The Effect of Physical Activity on Cognition Relative to APOE Genotype

体力活动对 APOE 基因型认知的影响

基本信息

批准号：
8385445
负责人：
JENNIFER L ETNIER
金额：
$ 21.53万
依托单位：
UNIVERSITY OF NORTH CAROLINA GREENSBORO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8385445
关键词：
Adherence Adverse effects Alzheimer&apos s Disease Alzheimer&apos s disease risk Animals Apolipoproteins Behavioral Brain-Derived Neurotrophic Factor Cognition Cognitive Data Development Dose Elderly Family history of Future Gender Genetic Risk Genotype Gray unit of radiation dose Human Impaired cognition Individual Intervention Length Link Literature Maintenance Measures Mediating Memory Memory impairment Modeling Motivation Participant Performance Peripheral Persons Physical activity Prevalence Prevention strategy Preventive Process Prospective Studies Public Health Randomized Controlled Trials Recruitment Activity Relative (related person)Research Research Design Resources Risk Role Sampling Simulate Statistical Methods Statistical Models Susceptibility Gene Techniques Testing Time Work apolipoprotein E-4 base cost effective design effective intervention executive function experience interest middle age mild neurocognitive impairment performance tests pre-clinical programs prospective research study response simulation

项目摘要

DESCRIPTION (provided by applicant): By 2030, the global prevalence of Alzheimer's disease (AD) is predicted to reach 65.7 million. Despite worldwide research efforts, a cure for AD has not been identified. Thus, it is important to identify preventive strategies that can reduce the risk of or delay the onset of AD [1]. Physical activity (PA) has potential as a preventative strategy. Our research [2, 3] and that of others [4, 5] shows that older adults who participate in PA experience larger gains in cognitive performance than do controls. Prospective studies also show that PA is associated with a lower risk of AD [6-9] and that the relationship between baseline PA and subsequent cognitive performance is moderated by a susceptibility gene for AD (apolipoprotein, APOE) [10-13]. However, the potential moderating role of APOE genotype on the effects of PA on cognitive performance has not been tested experimentally in humans; thus we do not know who receives the greatest cognitive benefits from PA. Additionally, we do not understand the mechanisms which explain how PA benefits cognitive performance. These gaps in the literature are the motivation behind our long range plan of research designed to further our understanding of the potential role of PA in the mitigation of cognitive decline and in the delay of AD. These gaps are also the impetus for this specific study in which we: 1) establish the feasibility of an 8-month PA intervention with persons with a family history of AD and use statistical modeling to inform the design of a future randomized control trial (RCT); 2) assess change in cognitive performance across the PA intervention and determine whether this change differs as a function of APOE genotype; 3) determine whether change in peripheral brain-derived neurotrophic factor, pBDNF (which is a plausible mechanism of the effects and has been linked to AD) predicts change in cognitive performance across the PA intervention; and 4) examine the differential effects of APOE genotype on the effects of PA on various cognitive domains. We will ascertain APOE genotype in 100 older cognitively normal individuals to identify APOE e4 carriers (n=30) and gender-matched non-carriers (n=30) to participate in an 8-month PA program. We will assess cognitive performance at baseline and will assess cognitive performance and pBDNF at the pre-test, mid-test, and post-test. This initial study will provide foundational evidence and will guide the development of a RCT further testing the moderating role of APOE genotype and the mediating role of pBDNF on the effects of PA on cognitive performance. The identification of effective interventions for the maintenance of cognitive performance in older adults at risk for AD has important public health implications because few preventive strategies for AD have been identified and because a therapy that delays the development of AD by 5 years could reduce the risk of AD by 50%. PA has promise in this regard and is particularly attractive because it is cost-effective and has relatively few negative side-effects. Further, if PA is beneficial for persons with a genetic risk for AD, this cold be particularly important because these individuals show signs of preclinical AD in middle-age [14, 15]. PUBLIC HEALTH RELEVANCE: Delaying the onset of AD by 6 months can reduce the prevalence of AD by 100,000 persons after 10 years [16]; thus, understanding the potential of PA as a preventative treatment to delay AD has important public health implications. If our research indicates that PA is specifically beneficial for persons with a genetic risk for AD, this would be particularly important because evidence suggests that these individuals show signs of preclinical AD in middle-age [14, 15]. Further, if our research demonstrates that peripheral BDNF is an underlying mechanism of the effect, this would contribute to our ability to effectively prescribe the optimal dose of PA for cognitive benefits. This line of research may ultimately establish PA as a behavioral preventive treatment for individuals with an APOE genotype that puts them at increased genetic risk for AD.

描述（由申请人提供）：到 2030 年，全球阿尔茨海默病 (AD) 患病率预计将达到 6570 万。尽管全世界都在努力进行研究，但尚未找到治疗 AD 的方法。因此，确定可以减少风险的预防策略非常重要 AD 发病的风险或延迟发病的风险[1]。体力活动 (PA) 具有作为预防策略的潜力。我们的研究 [2, 3] 和其他人的研究 [4, 5] 表明，参与 PA 的老年人比对照组的认知表现有更大的提高。前瞻性研究还表明，PA 与较低的 AD 风险相关[6-9]，并且基线 PA 与随后的认知表现之间的关系受到 AD 易感基因（载脂蛋白，APOE）的调节[10-13]。然而，APOE 基因型对 PA 对认知表现的影响的潜在调节作用尚未在人体中进行实验测试；因此，我们不知道谁能从 PA 中获得最大的认知益处。此外，我们不了解 PA 如何有益于认知表现的机制。文献中的这些空白是我们长期研究计划背后的动机，该计划旨在进一步了解 PA 在缓解认知能力下降和改善认知能力方面的潜在作用。 AD的延迟。这些差距也是这项具体研究的动力，在这项研究中，我们：1) 确定对有 AD 家族史的人进行 8 个月 PA 干预的可行性，并使用统计模型为未来随机对照试验 (RCT) 的设计提供信息）； 2) 评估 PA 干预期间认知表现的变化，并确定这种变化是否因 APOE 基因型而异； 3) 确定外周脑源性神经营养因子 pBDNF（这是一种可能的效应机制，与 AD 相关）的变化是否可以预测 PA 干预期间认知表现的变化； 4) 检查 APOE 基因型对 PA 对各个认知领域的影响的不同影响。我们将确定 100 名认知正常的老年人的 APOE 基因型，以确定 APOE e4 携带者 (n=30) 和性别匹配的非携带者 (n=30)，以参加为期 8 个月的 PA 计划。我们将评估基线的认知表现，并评估测试前、测试中和测试后的认知表现和 pBDNF。这项初步研究将提供基础证据，并指导随机对照试验的制定，进一步测试 APOE 基因型的调节作用和 pBDNF 对 PA 对认知表现影响的调节作用。确定有效的干预措施来维持有 AD 风险的老年人的认知能力具有重要的公共卫生意义，因为目前尚未确定 AD 的预防策略，而且延迟 5 年 AD 发展的治疗可以降低 AD 的风险。 AD 降低 50%。 PA 在这方面很有前景，并且特别有吸引力，因为它具有成本效益且负面副作用相对较少。此外，如果 PA 对有 AD 遗传风险的人有益，那么这种感冒就特别重要，因为这些人在中年时表现出临床前 AD 的迹象 [14, 15]。公共卫生相关性：将 AD 发病延迟 6 个月可以在 10 年后减少 100,000 人的 AD 患病率[16]；因此，了解 PA 作为延缓 AD 的预防性治疗的潜力具有重要的公共卫生意义。如果我们的研究表明 PA 对有 AD 遗传风险的人特别有益，那么这一点就特别重要，因为有证据表明这些人在中年时表现出临床前 AD 的迹象 [14, 15]。此外，如果我们的研究表明外周 BDNF 是该效应的潜在机制，这将有助于我们有效地开出最佳 PA 剂量以实现认知益处的能力。这一系列研究最终可能会将 PA 作为一种针对 APOE 基因型个体的行为预防治疗方法，因为 APOE 基因型会使他们患 AD 的遗传风险增加。