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Genetic variations in promoter sequences that alter gene expression play a prominent role in increasing susceptibility to complex diseases. Also, expression levels of APP are essentially regulated by its core promoter and 5′ upstream regulatory region and correlate with amyloid β levels in Alzheimer disease (AD) brains. Here, we systematically sequenced the proximal promoter (-766/+204) and two functional distal regions (-2634/-2159 and -2096/-1563) of APP in two independent AD series with onset ages ≤70 years (Belgian sample, n = 180; Dutch sample, n = 111) and identified eight novel sequence variants. Three mutations (-118C→A, -369C→G, and -534G→A) identified only in patients with AD showed, in vitro, a nearly twofold neuron-specific increase in APP transcriptional activity, similar to what is expected from triplication of APP in Down syndrome. These mutations either abolished (AP-2 and HES-1) or created (Oct1) transcription-factor binding sites involved in the development and differentiation of neuronal systems. Also, two of these clustered in the 200-bp region (-540/-340) of the APP promoter that showed the highest degree of species conservation. The present study provides evidence that APP-promoter mutations that significantly increase APP expression levels are associated with AD. © 2006 by The American Society of Human Genetics. All rights reserved.

Original publication




Journal article


American Journal of Human Genetics

Publication Date





936 - 946