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Genetic Variants of GSK3B are Associated with Biomarkers for Alzheimer's Disease and Cognitive Function.

Kettunen, Petronella; Larsson, Susanna; Holmgren, Sandra; Olsson, Sandra; Minthon, Lennart LU ; Zetterberg, Henrik LU ; Blennow, Kaj LU ; Nilsson, Staffan and Sjölander, Annica (2015) In Journal of Alzheimer's Disease 44(4). p.1313-1322
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... (More)
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. Conclusion: 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Alzheimer's Disease
volume
44
issue
4
pages
1313 - 1322
publisher
IOS Press
external identifiers
  • pmid:25420549
  • wos:000350001000024
  • scopus:84944881412
ISSN
1387-2877
DOI
10.3233/JAD-142025
language
English
LU publication?
yes
id
f38c8959-97da-4e0d-8021-3dd48bd9903b (old id 4816202)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25420549?dopt=Abstract
date added to LUP
2014-12-03 17:48:22
date last changed
2017-10-01 03:32:33
@article{f38c8959-97da-4e0d-8021-3dd48bd9903b,
  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. Conclusion: 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.},
  author       = {Kettunen, Petronella and Larsson, Susanna and Holmgren, Sandra and Olsson, Sandra and Minthon, Lennart and Zetterberg, Henrik and Blennow, Kaj and Nilsson, Staffan and Sjölander, Annica},
  issn         = {1387-2877},
  language     = {eng},
  number       = {4},
  pages        = {1313--1322},
  publisher    = {IOS Press},
  series       = {Journal of Alzheimer's Disease},
  title        = {Genetic Variants of GSK3B are Associated with Biomarkers for Alzheimer's Disease and Cognitive Function.},
  url          = {http://dx.doi.org/10.3233/JAD-142025},
  volume       = {44},
  year         = {2015},
}