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

锻炼有益于大脑健康，但会增加阿尔茨海默病的遗传风险

• 批准号: 10407361
• 负责人: JEROME CARSON SMITH
• 金额: $ 60.8万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407361
• 关键词: Address; Administrative Supplement; Aerobic Exercise; Alleles; Alzheimer associated neurodegeneration; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Apolipoprotein E; Attenuated; Auditory; Biological Markers; Brain; Brain region; COVID-19 pandemic; Cardiovascular system; Cerebrovascular Circulation; Clinical; Cognition; Cognitive; Communities; Dementia; Discrimination; Disease; Disease Progression; Elderly; Episodic memory; Exercise; Genetic Risk; Health; Impaired cognition; Intervention; Knowledge; Magnetic Resonance Imaging; Measures; Memory; Metabolic; Names; Neurons; Outcome; Performance; Physical Function; Physical activity; Primary Prevention; Public Health; Publishing; Quality of life; Randomized; Rest; Retirement; Risk; Running; Supervision; Symptoms; Testing; Thick; Verbal Learning; apolipoprotein E-4; base; brain health; cognitive function; comorbidity; cost; exercise intervention; exercise training; flexibility; improved; improved functioning; innovation; intervention effect; magnetic resonance imaging biomarker; memory retrieval; modifiable lifestyle factors; neural network; novel; parent project; post intervention; prospective; response; side effect

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.

项目摘要已知载脂蛋白 E epsilon4 (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。 谁将出现该疾病的临床症状的预测因子，表明可改变的生活方式因素，例如 因为运动可能会减轻其对疾病进展的影响，我们的团队具有独特的资质，而且我们拥有。 发表的几项初步研究表明体力活动可能为 APOE-ε4 等位基因提供保护 AD 相关神经变性和认知能力下降的携带者，甚至包括运动等干预措施。 适度延缓认知障碍的发生或改善健康 APOE-e4 携带者的认知功能将 然而，目前尚不清楚运动是否能够前瞻性地改变这种疾病。 AD 遗传风险增加的健康无症状老年人的轨迹。 我们提案的创新之处是检验运动训练将提高神经系统效率的假设 记忆检索期间的网络，增加静息脑血流量、神经网络连接和皮质 APOE-e4 等位基因携带者的厚度和提高情景记忆性能有三个关键知识。 运动作为 AD 遗传风险人群认知能力下降的主要预防措施存在分歧。 现已证实，运动可以改善认知过程中神经网络的功能和效率， 包括记忆恢复，在 APOE-e4 等位基因携带者中，尚不清楚神经营养是否增加。 运动对静息脑血流的影响也适用于 APOE-e4 等位基因携带者。第三，尚未得到证实。 运动干预将产生持久的效果，延缓认知能力下降或向 MCI 的转变。 我们提案的显着特点是通过 MRI 和认知结果来解决前两个知识差距 对认知完整的老年 APOE-e4 等位基因携带者进行运动训练后。 将被随机分配接受为期 6 个月的监督中等强度有氧运动训练 (ET) 或 监督灵活性运动控制 (FC) ET 和 FC 均包含基于小组的运动组件。 我们的主要目标是比较干预前和干预后。 1) MRI 生物标志物的变化；以及 2) 通过 Rey 听觉语言测量的情景记忆表现 学习测试（RAVLT）我们勇敢地承认，与 FC 相比，ET 后，记忆过程中的大脑激活。 检索将减少，额叶区域的静息脑血流量和功能连接将增加， 情景记忆表现将在干预后得到改善。 我们的著名名字歧视任务在跟踪效果方面有几个优势。 对神经网络效率的任何干预都会激活与“默认模式”相关的大脑区域 网络”，已知该网络含有淀粉样蛋白，并会随着 AD 的进展而受到破坏。 与 COVID-19 大流行延误和费用相关的补充不会扩大父项目的范围。

项目成果

Evidence for exercise-related plasticity in functional and structural neural network connectivity.

功能和结构神经网络连接中与运动相关的可塑性的证据。

• 发表时间: 2021-12
• 影响因子: 8.2
• 作者: Won, Junyeon;Callow, Daniel D;Pena, Gabriel S;Gogniat, Marissa A;Kommula, Yash;Arnold;Jordan, Leslie S;Smith, J Carson
• 通讯作者: Smith, J Carson