Methods to Test Biomarkers of Aging as Shared Determinants of Alzheimers Disease and Related Dementias and Physical Disability

痴呆症影响全球超过4400万成年人，阿尔茨海默病（AD）和相关痴呆症 ADRD占老年人所有病例的60%-80%。身体残疾往往是最后的 死亡前的ADRD。三分之一的痴呆症病例可能归因于可改变的因素， 由于AD治疗的益处尚不清楚，因此需要确定干预目标以预防ADRD 和身体残疾。由于这两种情况都可能在认知和身体表现不佳之前发生， 十多年来，双重认知-身体衰退的共同生物决定因素影响了神经系统和 肌肉骨骼系统可以预测和告知治疗目标，以防止ADRD和身体残疾。 老年科学假说认为，针对衰老的生物学可能会更好地影响人类健康，例如， 预防ADRD和身体残疾，而不是针对特定疾病。事实上，平行线的研究 这表明反映衰老生物学基础的生物标志物与认知和身体衰退有关 作为单独的端点。这项工作包括炎症的生物标志物和衰老标志的生物标志物 例如细胞衰老、改变的细胞通讯、表观遗传变化、端粒磨损、营养信号传导 和蛋白质稳态的丧失。然而，严格的流行病学研究还没有充分调查是否生物学 衰老机制影响认知和身体衰退之间的关系和动态，或ADRD， 随着时间的推移，身体残疾的发生。因此，识别生物衰老机制的早期生物标志物， 在最初健康的老年人中， 迈向老年科学指导的预防试验。实现这一目标的一个主要障碍是， 认知和身体终点易受生存偏倚和未测量混杂因素的影响。现存 统计学方法克服这一障碍的能力有限;因此， 认知和身体终点的准确性尚不完全清楚，需要新的统计方法。克服 填补这些知识空白的障碍，本提案的具体目标是：1）测试生物标志物的关系 2）测试衰老生物标志物与时间的关系， 偶发性关节痴呆（即，ADRD）-残疾发作;和3）开发/验证衰老风险评分的生物标志物， 预测关节痴呆（即，ADRD）-残疾。为此，我们建议将统计方法扩展到多个 评估纵向和至事件发生时间结局，并将其应用于8项队列研究的协调数据， 超过11，000名65岁以上的社区居住成年人。我们假设衰老的生物标志物可以预测 并在一定程度上解释了已知风险因素之外的认知和身体终点之间的关系。新 将共享作为共同研究认知和身体终点的基本工具而开发的统计方法 与科学界。该项目的最终公共卫生影响是新的生物标志物的潜力 为老年科学策略提供信息，以预防和预测老年人的ADRD和身体残疾。

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 ADRD before death. One-third of dementia cases may be attributable to modifiable factors, and due to unclear benefit of AD treatments, there is a need to identify intervention targets to prevent ADRD and physical disability. Since both conditions may be preceded by poor cognitive and physical performance by over a decade, shared biological determinants of dual cognitive-physical decline that impact neurological and musculoskeletal systems may predict and inform therapeutic targets to prevent ADRD and physical disability. The geroscience hypothesis posits that targeting the biology of aging may better impact human health, such as prevention of ADRD and physical disability, than targeting specific diseases. Indeed, parallel lines of research indicate that biomarkers reflecting the underlying biology of aging are related to cognitive and physical decline as separate endpoints. This work includes biomarkers of inflammation and biomarkers of hallmarks of aging such as cell senescence, altered cell communication, epigenetic changes, telomere attrition, nutrient signaling, and loss of proteostasis. However, rigorous epidemiologic studies have not fully investigated whether biological mechanisms of aging affect relations and dynamics between cognitive and physical decline, or ADRD and physical disability onset, over time. Thus, identifying early biomarkers of biological aging mechanisms that are related to dual cognitive-physical decline and joint ADRD-disability onset in initially healthy older adults is a key step toward geroscience-guided prevention trials. A major barrier to this goal is that studies of longitudinal cognitive and physical endpoints are vulnerable to survival bias and unmeasured confounding. Extant statistical methods are limited in their ability to overcome this barrier; therefore, shared biological mechanisms of cognitive and physical endpoints are not fully known, and new statistical methods are needed. To overcome the barriers to filling these knowledge gaps, specific aims of this proposal are to: 1) test relations of biomarkers of aging with longitudinal dual cognitive-physical decline; 2) test relations of biomarkers of aging with time to incident joint dementia (i.e., ADRD)-disability onset; and 3) develop/validate a biomarker of aging risk score to predict joint dementia (i.e., ADRD)-disability. To this end, we propose to extend statistical methods for multi- iate longitudinal and time-to-event outcomes and apply them to harmonized data from 8 cohort studies of >11,000 community-dwelling adults aged at least 65 years. We hypothesize that biomarkers of aging predict and explain, in part, relations between cognitive and physical endpoints beyond known risk factors. New statistical methods developed as essential tools to jointly study cognitive and physical endpoints will be shared with the scientific community. This project’s ultimate public health impact is the potential for novel biomarkers of aging to inform geroscience strategies to prevent and predict ADRD and physical disability in older adults.