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A Risk Variant rs6922617 in TREM Is Discrepantly Associated With Defining Neuropathological Hallmarks in the Alzheimer’s Continuum
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences ( IF 4.3 ) Pub Date : 2024-07-25 , DOI: 10.1093/gerona/glae185
Shuangjie Qian 1 , Yi Zheng 1 , Tao Jiang 1 , Jialong Hou 1 , Ruixue Cao 2, 3 , Jinlai Cai 1 , Enzi Ma 1 , Wenwen Wang 4 , Weihong Song 3, 5 , Chenglong Xie 1, 3
Affiliation  

The single nucleotide polymorphism (SNP)-rs6922617 in the triggering receptor expressed on myeloid cells (TREM) gene cluster is a potential risk factor for Alzheimer’s disease (AD). Here, we examined whether rs6922617 is associated with AD-defining neuropathological hallmarks and memory performance. We assessed the interaction between the variant rs6922617 and levels of beta-amyloid (Aβ), tau pathology, neurodegeneration, namely amyloid-tau-neurodegeneration framework, and cognition functions in 660 healthy controls, 794 mild cognitively impaired, and 272 subjects with AD. We employed linear regression and linear mixed models to examine the association. Here we find that the SNP-rs6922617 in the TREM gene cluster is associated with a higher global amyloid-ligands positron emission tomography (Aβ-PET) burden and lower fluorodeoxyglucose positron emission tomography (FDG-PET) load. Interestingly, rs6922617 risk allele carriers exhibit a significantly reduced tau accumulation compared to the non-carriers, indicating a discrepant association with Aβ and tau pathologies. Though the participants carrying the rs6922617 risk allele do not show a correlation with poorer cognitive performance, stronger neuropathological phenotypes, and memory impairments are evident in ApoE ε4 carriers with the rs6922617 risk allele. These results support the notion that the SNP-rs6922617 in the TREM gene cluster is associated with AD-related neuropathological hallmarks, such as Aβ and FDG-mediated neurodegeneration, rather than tau accumulation. Although the direct association with memory impairment in the Alzheimer’s continuum remains inconclusive, our findings suggest a potential role of rs6922617 in facilitating neuropathology hallmarks.

中文翻译:


TREM 中的风险变异 rs6922617 与定义阿尔茨海默病连续体中的神经病理学特征不同



髓系细胞上表达的触发受体 (TREM) 基因簇中的单核苷酸多态性 (SNP)-rs6922617 是阿尔茨海默病 (AD) 的潜在危险因素。在这里,我们检查了 rs6922617 是否与 AD 定义的神经病理学特征和记忆表现有关。我们评估了 660 名健康对照者、794 名轻度认知障碍和 272 名 AD 受试者的变体 rs6922617 与 β-淀粉样蛋白 (Aβ) 水平、tau 病理学、神经退行性变性(即淀粉样蛋白-tau 神经变性框架)和认知功能之间的相互作用。我们采用线性回归和线性混合模型来检查相关性。在这里,我们发现 TREM 基因簇中的 SNP-rs6922617 与较高的整体淀粉样蛋白配体正电子发射断层扫描 (Aβ-PET) 负荷和较低的氟代脱氧葡萄糖正电子发射断层扫描 (FDG-PET) 负荷相关。有趣的是,与非携带者相比,rs6922617 风险等位基因携带者表现出显着减少的 tau 积累,表明与 Aβ 和 tau 病理学之间存在不同的关联。尽管携带 rs6922617 风险等位基因的参与者与较差的认知表现没有相关性,但在具有 rs6922617 风险等位基因的 ApoE ε4 携带者中,更强的神经病理表型和记忆障碍是明显的。这些结果支持这样的观点,即 TREM 基因簇中的 SNP-rs6922617 与 AD 相关的神经病理学特征(如 Aβ 和 FDG 介导的神经变性)相关,而不是 tau 积累。尽管与阿尔茨海默病连续体中记忆障碍的直接关联仍不确定,但我们的研究结果表明 rs6922617 在促进神经病理学标志方面具有潜在作用。
更新日期:2024-07-25
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