Statistical Methods for Kidney Markers as Shared Determinants of Dementia and Physical Disability in Older Adults

痴呆症影响着全世界4400万成年人，阿尔茨海默病(AD)和相关的痴呆症 老年人(ADRD)占所有病例的60%-80%。身体残疾往往是最终的后果 死前患有痴呆症。三分之一的痴呆症病例可能归因于可修改的因素，并由于 批准的AD治疗的益处尚不清楚，需要确定预防痴呆症的干预目标 和身体残疾。由于这两种情况之前可能会出现认知和体力表现下降- 十多年来，共同的认知-身体双重衰退的生物学决定因素影响了神经- 逻辑、肌肉骨骼和其他器官系统可以为预防痴呆症和 身体残疾。对这些终点的单独研究表明，肾功能下降是一种 过早衰老的模式，与认知和身体衰退有关。肾逆变疗法的临床研究 疾病正在进行中，但预防可能更有效。因此，确定肾脏衰退的早期标志物 在最初健康的老年人中，与认知-身体双重衰退和关节痴呆-残疾发病有关 成年人是实现这一目标的关键一步。除了已知的肾脏对骨骼的影响外，肾脏-脑轴和肾脏- 肌轴提出多种机制，肾脏健康状况下降可能导致痴呆症和体力衰竭 残疾，如肾脏老化、矿物质平衡受损和尿毒症标志物积聚。然而， 流行病学研究还没有严格调查肾脏标志物是否具有这些生物学机制 影响认知和身体端点之间的关系和动态。此外，对纵向认知的研究 而物理终端很容易受到生存偏见和无法测量的混淆的影响。电流的限制 统计方法是准确量化认知和认知之间关系强度的关键障碍 物理终点，并确定共同生物机制的标记以解释这些关系。 因此，需要新的统计方法来克服这些障碍。这项建议的具体目的是：1) 量化认知和身体终点之间随时间的关系；2)测试肾脏标记物与 认知-身体终点；以及3)开发/验证生物标记物风险分数以联合和动态地预测 痴呆症和残疾。为此，我们建议扩展新的多变量纵向结构模型 和事件发生时间的结果，并将它们应用于来自8项队列研究的协调数据，这些研究涉及22,000个社区- 居住年龄在65岁以上的成年人。我们假设，在解决生存偏见之后，认知和 生理终点会有更强的关系，这部分是由肾脏的标志物解释和预测的。 衰老、矿物质动态平衡受损和尿毒症标志物的积累。新的统计方法 作为联合研究认知和身体终点的基本工具，将向 科学界。这个项目对公共卫生的最终影响是潜在的新候选人 生物标志物，为制定预防ADRD和老年人身体残疾的新战略提供信息。

Dementia affects over 44 million adults worldwide, and Alzheimer’s disease (AD) and related dementias (ADRD) account for 60-80% of all cases among older adults. Physical disability is often the final consequence of dementia before death. One-third of dementia cases may be attributable to modifiable factors, and due to unclear benefit of approved AD treatment, there is a need to identify intervention targets to prevent dementia and physical disability. Since both conditions may be preceded by declining cognitive and physical perform- ance by over a decade, shared biological determinants of dual cognitive-physical decline that impact neuro- logical, musculoskeletal, and other organ systems may inform therapeutic targets to prevent dementia and physical disability. Separate research on these endpoints indicates that declining kidney function, which is a model of premature aging, relates to both cognitive and physical decline. Trials of treatments to reverse kidney disease are underway, but prevention may be more effective. Thus, identifying early markers of kidney decline that are related to dual cognitive-physical decline and joint dementia-disability onset in initially health older adults is a key step toward this goal. Beyond known kidney effects on bone, a kidney-brain axis and kidney- muscle axis posit multiple mechanisms by which declining kidney health may lead to dementia and physical disability such as kidney aging, impaired mineral homeostasis, and accumulation of uremic markers. However, epidemiologic studies have not rigorously investigated whether kidney markers of these biological mechanisms affect relations and dynamics between cognitive and physical endpoints. Plus, studies of longitudinal cognitive and physical endpoints are vulnerable to survival bias and unmeasured confounding. Limitations of current statistical methods are a key barrier to accurately quantifying the strength of relations between cognitive and physical endpoints and to identifying markers of shared biological mechanisms to explain these relations. Thus, new statistical methods are needed to overcome these barriers. Specific aims of this proposal are to: 1) quantify relations between cognitive and physical endpoints over time; 2) test relations of kidney markers with cognitive-physical endpoints; and 3) develop/validate a biomarker risk score to jointly and dynamically predict dementia and disability. To this end, we propose to extend novel structural models for multivariate longitudinal and time-to-event outcomes and apply them to harmonized data from 8 cohort studies of >22,000 community- dwelling adults aged at least 65 years. We hypothesize that after addressing survival bias, cognitive and physical endpoints will have stronger relations that are explained and predicted, in part, by markers of kidney aging, impaired mineral homeostasis and by accumulation of uremic markers. New statistical methods developed as essential tools to jointly study cognitive and physical endpoints will be made available to the scientific community. The ultimate public health impact of this project is the potential for novel candidate biomarkers to inform development of new strategies to prevent ADRD and physical disability in older adults.