title: Genetic variants of GSK3B are associated with biomarkers for Alzheimer's disease and cognitive function.
abstract: BACKGROUND
  Glycogen synthase kinase 3 beta (GSK3B) is the major kinase phosphorylating tau protein. Hyperphosphorylated tau is one of the hallmarks of Alzheimer's disease (AD). Despite extensive research, the role of GSK3B in AD pathogenesis is not fully understood.
  
  
  OBJECTIVE
  To evaluate possible associations between gene variants of GSK3B and risk of AD.
  
  
  METHODS
  Twelve GSK3B tag single-nucleotide polymorphisms (SNPs), together with the previously AD-associated rs334558, were analyzed in 583 AD patients and 673 controls. Analyses on single marker and haplotype levels were done to relate to risk of AD, Mini-Mental State Examination (MMSE) scores, and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau (P-tau181), and amyloid-β (Aβ42).
  
  
  RESULTS
  After correction for multiple testing, we found a number of associations of gene variants with CSF biomarker levels and cognitive function in the AD patients. Firstly, rs334558 was associated with elevated T-tau levels (pc = 0.04). Next, rs1154597 showed association with reduced Aβ42 levels (pc = 0.007). Lastly, rs3107669 was associated with lower MMSE scores (pc = 0.03). In addition, one more SNP was nominally significantly associated with reduced Aβ42 levels and another was associated with reduced MMSE.
  
  
  CONCLUSIONS
  We found GSK3B gene variants associated with cognitive function and CSF biomarkers T-tau and Aβ42. To our knowledge, this is the first time GSK3B has been associated with cognitive function or CSF biomarkers reflecting neuronal degeneration (T-tau) and brain amyloid load (Aβ42). The regulation of GSK3B needs to be investigated further, to fully understand how these GSK3B gene variants are involved in AD pathogenesis.
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at University of Gothenburg, Sweden.
authors.forename: Petronella
authors.initials: P
authors.lastname: Kettunen
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at University of Gothenburg, Sweden.
authors.forename: Susanna
authors.initials: S
authors.lastname: Larsson
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at University of Gothenburg, Sweden.
authors.forename: Sandra
authors.initials: S
authors.lastname: Holmgren
authors.affiliation: Institute of Neuroscience and Physiology, Section for Clinical Neuroscience and Rehabilitation, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Sandra
authors.initials: S
authors.lastname: Olsson
authors.affiliation: Clinical Memory Research Unit, Department of Clinical Sciences in Malmö, Lund University, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Minthon
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at University of Gothenburg, Sweden UCL Institute of Neurology, Queen Square, London, United Kingdom.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at University of Gothenburg, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Institute of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Sweden.
authors.forename: Staffan
authors.initials: S
authors.lastname: Nilsson
authors.affiliation: Center for Culture and Health, University of Gothenburg, Sweden.
authors.forename: Annica
authors.initials: A
authors.lastname: Sjölander
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000150:complications* / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D001057:Apolipoproteins E; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: Alzheimer's disease; Mini-Mental State Examination; amyloid-β peptide; association; biomarker; cerebrospinal fluid; gene; glycogen synthase kinase 3 beta; single nucleotide polymorphism; tau