Further validation of the association between MAPT haplotype-tagging polymorphisms and Alzheimer's disease: neuropsychological tests, cerebrospinal fluid biomarkers, and APOE genotype

Mirjana Babić Leko; Ena Španić Popovački; Nanet Willumsen; Matea Nikolac Perković; Nikolina Pleić; Klara Zubčić; Lea Langer Horvat; Željka Vogrinc; Marina Boban; Fran Borovečki; Tatijana Zemunik; Rohan de Silva; Goran Šimić

doi:10.3389/fnmol.2024.1456670

Further validation of the association between MAPT haplotype-tagging polymorphisms and Alzheimer's disease: neuropsychological tests, cerebrospinal fluid biomarkers, and APOE genotype

Front Mol Neurosci. 2024 Sep 25:17:1456670. doi: 10.3389/fnmol.2024.1456670. eCollection 2024.

Authors

Mirjana Babić Leko¹, Ena Španić Popovački¹, Nanet Willumsen², Matea Nikolac Perković³, Nikolina Pleić⁴, Klara Zubčić⁵, Lea Langer Horvat¹, Željka Vogrinc⁶, Marina Boban^{7

8}, Fran Borovečki^{7

8

9}, Tatijana Zemunik^{4

10}, Rohan de Silva², Goran Šimić¹

Affiliations

¹ Department for Neuroscience, Croatian Institute for Brain Research, University of Zagreb Medical School, Zagreb, Croatia.
² Reta Lila Weston Institute, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, United Kingdom.
³ Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia.
⁴ Department of Biology and Human Genetics, School of Medicine, University of Split, Split, Croatia.
⁵ Department of Molecular Diagnostics and Genetics, Dubrava University Hospital, Zagreb, Croatia.
⁶ Laboratory for Neurobiochemistry, Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia.
⁷ Department of Neurology, University Hospital Centre Zagreb, Kišpatićeva, Zagreb, Croatia.
⁸ School of Medicine, University of Zagreb, Zagreb, Croatia.
⁹ Department for Functional Genomics, Centre for Translational and Clinical Research, University of Zagreb Medical School, Zagreb, Croatia.
¹⁰ Department of Nuclear Medicine, University Hospital Split, Split, Croatia.

Abstract

Introduction: Genetic studies have shown that variants in the microtubule-associated protein tau (MAPT) gene, which encodes tau protein, can increase the risk for Alzheimer's disease (AD). Additionally, two haplotypes of the MAPT gene (H1 and H2) are associated with various neurodegenerative disorders, including AD. This study aimed to test the association of MAPT haplotypes (H1 and H2) and MAPT haplotype-tagging polymorphisms (rs1467967, rs242557, rs3785883, rs2471738, del-In9, rs7521) with AD.

Methods: The study included 964 individuals: 113 with AD, 53 with mild cognitive impairment (MCI), 54 with other dementias, and 744 healthy controls.

Results: The results showed that individuals carrying the A allele in the MAPT rs1467967 polymorphism, the GG genotype in the MAPT rs7521 polymorphism, and the G allele in the MAPT rs242557 polymorphism had worse performance on various neuropsychological tests. Carriers of the C allele in MAPT rs2471738 polymorphism and CC homozygotes also showed worse performance on neuropsychological tests and pathological levels of several cerebrospinal fluid (CSF) biomarkers. However, T allele carriers in the MAPT rs2471738 polymorphism were more represented among patients with dementia and apolipoprotein E (APOE) ɛ4 carriers. Carriers of the H2 MAPT haplotype had worse performance on various neuropsychological tests, consistent with our previous study, which associated the H2 MAPT haplotype with pathological levels of CSF AD biomarkers. Regarding the MAPT rs3785883 polymorphism, further research is needed since both the AA and GG genotypes were associated with pathological levels of CSF and plasma AD biomarkers.

Discussion: In conclusion, further genetic studies are needed to elucidate the role of MAPT haplotypes and MAPT haplotype-tagging polymorphisms in the development of AD.

Keywords: APOE gene; Alzheimer’s disease; MAPT gene; MAPT haplotypes; MAPT polymorphisms; biomarkers; cerebrospinal fluid; dementia.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was funded by the National Recovery and Resilience Plan G.A. NPOO.C3.2.R3-I1.04.0257 to GŠ (“Detection and validation of molecular markers of inflammation in Alzheimer’s and Parkinson’s disease, multiple sclerosis, and schizophrenia”), University of Zagreb grant no. 10106–24-1526 to GŠ (“Inflammasome, tau protein, and nucleocytoplasmic transport in Alzheimer’s disease”), Croatian Science Foundation grant no. IP-2019-04-3584 to GŠ (“Role of the blood–brain barrier, innate immunity, and tau protein oligomerization in the pathogenesis of Alzheimer’s disease”), and Croatian Science Foundation grant no. IP-2019-04-2593 to TZ (“Regulation of thyroid and parathyroid function and blood calcium homeostasis”).