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Brain Advance Access published online on August 18, 2006
Brain, doi:10.1093/brain/awl203
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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 April 19, 2006
Revised June 18, 2006
Accepted July 4, 2006

Article

APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy

Kristel Sleegers 1, Nathalie Brouwers 1, Ilse Gijselinck 1, Jessie Theuns 1, Dirk Goossens 2, Jan Wauters 3, Jurgen Del-Favero 2, Marc Cruts 1, Cornelia M. van Duijn 4, and Christine Van Broeckhoven 1 *

1 Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp, Belgium
2 Applied Molecular Genomics Group, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp, Belgium
3 Center of Medical Genetics, University Hospital Antwerp, Antwerp, Belgium
4 Genetic Epidemiology Unit, Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, The Netherlands

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


  Abstract

We assessed the impact of amyloid precursor protein (APP) gene locus duplications in early onset Alzheimer's disease in a Dutch population-based sample. Using real-time PCR and an in-house-developed multiplex amplicon quantification assay, we identified a genomic APP duplication in 1 out of 10 multigenerational families segregating early onset Alzheimer's disease. In this family, cerebral amyloid angiopathy (CAA) coincided with this disease. The duplicated genomic region included no other genes than APP and extended maximally over 0.7 Mb. In a sample of 65 familial early onset patients, we observed the same APP genomic duplication in one patient (1.7%), while in 36 isolated patients duplications in the APP locus were absent. This indicated that APP locus duplications explained <2% of familial, non-autosomal dominant Alzheimer's disease and are an infrequent cause of de novo mutation. Our findings corroborated a recent French study, and indicated that investigating genomic duplications in the APP locus in families segregating Alzheimer's disease and CAA should be considered.

Keywords: APP; early onset Alzheimer's disease; genomic duplication.
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