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

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