Association of GSK3B with Alzheimer disease and frontotemporal dementia.
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.


METHODS
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.
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 2506 Gonda, 695 Charles E. Young Dr S, Los Angeles, CA 90095-1761, USA.
Barbara A J
BA
Schaffer
Lars
L
Bertram
Bruce L
BL
Miller
Kristina
K
Mullin
Sandra
S
Weintraub
Nancy
N
Johnson
Eileen H
EH
Bigio
Marsel
M
Mesulam
Martina
M
Wiedau-Pazos
George R
GR
Jackson
Jeffrey L
JL
Cummings
Rita M
RM
Cantor
Allan I
AI
Levey
Rudolph E
RE
Tanzi
Daniel H
DH
Geschwind
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D001921:Brain / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D003704:Dementia / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D005091:Exons / Q000235:genetics; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D005838:Genotype; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016875:tau Proteins / Q000378:metabolism
D005819:Genetic Markers; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3