Longitudinal Investigation of Cardiorespiratory Fitness and AD Biomarkers in an At-Risk Cohort

项目总结/摘要 目前可用的药物治疗阿尔茨海默病（AD）是没有治愈性的。此外，来自 测试新的疾病改善疗法的临床试验令人失望。因此，迫切需要 制止反倾销造成的全球危机的替代办法怎么强调也不过分。虽然数据来自 长期以来，队列研究和流行病学研究都表明，体力活动与痴呆症之间存在密切联系 由于AD，体力活动是否调节AD的潜在病理生理学的问题只有 最近开始受到关注。虽然新出现的证据似乎总体上支持这种作用， 在体育活动方面，一些关键的知识差距仍然存在。首先，过去的研究主要是横截面的。 这就留下了一个未解决的可能性，即观察到的效应只是反映了反向因果关系。第二，“体力 活动”已经通过各种方法进行了评估，包括自我报告，活动跟踪器和最大的 分级运动测试，导致相互矛盾的结果。第三，因为过去的研究主要是 在老年人中，关于身体活动对中年AD风险的潜在影响知之甚少， 大多数与AD相关的更改将开始。最后，需要更好地了解 体育活动发挥其有益的作用。为了解决这些知识差距（1），我们把这个项目的重点放在 心肺适能（CRF），它构成了 * 习惯性 * 体力活动的生理联系，（2） 我们采用纵向设计，这将使我们能够严格排除反向因果关系的可能性， (3)我们研究了一组中年晚期的成年人，原则上，他们可能只处于 我们研究了血管和葡萄糖调节功能，作为AD之间联系的可行换能器， CRF和AD病理生理学。重要的是，因为这项研究的目标参与者正在被跟踪， 纵向通过威斯康星州老年痴呆症预防登记处和威斯康星州老年痴呆症 疾病研究中心，我们将在长期的独特定位，以阐明中年的影响， CRF对轻度认知障碍和痴呆临床终点的影响。总之，多模式和综合 这里提出的一项研究为CRF作为一种潜在可行的治疗方法提供了重要的见解， 在AD的早期阶段，在广泛性神经退行性变之前的疾病轨迹，从而延迟 出现临床症状。

PROJECT SUMMARY/ABSTRACT Currently-available drug treatments for Alzheimer's disease (AD) are not curative. Furthermore, findings from clinical trials testing novel disease-modifying therapeutics have been disappointing. Accordingly, the urgency of alternative approaches for halting the global crisis posed by AD cannot be overstated. Although data from cohort and epidemiological studies have long suggested a strong link between physical activity and dementia due to AD, the question of whether physical activity modulates the underlying pathophysiology of AD has only recently begun receiving attention. While the emerging evidence appears overall supportive of such a role for physical activity, several critical knowledge gaps persist. First, past studies have been largely cross-sectional. This leaves unresolved the possibility that observed effects simply reflect reverse causation. Second, “physical activity” has been assessed via a variety of approaches including self-report, activity trackers, and maximal graded exercise testing, leading to conflicting findings. Third, because past research has primarily been done in elderly persons, little is known about the potential influence of physical activity on AD risk in midlife, when most AD-related changes begin. Lastly, there is need for a better understanding of the mechanisms by which physical activity exerts its salutary effects. To address these gaps in knowledge (1) we focus this project on cardiorespiratory fitness (CRF), which constitutes the physiological nexus for *habitual* physical activity, (2) we employ a longitudinal design, which would allow us rigorously exclude the possibility of reverse causation, (3) we study a cohort of late-middle-aged adults who are, in principle, potentially only at the inceptive stages of AD, and (4) we investigate vascular and glucoregulatory function as viable transducers of the link between CRF and AD pathophysiology. Importantly, because the participants targeted for this study are being followed longitudinally through the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center, we will be uniquely positioned in the long term to elucidate the impact of midlife CRF on clinical endpoints of mild cognitive impairment and dementia. In sum, the multimodal and integrative study proposed here stands to provide critical insights into CRF as a potentially viable therapeutic for altering disease trajectory in the early stages of AD, prior to pervasive neurodegeneration, thereby delaying the emergence of clinical symptoms.