The effect of physical activity on cognition relative to APOE genotype (PAAD-II)

项目摘要：到2050年，美国阿尔茨海默病（AD）的患病率预计将达到 达到1380万。尽管世界范围内的研究努力，尚未确定AD的治愈方法。因此， 以确定预防策略，可以降低风险或延迟AD的发作。体力活动（PA） 在这方面的潜力。元分析综述和我们自己的实验研究表明， 参与PA的人在认知表现上比对照组有更大的提高。前瞻性研究还 显示PA与AD的低风险相关，并且基线PA与 随后的认知表现受到AD易感基因（载脂蛋白，APOE）的调节。中 在第一阶段的概念验证试验中，我们发现有AD家族史的个体（FH+） 与PA相关的益处，这些益处甚至在具有AD遗传风险的人群中也很明显 (i.e., APOE e4携带者，APOE 4+）。然而，没有发表的随机对照试验评估了这种影响 PA对认知正常FH+个体相对于APOE 4状态的认知的影响。此外，在目前 资助的试验开始解决这一差距，重点是老年人（65岁以上）;因此限制了识别的能力 早期干预的保护作用可能更明显。最后，目前的证据并不 阐明PA如何有益于认知表现的机制。文献中的这些空白 促使我们进行II期试验，在该试验中，我们通过提出一项随机临床试验来扩展我们过去的工作，以：（a） 使用FH+测试PA与中年人（40-65岁）认知表现之间的因果关系， 和（B）确定所述作用是否被APOE 4携带者状态调节。我们将收集神经影像学指标， 大脑结构、白色物质完整性和静息状态连通性;评估推定的生物标志物;以及 （使用适度调解分析）增进对基本机制和 其作用受APOE 4携带者状态的调节。为了验证我们的假设，我们将随机分配240名 认知正常的中年人进行为期1年的PA计划或常规护理控制。我们将评估 认知表现在前，中期，和后测试，并获得MRI扫描和血液样本在前和后， test.我们将研究PA对认知能力以及神经和生物学的影响。 机制，并将探讨APOE 4的调节作用。这项研究的一个优点是， 在一项III期临床试验（1 R 01 AG 053952）中使用的认知测量和MRI序列， PA对老年人（65-80岁）的认知，我们正在与该试验的PI（埃里克森）合作。这 将使我们能够通过汇编广泛年龄范围内的数据来利用NIH的资源。重要的是，调查结果 这项研究可能支持PA作为改善认知表现的一种手段， AD的风险。这可能会对公共卫生产生影响，因为将AD延迟1年可能会降低其 发病率为11%。

Project Summary: By 2050, the prevalence of Alzheimer’s disease (AD) in the United States is predicted to reach 13.8 million. Despite worldwide research efforts, a cure for AD has not been identified. Thus, it is critical to identify preventive strategies that can reduce the risk of or delay the onset of AD. Physical activity (PA) has potential in this regard. Meta-analytic reviews and our own experimental studies show 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 and that the relationship between baseline PA and subsequent cognitive performance is moderated by a susceptibility gene for AD (apolipoprotein, APOE). In a Phase I proof-of-concept trial, we showed that individuals with a family history of AD (FH+) achieve cognitive benefits in association with PA and that these benefits were even evident in those with a genetic risk for AD (i.e., APOE e4 carriers, APOE4+). However, no published randomized controlled trial has assessed the effects of PA on cognition in cognitively normal FH+ individuals relative to APOE4 status. In addition, in currently funded trials beginning to address this gap, the focus is on older adults (65+); thus limiting the ability to identify protective effects that may be more evident with earlier interventions. Lastly, current evidence does not elucidate mechanisms to explain how PA benefits cognitive performance. These gaps in the literature have motivated our Phase II trial, in which we extend our past work by proposing a randomized clinical trial to: (a) test the causal link between PA and cognitive performance in middle-aged adults (40-65 years) with a FH+, and (b) determine if the effect is moderated by APOE4 carrier status. We will collect neuroimaging measures of cerebral structure, white matter integrity, and resting state connectivity; assess putative biological markers; and (using moderated mediation analyses) increase understanding of underlying mechanisms and of the extent to which effects are moderated by APOE4 carrier status. To test our hypotheses, we will randomly assign 240 cognitively normal, middle-aged adults to a 1-year PA program or a usual care control. We will assess cognitive performance at pre-, mid-, and post-test, and obtain MRI scans and blood samples at pre- and post- test. We will examine the effects of PA on cognitive performance and on neurological and biological mechanisms and will explore the moderating role of APOE4. A strength of this study is that we incorporate cognitive measures and MRI sequences used in a Phase III clinical trial (1R01AG053952) testing the effects of PA on cognition in older adults (65-80 years), and we are collaborating with the PI of that trial (Erickson). This will allow us to leverage NIH’s resources by compiling data across a broad age range. Importantly, findings from this study may support PA as a means of improving cognitive performance by those with a heightened risk for AD. This could have public health implications, because delaying AD by 1 year could reduce its incidence by 11%.