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

• Published in: Brain (London, England : 1878) Vol. 129; no. 11; pp. 2977 - 2983
• Main Authors: Sleegers, Kristel, Brouwers, Nathalie, Gijselinck, Ilse, Theuns, Jessie, Goossens, Dirk, Wauters, Jan, Del-Favero, Jurgen, Cruts, Marc, Duijn, Cornelia M. van, Broeckhoven, Christine Van
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.11.2006; Oxford Publishing Limited (England)
• Subjects: Adult; Age of Onset; Aged; Alzheimer Disease - complications; Alzheimer Disease - genetics; Amyloid beta-Protein Precursor - genetics; APP; Biological and medical sciences; Cerebral Amyloid Angiopathy - complications; Cerebral Amyloid Angiopathy - genetics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dementia; early onset Alzheimer's disease; Female; Gene Duplication; Genes, Dominant; genomic duplication; Humans; In Situ Hybridization, Fluorescence; Male; Medical sciences; Middle Aged; Neurology; Pedigree; Polymerase Chain Reaction - methods; Vascular diseases and vascular malformations of the nervous system; early onset Alzheimer's disease; APP; Nervous system diseases; Cerebral amyloid angiopathy; Duplication; Alzheimer disease; Central nervous system disease; Degenerative disease; genomic duplication; Cerebral disorder
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awl203

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.