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

Article type: Research Article

Authors: Kettunen, Petronella^{a; *; 1} | Larsson, Susanna^a | Holmgren, Sandra^a | Olsson, Sandra^b | Minthon, Lennart^c | Zetterberg, Henrik^{a; d} | Blennow, Kaj^a | Nilsson, Staffan^e | Sjölander, Annica^{f; 1}

Affiliations: [a] Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at University of Gothenburg, Sweden | [b] Institute of Neuroscience and Physiology, Section for Clinical Neuroscience and Rehabilitation, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden | [c] Clinical Memory Research Unit, Department of Clinical Sciences in Malmö, Lund University, Sweden | [d] UCL Institute of Neurology, Queen Square, London, United Kingdom | [e] Institute of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Sweden | [f] Center for Culture and Health, University of Gothenburg, Sweden

Correspondence: [*] Correspondence to: Petronella Kettunen, PhD, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden. Tel.: +46 31 342 7924; Fax: +46 31 828 458; E-mail: petronella.kettunen@neuro.gu.se.

Note: [1] These authors contributed equally this work.

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.

Keywords: Alzheimer's disease, amyloid-β peptide, association, biomarker, cerebrospinal fluid, gene, glycogen synthase kinase 3 beta, Mini-Mental State Examination, single nucleotide polymorphism, tau

DOI: 10.3233/JAD-142025

Journal: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1313-1322, 2015