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Brain Advance Access published online on August 24, 2006
Brain, doi:10.1093/brain/awl212
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org
Received May 22, 2006
Revised June 26, 2006
Accepted July 19, 2006

Article

Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease

Nathalie Brouwers 1, Kristel Sleegers 1, Sebastiaan Engelborghs 2, Veerle Bogaerts 1, Sally Serneels 1, Kenan Kamali 1, Ellen Corsmit 1, Evelyn De Leenheir 3, Jean-Jacques Martin 3, Peter P. De Deyn 2, Christine Van Broeckhoven 1 *, and Jessie Theuns 1

1 Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerpen, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium; University of Antwerp, Antwerpen, Belgium
2 Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium; University of Antwerp, Antwerpen, Belgium; Memory Clinic and Department of Neurology, Middelheim General Hospital, Antwerpen, Belgium
3 Laboratory of Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium; University of Antwerp, Antwerpen, Belgium

* To whom correspondence should be addressed.
Christine Van Broeckhoven, E-mail: christine.vanbroeckhoven{at}ua.ac.be


  Abstract

It is well established that Alzheimer's disease causing mutations in APP, PSEN1 and PSEN2 lead to a relative increased production of A{beta}42, thereby fostering its deposition in plaques. Recently others and we showed that amyloid precursor protein (APP) overproduction, either as a result of genomic locus duplication or altered regulatory sequences in the APP promoter region, leads to early-onset disease. Here, we have expanded our study of genetic variability in the APP promoter to a large group of well-documented Belgian patients (n = 750, mean onset age = 75.0 ± 8.6, range = 37-96). We identified three different APP promoter mutations (-369C->G, -534G->A and -479C->T) in seven patients. In patients with onset ≤70 years (n = 204), we identified one patient carrying the London APP V717I mutation while no patients carried an APP locus duplication, indicating that APP promoter mutations (n = 2) were more frequently associated with increased risk for early-onset Alzheimer's disease. The two mutations (-369C->G and -534G->A) increasing APP promoter activity by nearly 2-fold and mimicking an APP duplication, appeared in probands of families with multiple patients with dementia. The -479C->T mutation that increased APP expression only mildly (1.2-fold), was observed in four patients with onset ages ranging from 62 to 79 years (mean 71.5 years), suggesting that its contribution to disease risk is more pronounced at later age due to modulating factors. In conclusion, we provided evidence that mutations in APP regulatory sequences are more frequent than APP coding mutations, and that increased APP transcriptional activity constitutes a risk factor for Alzheimer's disease with onset ages inversely correlated with levels of APP expression.

Keywords: Alzheimer disease; risk factor; amyloid precursor protein; promoter; mutations.
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