Autosomal dominant early onset Alzheimer disease with cerebral amyloid angiopathy caused by APP duplication: clinical and neuropathological study of five French families. L. Guyant-Maréchal^1,2, L. Cabrejo¹, A. Laquerrière¹, M. Vercelletto³, F. De La Fournière⁴, C. Thomas-Antérion⁵, C. Verny⁶, F. Letournel⁷, F. Pasquier⁸, A. Vital⁹, F. Checler¹⁰, T. Frebourg^1,2, C. Campion², D. Hannequin^1,2. 1) Departments of Neurology, Genetics, and Neuropathology, University Hospital, Rouen, France; 2) Inserm U614, Faculty of Medicine, Rouen, France; 3) Department of Neurology, University Hospital, Nantes, France; 4) Department of Geriatrics, Pau Hospital France; 5) Department of Neurology, University Hospital, Saint-Etienne, France; 6) Department of Neurology, University Hospital, Angers, France; 7) Laboratory of Cellular Biology, University Hospital, Angers, France; 8) Department of Neurology, University Hospital, Lille, France; 9) Department of Pathology, University Hospital, Bordeaux, France; 10) Institute of Molecular and Cellular Pharmacology, UMR6097 CNRS/UNSA, Valbonne, France.
   We recently reported (Rovelet-Lecrux et al. Nature Genetics 2006, 38: 24-26), in 5 French families with autosomal dominant early-onset Alzheimer disease (ADEOAD) and cerebral amyloid angiopathy (CAA), the duplication of the APP locus located on chromosome 21, the duplication ranging from 0.58 to 6.37 Mb. The present study describes the phenotype of this new entity. The phenotype was not dependent on the size of the duplication and, remarkably, there was no clinical feature of Down's syndrome (DS). Dementia was observed in all cases (age of onset (AOO): 42-59 years), intracerebral haemorrhage (ICH) was reported in 6 (26 %; AOO: 53-64 years) and seizures occurred in 12 (57%)among 21 affected patients. Neuropathological examination in 5 cases demonstrated AD and severe CAA lesions which were reminiscent from those reported in brains of DS patients. A striking feature consisted in intraneuronal Ax-40 accumulation located in the granular cell layer of the dentate gyrus and in the pyramidal cell layer of the Ammon's horn. It could be speculated that both an overproduction of the A peptide and a possible shift toward a high A40/A42 ratio account for the pathological hallmarks of the disease.