Identification of biomarkers and molecular mechanisms implicated in genetic variations underlying Alzheimer's disease pathogenesis

Aspects of molecular medicine Pub Date : 2024-06-01 DOI:10.1016/j.amolm.2024.100045

Hai Duc Nguyen , Giang Huong Vu , Woong-Ki Kim

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Abstract

We analyzed data from human genome-wide association studies (GWASs) to identify genetic variants and biological pathways linked to Alzheimer's disease (AD). Ten AD biomarkers (APOE, NECTIN2, APOC1, APOC1P1, TOMM40, RNU4-67P, KRAS, Y_RNA, THORLNC, LINC01956) were found across studies, including six central genetic variants (MAPT (rs242557-A), GRIN2B (rs74442473-G), APOE (rs438811-T), ANK3 (rs438811-T), BIN1 (rs744373-G), and BDNF (rs7481773-A)). ANK3 (rs438811-T) and GRIN2B (rs74442473-G) were essential hub biomarkers for amyloid plaques, while MAPT (rs242557-A) and BIN1 (rs744373-G) were crucial for neurofibrillary tangles (NFTs). Higher-risk AD biomarkers were associated with increased protein-lipid complex formation, while lower-risk AD biomarkers were correlated with improved synaptic function. Six essential miRNAs (hsa-miR-124–3p, 15a-5p, 16–5p, 204–5p, 520g-3p, 520h) and three transcription factors (ZMAT4, ZBED6, FOXG1) emerged as possible candidates to reveal the genetic differences that lead to amyloid plaques, NFTs, and ultimately AD. These findings serve as a basis for potential AD treatments and offer new avenues for therapeutic approaches to directly target the genetic variations and processes associated with the disease.

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确定与阿尔茨海默病发病基因变异有关的生物标志物和分子机制

我们分析了人类全基因组关联研究（GWAS）的数据，以确定与阿尔茨海默病（AD）相关的基因变异和生物通路。在各项研究中发现了十种阿兹海默症生物标记物（APOE、NECTIN2、APOC1、APOC1P1、TOMM40、RNU4-67P、KRAS、Y_RNA、THORLNC、LINC01956）、包括六个中心基因变异（MAPT（rs242557-A）、GRIN2B（rs74442473-G）、APOE（rs438811-T）、ANK3（rs438811-T）、BIN1（rs744373-G）和 BDNF（rs7481773-A））。ANK3（rs438811-T）和GRIN2B（rs74442473-G）是淀粉样斑块的重要枢纽生物标志物，而MAPT（rs242557-A）和BIN1（rs744373-G）对神经纤维缠结（NFT）至关重要。高风险AD生物标志物与蛋白-脂质复合物形成增加有关，而低风险AD生物标志物与突触功能改善有关。六种重要的miRNA（hsa-miR-124-3p、15a-5p、16-5p、204-5p、520g-3p、520h）和三种转录因子（ZMAT4、ZBED6、FOXG1）成为揭示导致淀粉样蛋白斑块、NFT以及最终导致AD的遗传差异的可能候选因子。这些发现为潜在的注意力缺失症治疗奠定了基础，并为直接针对与该疾病相关的基因变异和过程的治疗方法提供了新的途径。

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Aspects of molecular medicine Molecular Biology, Molecular Medicine

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38 days