Exercise for Brain Health with Increased Genetic Risk for Alzheimer's Disease

项目总结。已知载脂蛋白E epsilon 4(apoE-e4)等位基因携带者基本上处于 认知能力下降和阿尔茨海默病(AD)的风险更大。然而，apoE-ε4等位基因遗传并不完美 预测谁会出现这种疾病的临床症状，表明可改变的生活方式因素，如 因为运动可以缓和其对疾病进展的影响。我们的团队是唯一有资格的，我们有 已发表的几项初步研究表明，体力活动可能为载脂蛋白E-ε4等位基因提供保护 携带者与AD相关的神经退行性变和认知能力下降。干预措施，如锻炼，甚至 适度推迟健康APOE-e4携带者的认知障碍或改善认知功能将 对公众健康有重大影响。然而，目前还不清楚运动是否会前瞻性地改变这种疾病 阿尔茨海默病遗传风险增加的健康无症状老年人的行为轨迹。焦点和 我们建议的创新之处在于检验运动训练将提高神经效率的假设 记忆提取过程中的网络，增加静息脑血流量、神经网络连接性和大脑皮层 厚度，并改善APOE-e4等位基因携带者的情景记忆性能。有三个关键知识 在AD的遗传风险人群中，运动是认知衰退的主要预防措施。首先，它没有 然而，运动在认知过程中提高了神经元网络的功能和效率，这一点已经得到了坚定的证实。 包括记忆恢复，在APOE-e4等位基因携带者中。其次，目前尚不清楚神经营养是否增加 运动对静息脑血流的影响延伸至载脂蛋白E-e4等位基因携带者。第三，它还没有被证明 运动干预将产生持久的影响，延缓认知能力下降或转化为MCI。这部小说和 我们建议的显著特点是通过磁共振成像和认知结果解决前两个知识差距 在认知正常的老年载脂蛋白E-e4等位基因携带者进行运动训练后。认知完整的载脂蛋白E-e4等位基因携带者 将随机分配到6个月的有监督的中等强度有氧运动训练(ET)或 有监督的灵活性运动控制(FC)。ET和FC每一个都包含基于组的练习组件 并在退休社区运营。我们的主要目标是比较干预前和干预后 1)MRI生物标记物的变化；以及2)由Rey听觉语言测量的情景记忆表现 学习测验(RAVLT)。我们假设，与FC相比，在ET之后，记忆过程中的大脑激活 恢复将减少，静息脑血流量和额区功能连接将增加， 情节记忆的表现也会有所改善。对干预措施的反应结果将在 基线和6个月。我们著名的名称辨别任务有几个优势来跟踪 任何对神经网络效率的干预都会激活与默认模式相关的脑区 网络“，已知含有淀粉样蛋白，并随着进展到阿尔茨海默病而被破坏。这项管理工作 与新冠肺炎疫情延误和费用相关的补充资金不会扩大母项目的范围。

PROJECT SUMMARY. Apolipoprotein E epsilon4 (APOE-e4) allele carriers are known to be at substantially greater risk for cognitive decline and Alzheimer’s disease (AD). Yet, APOE-ε4 allele inheritance is an imperfect predictor of who will develop clinical symptoms of the disease, suggesting that modifiable lifestyle factors such as exercise may moderate its influence on disease progression. Our team is uniquely qualified, and we have published several preliminary studies showing that physical activity may offer protection for APOE-ε4 allele carriers from AD-related neurodegeneration and cognitive decline. Interventions, such as exercise, that even modestly delay the onset of cognitive impairment or improve cognitive function in healthy APOE-e4 carriers will have a major public health impact. It is not yet known, however, if exercise prospectively modifies the disease trajectory in healthy asymptomatic older adults who are at increased genetic risk for AD. The focus and innovative aspect of our proposal is to test the hypothesis that exercise training will improve the efficiency of neural networks during memory retrieval, increase resting cerebral blood flow, neural network connectivity, and cortical thickness, and improve episodic memory performance in APOE-e4 allele carriers. There are three key knowledge gaps regarding exercise as a primary prevention of cognitive decline in those at genetic risk for AD. First, it has not yet been firmly established that exercise improves the function and efficiency of neuronal networks during cognition, including memory retrieval, in APOE-e4 allele carriers. Second, it is unknown if the neurotrophic and increased resting cerebral blood flow effects of exercise extend to APOE-e4 allele carriers. Third, it has not been demonstrated that an exercise intervention will have lasting effects that delay cognitive decline or conversion to MCI. The novel and distinguishing feature of our proposal is to address the first two knowledge gaps with MRI and cognitive outcomes after exercise training in cognitively intact older APOE-e4 allele carriers. Cognitively intact APOE-e4 allele carriers will be randomly assigned to 6-months of either supervised moderate intensity aerobic exercise training (ET) or supervised flexibility exercise control (FC). The ET and FC each contain a group-based exercise component and are run in retirement communities. Our primary aims are to compare pre-intervention to post-intervention changes in 1) MRI biomarkers; and 2) episodic memory performance measured by the Rey Auditory Verbal Learning Test (RAVLT). We hypothesize that after ET compared to FC, brain activation during memory retrieval will be reduced, resting cerebral blood flow and functional connectivity will increase in frontal regions, and episodic memory performance will improve. Outcomes in response to the intervention will be measured at baseline and 6 months. Our famous name discrimination task has several advantages to track the effects of any intervention on neural network efficiency and activates brain regions associated with the “default mode network”, which is known to harbor amyloid and to be disrupted with progression to AD. This administrative supplement related to COVID-19 pandemic delays and costs does not extend the scope of the parent project.