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From the Centre for Research in Neurodegenerative Diseases and Division of Neurology (Drs. Rogaeva, Song, Richard, Rogaev, and St. George–Hyslop, and H. Medeiros, C. Sato, and Y. Liang), Department of Medicine, The University Health Network, Toronto, Ontario, Canada; Athena Diagnostics Inc. (Dr. Boss and K. Fafel), Worcester, MA; Asklepios Klinik Schaufling (Dr. Frommelt), Department of Neurological Rehabilitation, Bavaria, Germany; Departments of Medical Genetics and Medicine (Dr. Sadovnick), Vancouver, British Columbia, Canada; Mental Health Research Center (Dr. Rogaev), Russian Academy of Medical Sciences, Moscow, Russia; Department of Medical Genetics (Dr. Meschino), North York General Hospital, North York, Ontario, Canada; Division of Geriatric Medicine (Dr. Rockwood), Dalhousie University, Halifax, Nova Scotia, Canada; and Taub Institute for Research on Alzheimer’s Disease and the Aging Brain (Dr. Mayeux), New York, NY.
Address correspondence and reprint requests to Dr. Ekaterina A. Rogaeva, Tanz Neuroscience Building, 6 Queen’s Park Cr. W, Toronto, ON M5S 3H2, Canada; e-mail: ekaterina.rogaeva{at}utoronto.ca
Background:— Mutations in the presenilin-1 gene (PS1) account for a majority of patients with early-onset familial AD. However, the clinical indications and algorithms for genetic testing in dementia are still evolving.
Methods:— The entire open reading frame of the PS1 gene was sequenced in a series of 414 consecutive patients referred for diagnostic testing, including 372 patients with AD and 42 asymptomatic persons with a strong family history of AD.
Results:— Forty-eight independent patients screened had a PS1 mutation including 21 novel mutations. In addition, 3% of subjects (11/413) had a known polymorphism, the Glu318Gly substitution. The majority of the mutations were missense substitutions but there were three insertions and 
exon 10 mutation. With six exceptions (codons 35, 178, 352, 354, 358, and 365) most of the mutations occurred at residues conserved in the homologous PS2 gene or in PS1 of other species.
Conclusions:— Eleven percent of a referral-based series of patients with AD can be explained by coding sequence mutations in the PS1 gene. The high frequency of PS1 mutations in this study indicates that screening for PS1 mutations in AD is likely to be successful, especially when directed at patients with a positive family history with onset before 60 years (90% of those with PS1 mutations were affected by age 60 years). This will also have significance for the secondary identification of at-risk relatives who might be candidates for future prophylactic therapies for AD.
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