Han Sang-Won, Lee Sang-Hwa, Kim Jong Ho, Lee Jae-Jun, Park Young Ho, Kim SangYun, Nho Kwangsik, Sohn Jong-Hee
Department of Neurology, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon-si, Gangwon-do, Republic of Korea.
Department of Anesthesiology and Pain Medicine, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon-si, Gangwon-do, Republic of Korea.
Front Aging Neurosci. 2024 Jul 24;16:1411466. doi: 10.3389/fnagi.2024.1411466. eCollection 2024.
Alzheimer's disease (AD) is a complex neurodegenerative disorder influenced by various factors, including liver function, which may impact the clearance of amyloid-β (Aβ) in the brain. This study aimed to explore how the apolipoprotein E () ε4 allele affects the relationship of liver function markers with AD pathology and cognition.
We analyzed data from two independent cohorts, including 732 participants from the Hallym University Medical Center and 483 from the Alzheimer's Disease Neuroimaging Initiative, each group consisting of individuals with and without the ε4 allele. Cross-sectional analyses evaluated the associations of liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, total bilirubin, and albumin) with AD diagnosis, amyloid positron emission tomography (PET) burden, and cerebrospinal fluid biomarkers for AD (Aβ42, total tau, and phosphorylated tau181) at baseline. Longitudinally, we investigated the associations between these liver enzymes and changes in cognitive performance over the course of a year. Logistic and linear regression models were used to analyze these associations and mediation analyses were conducted to assess whether age and amyloid PET burden mediated these associations.
Only in the ε4 carrier group, a high AST to ALT ratio and low ALT levels were significantly associated with AD diagnosis, increased amyloid PET burden, and faster longitudinal decline in cognitive function in both cohorts. In particular, the AST to ALT ratio was associated with cerebrospinal fluid Aβ42 levels exclusively in the ε4 carrier group in the Alzheimer's Disease Neuroimaging Initiative cohort but not with phosphorylated tau or total tau levels. Moreover, mediation analyses from both cohorts revealed that in the ε4 carriers group, age did not mediate the associations between liver enzymes and AD diagnosis or amyloid PET burden. However, amyloid PET burden partially mediated the association between liver enzymes and AD diagnosis exclusively in the ε4 carriers group.
This study provides valuable insights into the significant association of the ε4 allele with liver enzymes and their potential role in Aβ-related pathogenesis and cognition in AD. Further research is required to elucidate the underlying mechanisms and potential therapeutic implications of these findings.
阿尔茨海默病（AD）是一种受多种因素影响的复杂神经退行性疾病，包括肝功能，肝功能可能会影响大脑中β淀粉样蛋白（Aβ）的清除。本研究旨在探讨载脂蛋白E（）ε4等位基因如何影响肝功能标志物与AD病理及认知之间的关系。
我们分析了来自两个独立队列的数据，其中包括732名来自翰林大学医学中心的参与者和483名来自阿尔茨海默病神经影像学倡议组织的参与者，每组均由携带和不携带ε4等位基因的个体组成。横断面分析评估了肝酶（天冬氨酸转氨酶[AST]、丙氨酸转氨酶[ALT]、碱性磷酸酶、总胆红素和白蛋白）与基线时AD诊断、淀粉样蛋白正电子发射断层扫描（PET）负荷以及AD的脑脊液生物标志物（Aβ42、总tau蛋白和磷酸化tau181）之间的关联。纵向来看，我们研究了这些肝酶与一年中认知表现变化之间的关联。使用逻辑回归和线性回归模型分析这些关联，并进行中介分析以评估年龄和淀粉样蛋白PET负荷是否介导了这些关联。
仅在ε4携带者组中，高AST与ALT比值和低ALT水平与AD诊断、淀粉样蛋白PET负荷增加以及两个队列中认知功能的更快纵向下降显著相关。特别是，AST与ALT比值仅在阿尔茨海默病神经影像学倡议队列的ε4携带者组中与脑脊液Aβ42水平相关，而与磷酸化tau或总tau水平无关。此外，两个队列的中介分析显示，在ε4携带者组中，年龄并未介导肝酶与AD诊断或淀粉样蛋白PET负荷之间的关联。然而，淀粉样蛋白PET负荷仅在ε4携带者组中部分介导了肝酶与AD诊断之间的关联。
本研究为ε4等位基因与肝酶的显著关联及其在AD中Aβ相关发病机制和认知中的潜在作用提供了有价值的见解。需要进一步的研究来阐明这些发现的潜在机制和治疗意义。
