执行功能（Executive Function，EF）是对其他认知过程进行控制和调节的高级认知过程，是个体实现学习、推理和问题解决等智力活动的重要成分。研究表明，载脂蛋白E（Apolipoprotein E，APOE）基因多态性（Gene polymorphism）是各种神经退行性疾病的高强危险因素，包含6种不同的遗传基因表型，其中，携带APOEε4等位基因的个体是执行功能发生病理性受损的高危人群，其脑的功能活动和结构形态上均表现出异常，即使是年轻群体也存在相同的风险。虽然个体执行功能的发展受到遗传基因的影响，但近年来的研究也初步表明后天环境因素对执行功能发展的影响也不可忽视；当前，探索降低APOEε4基因对执行功能负面影响的有效途径已经成为多学科研究前沿与热点。

研究表明，有氧运动能力是影响个体执行功能发展和脑健康的重要因素。针对老年人和阿尔茨海默症患者的研究发现，较高的有氧运动能力可以延缓APOEε4基因对执行功能的负面影响。还有研究发现，规律的运动可以有效地缓解携带APOEε4基因老年人和阿尔茨海默症患者的执行功能衰退和损伤。近期，有研究（包括本团队的前期研究）发现，运动干预能够通过提升有氧运动能力进而提高大学生的执行功能。那么，有氧运动能力是否是降低APOEε4基因对大学生执行功能负面影响的关键因素；运动干预是否能够通过提升有氧运动能力，进而降低APOEε4基因对大学生执行功能的负面影响，与未携带APOEε4基因大学生相比，干预效果的差异及其机制如何，均值得深入探讨。

基于此，本研究以大学生为研究对象，首次综合采用体育测量技术、心理测量技术、分子遗传学技术和影像学技术，探索有氧运动能力对APOEε4基因影响大学生执行功能的调控作用；在此基础上，采用针对提升有氧运动能力的运动干预方案，对携带、未携带APOEε4大学生进行9周运动干预，揭示其降低APOEε4基因对大学生执行功能负面影响的作用及机制，为采用运动手段降低APOEε4基因对执行功能的负面影响提供干预靶点和神经生物学机制。本研究包括两部分：

研究一 APOEε4基因与有氧运动能力对大学生执行功能和脑结构形态的交互影响。以113名大学生为研究对象，采用2（有氧运动能力：高、低）×2（APOEε4基因：携带、未携带）组间实验设计。运用双因素方差分析高低有氧运动能力对携带、未携带APOEε4基因大学生执行功能各子功能（反应时、正确率）和脑结构形态（灰质体积、皮层厚度）的影响差异，结果发现：（1）在执行功能各子功能反应时上，APOEε4基因与有氧运动能力对大学生抑制、转换反应时的交互效应显著，具体表现为，在低有氧运动能力大学生中，携带APOEε4组抑制、转换功能反应时显著大于未携带APOEε4组；在高有氧运动能力大学生中，携带APOEε4组转换功能反应时显著小于未携带APOEε4组，抑制功能反应时无显著性差异；在携带APOEε4基因大学生中，高有氧运动能力组抑制、转换功能反应时显著小于低有氧运动能力组；在未携带APOEε4基因大学生中，高有氧运动能力组抑制、转换功能反应时显著小于低有氧运动能力组。APOEε4基因与有氧运动能力对大学生刷新功能反应时的交互效应不显著，但有氧运动能力的主效应显著，具体表现为，在携带、未携带APOEε4基因大学生中，高有氧运动能力组刷新功能反应时显著小于低有氧运动能力组。表明APOEε4基因对低有氧运动能力大学生的抑制、转换功能具有负面影响，对高有氧运动能力大学生的抑制、刷新和转换功能均无影响，高有氧运动能力对携带、未携带APOEε4基因大学生抑制、刷新和转换功能具有促进作用。（2）在执行功能各子功能正确率上，APOEε4基因与有氧运动能力对大学生执行功能各子功能正确率的交互效应均不显著。（3）在脑灰质体积上，有氧运动能力与APOEε4基因交互作用显著的脑区包括：右侧小脑、右侧额下回、右侧枕中回和右侧顶下小叶。具体表现为，在低有氧运动能力大学生中，携带APOEε4组的右侧小脑、右侧枕中回、右侧额下回灰质体积显著小于未携带APOEε4组；在高有氧运动能力大学生中，携带APOEε4组的右侧顶下小叶灰质体积显著小于未携带APOEε4组；在携带APOEε4基因大学生中，高有氧运动能力组右侧顶下小叶灰质体积显著小于低有氧运动能力组，右侧枕中回显著大于低有氧运动能力组；在未携带APOEε4基因大学生中，高有氧运动能力组右侧枕中回灰质体积显著大于低有氧运动能力组。表明APOEε4基因引起低有氧运动能力大学生右侧小脑、右侧枕中回、右侧额下回灰质体积变小，高有氧运动能力促进携带APOEε4基因大学生右侧顶下小叶灰质体积变小和右侧枕中回灰质体积增大，促进未携带APOEε4基因大学生右侧枕中回灰质体积增大。（4）在脑皮层厚度上，有氧运动能力与APOEε4基因交互作用显著的是左侧颞上沟，具体表现为，在高、低有氧运动能力大学生中，携带APOEε4组的左侧颞上沟皮层厚度与未携带APOEε4组均无显著性差异，在携带、未携带APOEε4基因大学生中，高有氧运动能力组左侧颞上沟皮层厚度均显著小于低有氧运动能力组。表明高有氧运动能力促进携带、未携带APOEε4基因大学生左侧颞上沟皮层厚度变薄。

研究二 运动干预对携带、未携带APOEε4大学生执行功能的影响及机制。以84名在校大学生为研究对象，采用2（组别：运动组、对照组）×2（APOEε4基因：携带、未携带）×2（时间：干预前、干预后）混合实验设计，采用三因素重复测量方差分析比较运动干预前后各组有氧运动能力、执行功能各子功能（反应时、正确率）和脑结构形态（灰质体积、皮层厚度）的变化及差异，结果发现：（1）在有氧运动能力上，干预前携带APOEε4运动组的有氧运动能力显著低于未携带APOEε4运动组，干预后携带、未携带APOEε4运动组大学生的有氧运动能力均显著提高，且组间无显著差异，表明运动干预能够提升携带、未携带APOEε4大学生有氧运动能力，且携带APOEε4运动组效果更好。（2）在执行功能各子功能上，干预前携带APOEε4运动组的抑制、转换功能反应时显著大于未携带APOEε4运动组，干预后携带、未携带APOEε4运动组大学生抑制、刷新、转换功能反应时显著缩短，且干预后携带APOEε4运动组大学生抑制、转换功能与未携带APOEε4运动组无显著性差异，但携带APOEε4对照组大学生抑制、转换反应时显著增加；运动干预后携带、未携带APOEε4运动组大学生执行功能各子功能正确率均无显著性变化。表明运动干预能够促进携带、未携带APOEε4大学生抑制、刷新、转换功能，且携带APOEε4大学生在抑制、转换功能上干预效果更好，携带APOEε4对照组大学生抑制和转换功能随时间变差。（3）在脑灰质体积上，干预前后，携带APOEε4运动组大学生左侧额上回、左侧小脑和左侧内侧前额叶共3个脑区的灰质体积显著增加，携带APOEε4对照组大学生左侧额上回灰质体积显著减小，未携带APOEε4运动组大学生左侧额上回1个脑区的灰质体积显著增加，表明运动干预使得携带、未携带APOEε4大学生脑灰质体积增大，且携带APOEε4组增加脑区更多。（4）在脑皮层厚度上，干预前后，携带APOEε4运动组大学生左侧顶上小叶和左侧顶下小叶的皮层厚度显著下降，而未携带APOEε4运动组皮层厚度无显著性变化，表明运动干预使得携带APOEε4大学生皮层厚度变薄。（5）基因-脑-行为关联分析，在携带APOEε4大学生中，左侧顶下小叶皮层厚度变薄在有氧运动能力提升与抑制功能提高的关系中起到中介作用。

综上，研究得出以下结论：

（1）携带、未携带APOEε4基因的低有氧运动能力大学生均具有更差的抑制、转换功能和脑结构形态特征，携带、未携带APOEε4基因的高有氧运动能力大学生均具有更好的抑制、刷新、转换功能和脑结构形态特征，因此，有氧运动能力在APOEε4基因影响大学生执行功能和脑结构形态中可能起到了调控作用。

（2）运动干预能够提升携带、未携带APOEε4基因大学生有氧运动能力和执行功能各子功能，且对携带APOEε4大学生有氧运动能力和抑制、转换功能的提升效果更好；运动干预能够降低APOEε4基因对大学生抑制、转换功能的负面影响。

（3）运动干预能够增大携带、未携带APOEε4基因大学生脑灰质体积，且携带APOEε4大学生脑灰质体积增大的区域更多，能够促进携带APOEε4大学生顶叶区域皮层发育的成熟；运动干预能够降低APOEε4基因对大学生脑灰质体积的负面影响。

（4）运动干预降低APOEε4基因对大学生抑制功能负面影响的潜在机制是：有氧运动能力的提升，促进了左侧顶下小叶的皮质发育成熟，进而提高了抑制功能。

Executive Function (EF) is a high-level cognitive process that controls and regulates other cognitive processes, and is an important component of an individual's intellectual activities such as learning, reasoning and problem solving.Studies have shown that Apolipoprotein E (ApoE) Gene polymorphism is a high risk factor for various neurodegenerative diseases, including 6 different genetic phenotypes.Individuals with the APOEε4 allele are at high risk for pathological impairment of executive function, with abnormalities in functional activity and structural morphology of the brain, even in younger populations.Although the development of individual executive function is affected by genetic factors, recent studies have initially shown that the influence of environmental factors on the development of executive function can not be ignored.At present, the exploration of effective ways to reduce the negative effect of APOEε4 gene on executive function has become the frontier and hotspot of multidisciplinary research.

Studies have shown that aerobic exercise capacity is an important factor affecting the development of individual executive function and brain health.Studies in older adults and Alzheimer's patients have found that higher aerobic exercise capacity may delay the negative effects of the APOEε4 gene on executive function.Other studies have found that regular exercise can effectively reduce the decline and impairment of executive function in the elderly carrying the APOEε4 gene and Alzheimer's disease patients.Recent studies (including our previous research) have found that exercise intervention can improve executive function of college students by improving aerobic exercise capacity.Whether aerobic exercise ability is the key factor to reduce the negative effect of APOEε4 gene on executive function of college students;Whether exercise intervention can reduce the negative effect of ApoE ε4 gene on executive function of college students by improving aerobic exercise ability, and the difference of intervention effect and its mechanism compared with those of college students without ApoE ε4 gene are worth further discussion.

Based on this, this study, taking college students as the research object, used physical measurement technology, psychological measurement technology, molecular genetics technology and imaging technology for the first time to explore the effect of aerobic exercise ability on the executive function of college students ApoE ε4 gene regulation.On this basis, the exercise intervention program aimed at improving aerobic exercise ability was used for 9 weeks in college students with and without ApoE ε4, to reveal the effect and mechanism of reducing the negative effect of ApoE ε4 gene on executive function of college students.To provide an intervention target and neurobiological mechanism for reducing the negative effect of APOEε4 gene on executive function by exercise.This study includes two parts:

Study1:To investigate the interaction of APOEε4 gene and aerobic exercise ability on executive function and brain morphology of college students.In this study, 113 college students were enrolled in a 2 (high and low aerobic exercise capacity) ×2 (with and without the APOEε4 gene) intergroup design.Two-way variance analysis was used to analyze the effects of high and low aerobic exercise ability on the executive function subfunctions (response time, accuracy) and brain structure (gray matter volume, cortex thickness) of college students with and without APOEε4 gene. The results showed that:(1) The interaction effect of ApoE ε4 gene and aerobic capacity on the inhibition and conversion response of executive function subfunctions was significant. Specifically, the inhibition and conversion response of ApoE ε4 group was significantly higher than that of the group without ApoE ε4 in the low aerobic capacity college students.Among the college students with high aerobic exercise ability, the conversion response time of the group with ApoE ε4 was significantly lower than that of the group without ApoE ε4, but there was no significant difference in the inhibition of functional response.Among college students with ApoE ε4 gene, the inhibition and conversion responses of high aerobic exercise ability group were significantly lower than those of low aerobic exercise ability group.Among college students without APOEε4 gene, the inhibition and conversion responses of high aerobic exercise ability group were significantly lower than those of low aerobic exercise ability group.There was no significant interaction between ApoE ε4 gene and aerobic capacity on the response to refresh function, but the main effect of aerobic capacity was significant. Specifically, in the college students with and without ApoE ε4 gene, the response to refresh function in the high aerobic capacity group was significantly lower than that in the low aerobic capacity group.The results showed that the ApoE ε4 gene had a negative effect on the inhibition and conversion function of the college students with low aerobic exercise ability, but had no effect on the inhibition, refresh and conversion function of the college students with high aerobic exercise ability, and the high aerobic exercise ability had a promoting effect on the inhibition, refresh and conversion function of the college students with and without ApoE ε4 gene.(2) ApoE ε4 gene and aerobic exercise ability had no significant interaction effect on the accuracy of executive function sub-functions.(3) The right cerebellum, the right inferior frontal gyrus, the right middle occipital gyrus, and the right inferior parietal lobule showed significant interaction between aerobic exercise capacity and the APOEε4 gene in the gray matter volume.Specifically, the gray matter volume of the right cerebellum, right middle occipital gyrus and right inferior frontal gyrus in the low aerobic exercise ability group was significantly lower than that in the non-carrying group.Among college students with high aerobic exercise capacity, the right inferior parietal lobular gray matter volume of the group carrying ApoE ε4 was significantly lower than that of the group without ApoE ε4.Among college students with ApoE ε4 gene, the right inferior parietal lobular gray matter volume in the high aerobic exercise capacity group was significantly lower than that in the low aerobic exercise capacity group, and the right middle occipital gyrus was significantly higher than that in the low aerobic exercise capacity group.In college students without APOEε4 gene, the gray matter volume of right middle occipital gyrus in the high aerobic exercise ability group was significantly higher than that in the low aerobic exercise ability group.Show that APOE epsilon4 genes low aerobic exercise ability to college students on the right side of the cerebellum in return, the right inferior frontal gyrus, right occipital gray matter volume smaller, high aerobic exercise ability promote carry APOE epsilon4 gene under the college students on the right side of the top lobule gray matter volume decreases and the right side of the pillow back to gray matter volume increases, promoting college did not carry APOE epsilon4 gene on the right side of the pillow back in gray matter volume increase.(4) In terms of cerebral cortex thickness, the interaction between aerobic exercise capacity and ApoE ε4 gene was significant in the left superior temporal sulcus. Specifically, there was no significant difference in the left superior temporal sulcus cortex thickness between the high and low aerobic exercise capacity college students and those without ApoE ε4.The cortical thickness of the left superior temporal sulcus in the high aerobic exercise ability group was significantly lower than that in the low aerobic exercise ability group.The results showed that high aerobic exercise ability promoted the thinning of the left superior temporal sulcus cortex in college students with and without APOEε4 gene.

Study2: To study the effect and mechanism of exercise intervention on executive function of college students with and without APOEε4.Eighty-four college students were selected as the study subjects, and 2 (group: exercise group, control group) ×2 (ApoE ε4 gene: carried, not carried) ×2 (time:A mixed experiment was designed before and after the intervention. Three-factor repeated-measure ANOVA was used to compare the changes and differences of aerobic exercise capacity, executive function sub-functions (response time, accuracy) and brain structure (gray matter volume, cortex thickness) of each group before and after the intervention. The results showed that:(1) In terms of aerobic exercise capacity, the aerobic exercise capacity of the group carrying ApoE ε4 before intervention was significantly lower than that of the group without ApoE ε4. After intervention, the aerobic exercise capacity of both the group carrying ApoE ε4 and the group without ApoE ε4 increased significantly, and there was no significant difference between the two groups.The results showed that the exercise intervention could improve the aerobic exercise ability of college students with and without ApoE ε4, and the exercise group with ApoE ε4 had better effect.(2) In the executive function subfunctions, the inhibition and conversion response times of the group carrying ApoE ε4 exercise before intervention were significantly higher than that of the group without ApoE ε4 exercise. The inhibition, refresh and conversion response times of the group carrying ApoE ε4 exercise after intervention were significantly shorter.After intervention, there was no significant difference in the inhibition and conversion function between the group carrying ApoE ε4 exercise and the group not carrying ApoE ε4 exercise, but the inhibition and conversion response were significantly increased in the control group.After exercise intervention, there was no significant change in the correct rate of each subfunction of executive function in the exercise group with or without APOEε4.The results showed that the exercise intervention could promote the inhibition, refresh and conversion function of college students with and without ApoE ε4, and the intervention effect on the inhibition and conversion function of college students with ApoE ε4 was better, and the inhibition and conversion function of college students with ApoE ε4 decreased with time in the control group.(3) Before and after the intervention, the gray matter volume in the left superior frontal gyrus, left cerebellum and left medial prefrontal cortex of college students in the exercise group with ApoE ε4 significantly increased, while the gray matter volume in the control group with ApoE ε4 significantly decreased.The gray matter volume of one brain region in the left superior frontal gyrus of college students without ApoE ε4 exercise group increased significantly, suggesting that the gray matter volume of college students with and without ApoE ε4 exercise group increased significantly, and the gray matter volume of college students with ApoE ε4 increased more.(4) Before and after the intervention, the left parietal lobule and the left inferior parietal lobule thickness were significantly decreased in the group carrying ApoE ε4 exercise, while there was no significant change in the group without ApoE ε4 exercise, suggesting that the intervention resulted in the thinning of the cortex.(5) Analysis of gene-brain-behavior association showed that the thinning of the left inferior parietal cortex played a mediating role in the relationship between the improvement of aerobic exercise ability and the improvement of inhibitory function in college students with APOEε4.

To sum up, the study draws the following conclusions:

(1) The ApoE ε4 gene had a negative effect on the inhibition and conversion function of college students with low aerobic exercise ability, but had no effect on the refreshing function. High aerobic exercise ability had a positive effect on the inhibition and conversion function of college students with ApoE ε4 gene.ApoE ε4 gene had a negative effect on the gray matter volume of college students with low aerobic exercise ability, while high aerobic exercise ability had a positive regulation effect on the gray matter volume of college students with ApoE ε4 gene.

(2) Exercise intervention can improve the aerobic exercise capacity and executive function of college students with and without ApoE ε4 gene, and has better effect on the aerobic exercise capacity, inhibition and conversion function of college students with ApoE ε4 gene; Exercise intervention can reduce the negative effects of APOEε4 gene on the inhibition and conversion function of college students.

(3) Exercise intervention can increase the gray matter volume of college students with and without ApoE ε4 gene, and the gray matter volume of college students with ApoE ε4 gene increased more areas, can promote the development of parietal cortex maturation of college students with ApoE ε4 gene; Exercise intervention can reduce the negative effect of APOEε4 gene on gray matter volume in college students.

(4) The potential mechanism of exercise intervention to reduce the negative effect of APOEε4 gene on inhibitory function of college students is that the improvement of aerobic exercise ability promotes the development and maturation of the cortex of the left inferior parietal lobule, and thus enhances the inhibitory function.