The Effect of Physical Activity on Cognition Relative to APOE Genotype

描述（由申请人提供）：到2030年，阿尔茨海默病（AD）的全球患病率预计将达到6570万。尽管世界范围内的研究努力，尚未确定AD的治愈方法。因此，重要的是要确定预防战略， 或延迟AD的发作[1]。身体活动（PA）是一种潜在的预防策略。我们的研究[2，3]和其他人的研究[4，5]表明，参与PA的老年人在认知表现方面的收益比对照组更大。前瞻性研究还表明，PA与AD风险较低相关[6-9]，并且基线PA与后续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对认知能力影响的潜在调节作用尚未在人类中进行实验测试;因此，我们不知道谁从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，旨在进一步了解PA在缓解认知衰退和改善认知功能方面的潜在作用。 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）建立一个8个月的PA干预与AD家族史的人的可行性，并使用统计模型，为未来的随机对照试验（RCT）的设计提供信息; 2）评估整个PA干预的认知表现的变化，并确定这种变化是否作为APOE基因型的功能不同; 3）确定外周脑源性神经营养因子pBDNF（其是作用的合理机制并且已经与AD相关联）的变化是否预测PA干预中认知表现的变化;以及4）检查APOE基因型对PA对各种认知领域的作用的差异作用。我们将在100名老年认知正常个体中确定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）参加为期8个月的PA计划。我们将在基线时评估认知表现，并在前测、中测和后测时评估认知表现和pBDNF。这项初步研究将提供基础证据，并将指导RCT的发展，进一步测试APOE基因型的调节作用和pBDNF对PA对认知能力的影响的介导作用。确定有效的干预措施，以维持老年人的认知能力的风险，AD具有重要的公共卫生意义，因为很少有预防策略，AD已被确定，因为治疗，延迟AD的发展5年，可以降低AD的风险50%。PA在这方面有希望，特别有吸引力，因为它具有成本效益，而且负面副作用相对较少。此外，如果PA对具有AD遗传风险的人有益，则这种感冒特别重要，因为这些人在中年时显示出临床前AD的迹象[14，15]。

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].