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

项目摘要/摘要 目前可用的治疗阿尔茨海默病(AD)的药物治疗并不能治愈。此外，来自以下方面的发现 测试新的疾病修正疗法的临床试验一直令人失望。因此，迫切需要 遏制AD引发的全球危机的替代方法怎么强调都不为过。尽管数据来自 长期以来，队列和流行病学研究表明，体力活动与痴呆症之间存在很强的联系 由于阿尔茨海默病，体力活动是否调节阿尔茨海默病的潜在病理生理的问题只有 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 在体力活动方面，几个关键的知识差距依然存在。首先，过去的研究在很大程度上是横向的。 这就留下了一个悬而未决的可能性，即观察到的影响只是反映了反向因果关系。第二，“身体上的 已通过包括自我报告、活动跟踪器和最大 分级运动测试，导致了相互矛盾的结果。第三，因为过去的研究主要是在 在老年人中，体力活动对中年AD风险的潜在影响知之甚少 大多数与AD相关的变化都开始了。最后，有必要更好地了解 体育活动起到了有益的作用。为了解决这些知识差距(1)，我们将重点放在这个项目上 心肺适合度(CRF)，它构成了“习惯性”身体活动的生理联系，(2) 我们采用纵向设计，这将严格排除反向因果关系的可能性， (3)我们研究了一组中晚期成年人，原则上他们可能只处于 AD，以及(4)我们研究了血管和糖调节功能作为之间联系的可行的转导 慢性肾功能衰竭和AD的病理生理学。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阿尔茨海默氏症预防登记处和威斯康星州阿尔茨海默氏症登记处 疾病研究中心，我们将长期处于独特的地位，阐明中年的影响 CRF对轻度认知障碍和痴呆症临床终点的影响。总之，多式联运和一体化 这里提出的研究将为CRF作为一种潜在的可行的治疗方法提供关键的见解 AD早期阶段的疾病轨迹，在弥漫性神经变性之前，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.