1. ^* Centre for Research into Neurodegenerative Diseases, Departments of Medicine (Neurology) and Medical Biophysics, University of Toronto, Toronto, and Department of Medicine, Division of Neurology, The Toronto Hospital, Toronto, Ontario, M5S 1A8, Canada
2. ^‡ Research Institute, The Hospital for Sick Children, and Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
3. ^§ Laboratoire de Neurohistologie, Ecole Pratique des Hautes Etudes and U106, INSERM La Salpetriere, 75651 Paris Cedex 13, France
4. USL-6 and UO-CNR, 88046 Lamezia Terme, Italy
5. ^¶ Department of Neurology and Psychiatry, University of Florence, viale Morgagni 85, Florence, Italy
6. ^£ Department of Neurology, University of Turin, via Cherasco 15, 10126 Turin, Italy
7. Clinical Neuropharmaeology Section, NINDS, 9000 Rockville Pike, Bethesda, Maryland 20892, USA
8. ^** Centre d'Etude Polymorphisme Humaine, 27 Rue Juliette Dodu, 75010, Paris, France
9. ^†† Department of Neurology, University of Massachusetts Medical Center, 55 Lake Avenue, Worcester, Massachusetts 01655, USA
10. ^‡‡ Molecular Neurogenetics Laboratory and Laboratory of Genetics and Aging, Massachusetts General Hospital, Departments of Neurology and Genetics, Harvard Medical School, Boston, Massachusetts 02114, USA
11. ^§§ Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, North Carolina 27710, USA
12. ^¶¶ Molecular Pathology, Glaxo Research and Development, Greenford Road, Greenford, Middlesex UB6 OHE, UK
13. ^££ Sandoz Research Institute, Sandoz Pharmaceuticals Corporation, 59 Route 10, East Hanover, New Jersey 07936, USA
14. ^† MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh, UK
15. To whom correspondence should be addressed.

Abstract

Some cases of Alzheimer's disease are inherited as an autosomal dominant trait. Genetic linkage studies have mapped a locus (AD3) associated with susceptibility to a very aggressive form of Alzheimer's disease to chromosome 14q24.3. We have defined a minimal cosegregating region containing the AD3 gene, and isolated at least 19 different transcripts encoded within this region. One of these transcripts (S182) corresponds to a novel gene whose product is predicted to contain multiple transmembrane domains and resembles an integral membrane protein. Five different missense mutations have been found that cosegregate with early-onset familial Alzheimer's disease. Because these changes occurred in conserved domains of this gene, and are not present in normal controls, they are likely to be causative of AD3.