Segregation of a missense mutation in the amyloid beta-protein precursor gene with familial Alzheimer's disease

Abstract

In 1991 we described a missense mutation in the amyloid beta-protein precursor (AbetaPP) gene in two familial Alzheimer's disease (FAD) kindreds. This gene encodes the amyloid beta peptide deposited in senile plaques in AD. We made four predictions based upon these results: 1. Other FAD kindreds would be identified with AbetaPP mutations; 2. FAD is genetically heterogeneous; 3. Abeta deposition is central to the pathogenesis of AD and 4, Regulatory variants in the AbetaPP gene lead to late onset AD. In the ensuing years substantial evidence has accrued in support of these predictions. Nineteen mutations in the AbetaPP gene have been reported. These mutations have all been shown to alter AbetaPP processing or Abeta fibrillogenesis, leading to early Abeta deposition. Furthermore, mutations in the genes encoding presenilin 1 and presenilin 2, that cause FAD, also lead to changes in AbetaPP processing and Abeta deposition. Together these observations strongly support the hypothesis that Abeta deposition is central to AD pathogenesis. Suprisingly, the fourth prediction, that variation in AbetaPP expression may predispose to late onset AD, has not been rigorously tested, despite the fact that overexpression of AbetaPP is sufficient to cause dementia and AD neuropathology in Down Syndrome.