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

IF 3.5 3区医学 Q2 NEUROSCIENCES Frontiers in Molecular Neuroscience Pub Date : 2024-09-25 eCollection Date: 2024-01-01 DOI:10.3389/fnmol.2024.1456670

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

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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.

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进一步验证 MAPT 单倍型标记多态性与阿尔茨海默病之间的关联：神经心理测试、脑脊液生物标志物和 APOE 基因型。

简介遗传学研究表明，编码 tau 蛋白的微管相关蛋白 tau（MAPT）基因的变异可增加阿尔茨海默病（AD）的患病风险。此外，MAPT 基因的两种单倍型（H1 和 H2）与包括阿尔茨海默病在内的多种神经退行性疾病有关。本研究旨在检测 MAPT 单倍型（H1 和 H2）和 MAPT 单倍型标记多态性（rs1467967、rs242557、rs3785883、rs2471738、del-In9、rs7521）与 AD 的相关性：研究纳入了 964 人：方法：研究对象包括 964 人：113 名 AD 患者、53 名轻度认知障碍患者 (MCI)、54 名其他痴呆症患者和 744 名健康对照组：结果显示，MAPT rs1467967 多态性中的 A 等位基因、MAPT rs7521 多态性中的 GG 基因型和 MAPT rs242557 多态性中的 G 等位基因携带者在各种神经心理测试中的表现较差。MAPT rs2471738 多态性的 C 等位基因携带者和 CC 同卵双生者在神经心理测试中的表现也较差，几种脑脊液（CSF）生物标志物的病理水平也较低。然而，MAPT rs2471738 多态性的 T 等位基因携带者在痴呆症患者和载脂蛋白 E（APOE）ɛ4 携带者中的比例更高。H2 MAPT单倍型携带者在各种神经心理测试中的表现较差，这与我们之前的研究一致，该研究将H2 MAPT单倍型与CSF AD生物标志物的病理水平相关联。关于MAPT rs3785883多态性，由于AA和GG基因型均与CSF和血浆AD生物标志物的病理水平相关，因此还需要进一步研究：总之，要阐明MAPT单倍型和MAPT单倍型标记多态性在AD发病中的作用，还需要进一步的遗传学研究。

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来源期刊

Frontiers in Molecular Neuroscience NEUROSCIENCES-

CiteScore

5.70

自引率

2.10%

发文量

669

审稿时长

14 weeks

期刊介绍： Frontiers in Molecular Neuroscience is a first-tier electronic journal devoted to identifying key molecules, as well as their functions and interactions, that underlie the structure, design and function of the brain across all levels. The scope of our journal encompasses synaptic and cellular proteins, coding and non-coding RNA, and molecular mechanisms regulating cellular and dendritic RNA translation. In recent years, a plethora of new cellular and synaptic players have been identified from reduced systems, such as neuronal cultures, but the relevance of these molecules in terms of cellular and synaptic function and plasticity in the living brain and its circuits has not been validated. The effects of spine growth and density observed using gene products identified from in vitro work are frequently not reproduced in vivo. Our journal is particularly interested in studies on genetically engineered model organisms (C. elegans, Drosophila, mouse), in which alterations in key molecules underlying cellular and synaptic function and plasticity produce defined anatomical, physiological and behavioral changes. In the mouse, genetic alterations limited to particular neural circuits (olfactory bulb, motor cortex, cortical layers, hippocampal subfields, cerebellum), preferably regulated in time and on demand, are of special interest, as they sidestep potential compensatory developmental effects.