Functional characterization of amyloid beta precursor protein regulatory elements: rationale for the identification of genetic polymorphism.

Alzheimer's disease (AD) is characterized by the formation of senile plaques of the amyloid peptide (Abeta) derived from a large Abeta precursor protein (APP). Autosomally inherited or "familial" AD has only been previously demonstrated in connection with coding sequence missense mutations. Abnormal regulation of APP gene expression has been demonstrated to play a role in AD. Genome screen and linkage analysis suggest that the APP locus may predispose to AD. The aim is to characterize genetic variability in the APP gene within its upstream regulatory region and to determine whether that variability is associated with AD and affects the expression of APP. This article describes the rationale and strategy for identifying genetic polymorphisms in the APP regulatory region, including its promoter, to associate any variability with the disease.