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Barbara A. J. Schaffer, MA; Lars Bertram, MD; Bruce L. Miller, MD; Kristina Mullin, BSc; Sandra Weintraub, PhD; Nancy Johnson, PhD; Eileen H. Bigio, MD; Marsel Mesulam, MD; Martina Wiedau-Pazos, MD, PhD; George R. Jackson, MD, PhD; Jeffrey L. Cummings, MD; Rita M. Cantor, PhD; Allan I. Levey, MD, PhD; Rudolph E. Tanzi, PhD; Daniel H. Geschwind, MD, PhD

Arch Neurol. 2008;65(10):1368-1374.

Background  Deposits of abnormally hyperphosphorylated tau are a hallmark of several dementias, including Alzheimer disease (AD), and about 10% of familial frontotemporal dementia (FTD) cases are caused by mutations in the tau gene. As a known tau kinase, GSK3B is a promising candidate gene in the remaining cases of FTD and in AD, for which tau mutations have not been found.

Objective  To examine the promoter of GSK3B and all 12 exons, including the surrounding intronic sequence, in patients with FTD, patients with AD, and aged healthy subjects to identify single-nucleotide polymorphisms associated with disease.

Design, Setting, and Participants  Single-nucleotide polymorphism frequency was examined in a case-control cohort of 48 patients with probable AD, 102 patients with FTD, 38 patients with primary progressive aphasia, and 85 aged healthy subjects. Results were followed up in 2 independent AD family samples consisting of 437 multiplex families with AD (National Institute of Mental Health Genetics Initiative AD Study) or 150 sibships discordant for AD (Consortium on Alzheimer's Genetics Study).

Results  Several rare sequence variants in GSK3B were identified in the case-control study. An intronic polymorphism (IVS2-68G>A) occurred at more than twice the frequency among patients with FTD (10.8%) and patients with AD (14.6%) than in aged healthy subjects (4.1%). The polymorphism showed association with disease in both follow-up samples independently, although only the Consortium on Alzheimer's Genetics sample showed the same direction of association as the case-control sample.

Conclusions  To our knowledge, this is the first evidence that a gene known to be involved in tau phosphorylation, GSK3B, is associated with risk for primary neurodegenerative dementias. This supports previous work in animal models suggesting that such genes are therapeutic targets.

Author Affiliations: Program in Neurogenetics, Department of Neurology (Ms Schaffer and Drs Wiedau-Pazos, Jackson, and Geschwind) and Departments of Neurology (Dr Cummings), Psychiatry and Biobehavioral Sciences (Dr Cummings), Human Genetics (Dr Cantor), and Pediatrics (Dr Cantor), David Geffen School of Medicine, University of California, Los Angeles; Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown (Drs Bertram and Tanzi and Ms Mullin); Center for Memory and Aging, Department of Neurology, University of California, San Francisco (Dr Miller); Cognitive Neurology and Alzheimer's Disease Center (Drs Weintraub, Johnson, and Mesulam) and Department of Pathology (Dr Bigio), Feinberg School of Medicine, Northwestern University, Chicago, Illinois; and Alzheimer's Disease Center and Department of Neurology, Emory University, Atlanta, Georgia (Dr Levey).

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