Study on Interactive Effects of APOE <i>ε</i>4 and Tau Pathology on Cognitive Trajectories in Mild Cognitive Impairment

背景：轻度认知障碍(MCI)被认为是阿尔茨海默病(AD)由正常衰老向痴呆进展的关键过渡阶段。APOE ε4是AD最主要的遗传易感基因，已被广泛证实与Aβ沉积及tau蛋白异常密切相关。然而，APOE ε4与tau蛋白在认知功能变化中的交互作用尚不明确，尤其是在MCI人群中。方法：本研究从阿尔茨海默病神经影像学倡议(ADNI)数据库中纳入了321例轻度认知障碍(MCI)受试者，并进行了为期2年的随访观察。APOE ε4携带者(APOE ε4+)定义为携带至少一个ε4等位基因。tau阳性(T+)定义为脑脊液(CSF)中p-tau181浓度 ≥ 23 pg/mL。采用线性混合效应模型评估APOE ε4状态与tau状态(基于CSF p-tau181水平)对认知功能纵向变化的影响。结果：与APOE ε4非携带者相比，APOE ε4携带者有更严重的Aβ和tau病理负荷，更显著的情景记忆、执行功能和整体认知衰退。随访2年发现，APOE ε4携带者在执行功能、整体认知、日常功能和注意力方面呈现出更快的退化趋势。进一步的组间比较显示，与APOE ε4−/T+组相比，APOE ε4+/T+组在日常功能、注意力和执行功能方面的退化显著加剧；同时，相较于APOE ε4−/T−组，APOE ε4+/T+组在整体认知水平上也表现出显著下降。这些结果共同支持APOE ε4与tau状态之间可能存在协同交互作用，加速认知功能衰退。此外，在APOE ε4携带者中，T+个体较T−个体在整体认知和日常功能方面的退化亦更为显著，进一步提示tau病理可能在APOE ε4背景下加剧认知恶化。结论：本研究强调了APOE ε4与tau状态对MCI患者认知功能变化的交互影响，提示二者在MCI向AD进展过程中的潜在协同作用。Background: Mild cognitive impairment (MCI) is considered a critical transitional stage in the progression from normal aging to dementia in Alzheimer’s disease (AD). APOE ε4 is the most prominent genetic susceptibility factor for AD and has been widely confirmed to be closely associated with Aβ deposition and tau protein abnormalities. However, the combined effects of APOE ε4 and tau protein on cognitive function changes remain unclear, particularly in individuals with MCI. Methods: This study included 321 individuals with mild cognitive impairment (MCI) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, who were followed for a period of two years. APOE ε4 carriers (APOE ε4+) were defined as individuals carrying at least one ε4 allele. Tau positivity (T+) was determined based on a cerebrospinal fluid (CSF) p-tau181 concentration ≥ 23 pg/mL. Linear mixed-effects models were used to assess the impact of APOE ε4 status and tau status (based on CSF p-tau181 levels) on longitudinal changes in cognitive function. Results: APOE ε4 carriers exhibited a greater burden of Aβ and tau pathology and showed significantly poorer performance in episodic memory, executive function, and global cognition compared to non-carriers of APOE ε4. Over the 2-year follow-up period, APOE ε4 carriers demonstrated a more rapid decline across multiple cognitive domains, including executive function, global cognition, functional abilities, and attention. Further groupwise comparisons revealed that, compared to the APOE ε4−/T+ group, the APOE ε4+/T+ group experienced significantly greater declines in functional abilities, attention, and executive function. Additionally, compared to the APOE ε4−/T− group, the APOE ε4+/T+ group exhibited a significantly greater decline in global cognition. These findings collectively support a potential synergistic interaction between APOE ε4 and tau status in accelerating multidomain cognitive deterioration. Moreover, among APOE ε4 carriers, T+ individuals exhibited more pronounced declines in global cognition and functional ability than T− individuals, further suggesting that tau pathology may exacerbate cognitive decline in the context of APOE ε4. Conclusion: This study highlights the interactive effect of APOE ε4 and tau status on cognitive function changes in patients with MCI, suggesting a potential synergistic role of both factors in the progression from MCI to AD.