Interactive Effects of APOE <i>ε</i>4 and Amyloid-<i>β</i> on Cerebrospinal Fluid Biomarkers, Hippocampal Atrophy, and Cognitive Decline in Individuals with Mild Cognitive Impairment

背景：轻度认知障碍(MCI)被视为阿尔茨海默病(AD)的临床前期阶段。载脂蛋白E (APOE) ε4等位基因是散发性AD最明确的遗传风险因子之一，其在Aβ沉积、tau病理和认知功能障碍中的作用已被广泛报道。然而，APOE ε4与Aβ状态在MCI阶段对脑脊液生物标志物、脑结构及认知功能变化的交互影响尚不明确。方法：本研究基于阿尔茨海默病神经影像学倡议(ADNI)数据库，纳入396例符合MCI诊断的受试者。Aβ阳性(Aβ+)定义为18F-AV45 PET标准摄取值比(SUVR) ≥ 1.11，APOE ε4携带者(APOE ε4+)为至少携带一个ε4等位基因者。采用多元线性回归模型探讨APOE ε4与Aβ的对脑脊液Aβ1-42、t-tau和p-tau181水平、海马体积及认知功能的交互作用。结果：与非携带者相比，APOE ε4携带者的脑脊液Aβ1-42水平显著降低，t-tau和p-tau181水平显著升高，提示其具有更严重的Aβ沉积与tau病理负荷。其次，APOE ε4携带者在海马体积、情景记忆、执行功能、语言能力及整体认知能力方面表现出显著下降。此外，进一步分析显示，APOE ε4+/Aβ+个体的脑脊液t-tau和p-tau181水平升高，海马萎缩和认知退化最为明显，提示二者在MCI阶段可能协同促进神经退行性进展。结论：本研究强调了APOE ε4与Aβ状态在MCI患者中对脑脊液生物标志物，脑结构改变及认知功能损害的交互影响，支持其在AD早期发病机制中的协同作用。Background: Mild cognitive impairment (MCI) is widely recognized as a prodromal stage of Alzheimer’s disease (AD). The apolipoprotein E ε4 (APOE ε4) allele is a well-established genetic risk factor for sporadic AD and has been implicated in Aβ accumulation, tau pathology, and cognitive decline. However, the interactive effects of APOE ε4 and Aβ status on cerebrospinal fluid (CSF) biomarkers, brain structure, and cognitive outcomes in individuals with MCI remain unclear. Methods: A total of 396 individuals with MCI were included from the ADNI database. Aβ positivity (Aβ+) was defined as a standardized uptake value ratio (SUVR) ≥ 1.11 on 18F-AV45 PET imaging. APOE ε4 carriers (APOE ε4+) were defined as individuals possessing at least one ε4 allele. Multivariable linear regression models were employed to assess the interaction effects of APOE ε4 status and Aβ positivity on CSF Aβ1-42, total tau (t-tau), phosphorylated tau at threonine 181 (p-tau181), hippocampal volume, and cognitive performance. Results: Compared with non-carriers, APOE ε4 carriers exhibited significantly reduced levels of CSF Aβ1-42 and significantly elevated levels of t-tau and p-tau181, indicating more severe Aβ deposition and tau pathological burden. Additionally, APOE ε4 carriers showed significant declines in hippocampal volume, episodic memory, executive function, language ability, and global cognitive function. Furthermore, further analysis revealed that individuals who were APOE ε4+/Aβ+ had the most pronounced increases in CSF t-tau and p-tau181 levels, as well as the most significant hippocampal atrophy and cognitive decline, suggesting that the two factors may synergistically promote neurodegenerative progression during the MCI stage. Conclusion: This study emphasizes the interactive effects of APOE ε4 and Aβ status on CSF biomarkers, brain structural changes, and cognitive impairment in patients with MCI, supporting their synergistic role in the early pathogenesis of AD.