M Mullan

Genetics of Alzheimer's disease

The discovery of pathogenic mutations in the amyloid precursor protein gene in families with Alzheimers disease is a major advance in the understanding of the pathogenesis of Alzheimers disease. In certain families at least, beta-amyloid metabolism plays a central role in the disease process. It is tempting to speculate that beta-amyloid is common to the majority of Alzheimer cases. In the immediate future the discovery of the mutations responsible for the condition in those families that show linkage to chromosomes 14 and 19 will enable it to be established whether beta-amyloid is involved in these pedigrees as well. If amyloid metabolism is involved in APP and chromosomes 14 and 19 families, it suggests that Alzheimers disease is a single disease with a common metabolic pathway. However, if other mechanisms are implicated, evidence is provided that Alzheimers disease is a heterogeneous disorder that shares common clinicopathological features.

Clinical and Pathologic Features of Chromosome 21-Linked Familial Alzheimer's Disease

Many pedigrees have been described in which histologically proven Alzheimers disease (AD) is apparently inherited as an autosomal dominant disorder (Nee et al. 1983). Genetic analysis in such pedigrees indicates that some cases of early onset AD are linked to markers on chromosome 21 (St. George-Hyslop et al. 1987; Goate et al. 1989). However, the absence of proven linkage to chromosome 21 in families with late onset AD and in a group of families of Volga German origin suggests a genetic heterogeneity (Schellenberg et al. 1988). This possible genetic heterogeneity has not allowed us to ascribe a specific genetic etiology to any family with defined clinical or pathologic features. In this study, genetic data that demonstrate linkage in a single family between markers on chromosome 21 and AD are presented together with clinical features and neuropathologic findings in one case.