproduction of the amyloid protein, or production of an abnormal variant of the protein, may be the underlying pathological change causing Alzheimer's disease. We have identified a restriction fragment length polymorphism of the A4-amyloid gene, and find recombinants in two Alzheimer's disease families between Alzheimer's disease and the A4-amyloid locus. This demonstrates that the gene for plaque core A4-amyloid cannot be the locus of a defect causing Alzheimer's disease in these families. These data indicate that alterations in the plaque core amyloid gene cannot explain the molecular pathology for all cases of Alzheimer's disease.

Alzheimer's Disease

“…More over, four families with well-documented familial AD have been s�died by genetic linkage analysis, and an alteration has been found in t he region 2Iql1.2-21q22.2. This is the same general location as that mapped for the amyloid gene, although the two regions are not identical (130,137).…”

Genetic dissection of Alzheimer disease, a heterogeneous disorder.

“…Identification of the chromosome 14 locus permitted reevaluation of the hypothesis that there is an FAD gene on chromosome 21, distinct from the APP locus (19,21,22,78 (88). The clinical features characteristic of AD in these families include prominent seizures, myoclonus, and paratonia, which have been observed in many of the sub- jects from different families (81,83,87,88).…”

Polymorphic DNA markers and mental disease

“…However, evidence that this is not the case has come from two studies in which the A4 locus was only weakly linked to the disease. Moreover, in several families, there was recombination between the A4 gene and AD (Van Broeckhoven et al 1987;. These findings suggest that the disease locus is on the neighbouring portion of chromosome 21.…”