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Brain Advance Access originally published online on August 24, 2006
Brain 2006 129(11):2984-2991; 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

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

Nathalie Brouwers1,2,5, Kristel Sleegers1,2,5, Sebastiaan Engelborghs3,5,6, Veerle Bogaerts1,2,5, Sally Serneels1,2,5, Kenan Kamali1,2,5, Ellen Corsmit1,2,5, Evelyn De Leenheir4,5, Jean-Jacques Martin4,5, Peter P. De Deyn3,5,6, Christine Van Broeckhoven1,2,5 and Jessie Theuns1,2,5

1 Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium 2 Laboratory of Neurogenetics, Institute Born-Bunge Antwerpen, Belgium 3 Laboratory of Neurochemistry and Behavior, Institute Born-Bunge Antwerpen, Belgium 4 Laboratory of Neuropathology, Institute Born-Bunge Antwerpen, Belgium 5 University of Antwerp Antwerpen, Belgium 6 Memory Clinic and Department of Neurology, Middelheim General Hospital Antwerpen, Belgium

Correspondence to: Prof. Dr Christine Van Broeckhoven PhD, DSc, Neurodegenerative Brain Diseases Group, VIB8—Department of Molecular Genetics, University of Antwerp, CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium E-mail: christine.vanbroeckhoven{at}ua.ac.be

It is well established that Alzheimer's disease causing mutations in APP, PSEN1 and PSEN2 lead to a relative increased production of Aß42, 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.

Key Words: Alzheimer disease; risk factor; amyloid precursor protein; promoter; mutations

Abbreviations: AAO, age at onset in patients; Aß, amyloid ß; APP, amyloid precursor protein; MAQ, multiplex amplicon quantification; MMSE, Mini-Mental State Examination; SPECT, single photon emission computed tomography; STR, short tandem repeat

Received May 22, 2006. Revised June 26, 2006. Accepted July 19, 2006.


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