The Effect of Physical Activity on Cognition Relative to APOE Genotype

描述(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研究，但治疗阿尔茨海默病的方法还没有确定。因此，重要的是确定预防战略，以减少 AD发病的风险或延迟[1]。体力活动(PA)有可能成为一种预防策略。我们的研究[2，3]和其他人的研究[4，5]表明，参加PA的老年人在认知表现上比对照组有更大的进步。前瞻性研究还表明，PA与较低的AD风险相关[6-9]，基线PA和随后的认知表现之间的关系受到AD(载脂蛋白，APOE)易感基因的调节[10-13]。然而，APOE基因对PA对认知表现影响的潜在调节作用尚未在人类身上进行实验测试；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如何有助于认知表现的机制。文献中的这些空白是我们长期研究计划背后的动机，该计划旨在加深我们对PA在缓解认知衰退和治疗中的潜在作用的理解 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)建立了对有AD家族史的人进行为期8个月的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干预过程中认知表现的变化，并确定这种变化是否作为APOE基因的函数而不同；3)确定外周脑源性神经营养因子pBDNF的变化是否预测了PA干预过程中认知表现的变化(这是一个合理的影响机制，并与AD有关)；4)考察APOE基因在不同认知领域对PA效应的不同影响。我们将确定100名认知正常的老年个体的APOE基因，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，并在测试前、测试中和测试后评估认知表现和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基因的调节作用和pBDNF对PA对认知成绩的影响的中介作用。确定有效的干预措施，以维持有AD风险的老年人的认知能力，具有重要的公共卫生意义，因为几乎没有确定AD的预防策略，而且将AD的发展推迟5年的疗法可以将AD的风险降低50%。PA在这方面很有希望，特别有吸引力，因为它具有成本效益，而且相对较少的负面副作用。此外，如果PA对有AD遗传风险的人有益，这一点尤其重要，因为这些人在中年就表现出临床前AD的迹象[14，15]。 公共卫生相关性：将AD发病推迟6个月可使10年后AD患病率降低100,000人[16]；因此，了解PA作为一种预防性治疗延迟AD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，这将是特别重要的，因为有证据表明这些人在中年显示出临床前AD的迹象[14，15]。此外，如果我们的研究证明外周BDNF是这种效应的潜在机制，这将有助于我们有效地为认知益处开出最佳剂量的PA。这一系列研究可能最终将PA确立为APOE基因携带者的一种行为预防性治疗，这会增加他们患AD的遗传风险。

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.