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

项目摘要。已知载脂蛋白E ε 4（APOE-e4）等位基因携带者基本上是 认知能力下降和阿尔茨海默病（AD）的风险更大。然而，APOE-ε4等位基因遗传是一个不完美的， 预测谁将发展疾病的临床症状，这表明，可改变的生活方式因素， 因为运动可以缓和其对疾病进展的影响。我们的团队是唯一合格的，我们有 发表了几项初步研究，表明体力活动可能会保护APOE-ε4等位基因 AD相关神经退行性变和认知能力下降的携带者。干预措施，如运动，甚至 适度延迟健康APOE-e4携带者的认知障碍发作或改善认知功能， 对公众健康有重大影响。然而，目前尚不清楚运动是否能前瞻性地改变这种疾病 在健康无症状老年人中，AD的遗传风险增加。的重点和 我们的建议的创新方面是测试假设，运动训练将提高神经的效率， 在记忆检索过程中，增加静息脑血流量，神经网络连接和皮质 厚度，并改善APOE-e4等位基因携带者的情景记忆表现。有三个关键知识 关于运动作为AD遗传风险人群认知能力下降的主要预防的差距。首先，它没有 然而已经确定的是，运动可以改善认知过程中神经网络的功能和效率， 包括记忆提取。其次，尚不清楚是否神经营养和增加 运动对APOE-e4等位基因携带者静息脑血流的影响。三是没有经过论证 运动干预将产生持久的影响，延迟认知能力下降或转化为MCI。小说和 我们建议的一个显著特点是解决MRI和认知结果的前两个知识差距 在认知完整的老年APOE-e4等位基因携带者中运动训练后。APOE-e4等位基因携带者 将被随机分配到6个月的监督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都包含一个基于组的运动组件 在退休社区里运营。我们的主要目的是比较干预前和干预后 1）MRI生物标志物的变化;和2）通过Rey听觉言语测试测量的情景记忆表现 学习测试（RAVLT）。我们假设，与FC相比，ET后，记忆过程中的大脑激活 提取将减少，额叶区域的静息脑血流量和功能连接将增加， 情景记忆能力也会提高干预措施的结果将在以下方面进行衡量： 基线和6个月。我们著名的名字辨别任务有几个优点，可以跟踪 对神经网络效率的任何干预都可以激活与“默认模式”相关的大脑区域 已知淀粉样蛋白含有淀粉样蛋白，并且随着向AD的进展而被破坏。这一行政 与COVID-19疫情延迟及成本相关的补充并未扩大母项目的范围。

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.