Wang Zhiyuan, Guo Hongyu, Li Jianshuai, Hu Xuejie, Li Xin, Sun Jinping
Department of Emergency Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China.
Health Management Center, The Affiliated Hospital of Qingdao University, Qingdao, China.
Front Neurosci. 2025 Jul 16;19:1629254. doi: 10.3389/fnins.2025.1629254. eCollection 2025.
rs440446 (+ 113G/C), located in the intron of the APOE gene, has unclear effects on cognition, blood lipids, metabolic markers, and neural activity in older Chinese adults.
A total of 505 older adults from communities in Qingdao were enrolled and categorized into C-allele carriers ( = 451) and GG homozygotes ( = 54) based on the sequencing result. Neuropsychological tests, lipid/metabolic markers ( = 326), and resting-state fMRI (rs-fMRI) data ( = 216) were collected. Multivariable linear regression was used to assess associations between rs440446 and cognitive performance, lipids, and metabolic indicators. Subgroup analyses stratified by age, gender, and APOE ε4 status were conducted, along with interaction tests. Propensity score matching (PSM) was applied to balance sample sizes in the rs-fMRI subgroup. Fractional amplitude of low-frequency fluctuations (fALFF) was used to evaluate differences in spontaneous neural activity, and Pearson correlations were calculated between fALFF values and cognitive function.
rs440446 GG homozygotes were associated with poorer language function. This association was consistently observed in female, ≥ 60 years old, and APOE ε4 non-carrier subgroups. However, no significant relationship was found between the GG genotype and lipid or metabolic markers. In fALFF analysis, GG homozygotes exhibited decreased spontaneous neural activity in the left middle occipital gyrus (MOG.L) and right cuneus (CUN.R), while showing increased activity in the right superior temporal gyrus (STG.R) and left fusiform gyrus (FFG.L). Additionally, fALFF values in the CUN.R were positively correlated with attention, whereas fALFF values in the STG.R were negatively correlated with memory.
rs440446 GG homozygote may be associated with alterations in language function and spontaneous neural activity among older adults.
位于载脂蛋白E（APOE）基因内含子中的rs440446（+113G/C）对中国老年成年人的认知、血脂、代谢指标和神经活动的影响尚不明确。
招募了来自青岛社区的505名老年人，并根据测序结果将其分为C等位基因携带者（n = 451）和GG纯合子（n = 54）。收集了神经心理学测试、血脂/代谢指标（n = 326）和静息态功能磁共振成像（rs-fMRI）数据（n = 216）。采用多变量线性回归评估rs440446与认知表现、血脂和代谢指标之间的关联。进行了按年龄、性别和APOE ε4状态分层的亚组分析以及交互作用检验。应用倾向得分匹配（PSM）来平衡rs-fMRI亚组中的样本量。使用低频振幅分数（fALFF）评估自发神经活动的差异，并计算fALFF值与认知功能之间的Pearson相关性。
rs440446 GG纯合子与较差的语言功能相关。在女性、≥60岁和APOE ε4非携带者亚组中一致观察到这种关联。然而，未发现GG基因型与血脂或代谢指标之间存在显著关系。在fALFF分析中，GG纯合子在左侧枕中回（MOG.L）和右侧楔叶（CUN.R）的自发神经活动降低，而在右侧颞上回（STG.R）和左侧梭状回（FFG.L）的活动增加。此外，CUN.R中的fALFF值与注意力呈正相关，而STG.R中的fALFF值与记忆力呈负相关。
rs440446 GG纯合子可能与老年人的语言功能和自发神经活动改变有关。
