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Brain Advance Access originally published online on August 18, 2006
Brain 2006 129(11):2977-2983; 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
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APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy

Kristel Sleegers1, Nathalie Brouwers1, Ilse Gijselinck1, Jessie Theuns1, Dirk Goossens2, Jan Wauters3, Jurgen Del-Favero2, Marc Cruts1, Cornelia M. van Duijn4 and Christine Van Broeckhoven1

1 Neurodegenerative Brain Diseases Group 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

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

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.

Key Words: APP; early onset Alzheimer's disease; genomic duplication

Abbreviations: APP, amyloid precursor protein; CAA, cerebral amyloid angiopathy; DQs, dosage quotients; FISH, fluorescence in situ hybridization; MAQ, multiplex amplicon quantification; PCR, polymerase chain reaction

Received April 19, 2006. Revised June 18, 2006. Accepted August 18, 2006.


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