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

测试衰老生物标志物作为阿尔茨海默病及相关痴呆和身体残疾的共同决定因素的方法

• 批准号: 10561249
• 负责人: Michelle Denise Shardell
• 金额: $ 81万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561249
• 关键词: Address; Adult; Affect; Age; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease related dementia; Biological; Biological Aging; Biological Markers; Biology of Aging; Cell Aging; Cell Communication; Cell physiology; Cessation of life; Clinical; Code; Cognition; Cognitive; Cohort Studies; Communities; Data; Dementia; Disease; Early identification; Elderly; Epigenetic Process; Event; GDF15 gene; Geroscience; Goals; Guide prevention; Health; Human; Inflammation; Interleukin-6; Intervention; Joints; Kidney; Knowledge; Longevity; Longitudinal Studies; Measures; Methods; Mitochondria; Modeling; Molecular; Musculoskeletal; Musculoskeletal System; Neurologic; Nutrient; Outcome; Pathology; Persons; Physical Performance; Prevention; Prevention trial; Process; Proteins; Proteomics; Public Health; Research; Risk; Risk Factors; Signal Transduction; Source; Statistical Methods; Statistical Models; Structural Models; TNF gene; Testing; Time; Work; age related; aged; biobank; biological adaptation to stress; biomarker identification; body system; candidate marker; circulating biomarkers; cognitive performance; cohort; data harmonization; data sharing; disability; early detection biomarkers; epidemiology study; high dimensionality; human old age (65+); improved; innovation; metabolomics; method development; motor control; novel; novel marker; physically handicapped; post gamma-globulins; prevent; preventive intervention; proteostasis; risk prediction; telomere; therapeutic target; tool

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.

痴呆症影响全球超过4400万成人，阿尔茨海默氏病（AD）和相关痴呆症 （ADRD）占老年人所有病例的60％-80％。身体残疾通常是最后的 死后阿德德的后果。三分之一的痴呆病例可能归因于可修改的因素， 而且由于广告处理的不明确益处，有必要确定干预目标以防止ADRD 和身体残疾。由于这两种情况都可能在认知和身体表现之前， 十年来，共享的生物学决定者的双重认知形态下降，影响神经系统和 肌肉骨骼系统可以预测并为治疗靶标提供信息，以防止ADRD和身体残疾。 Geroscience假设认为，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。确实，平行研究线 表明反映基本衰老生物学的生物标志物与认知和身体下降有关 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 例如细胞感应，细胞通信改变，表观遗传变化，端粒损耗，营养信号传导， 和蛋白质的丧失。但是，严格的流行病学研究尚未完全研究生物学 衰老的机制会影响认知与身体衰落之间的关系和动态，或者ADRD和ADRD和 身体残疾发作，随着时间的流逝。这是确定生物衰老机制的早期生物标志物 与最初健康的老年人的双重认知物理下降和联合ADRD-DISASIS相关的是关键 迈向Geroscience引导的预防试验。该目标的主要障碍是纵向研究 认知和物理终点很容易受到生存偏见和无法衡量的混淆。现存 统计方法克服这一障碍的能力受到限制。因此，共享的生物学机制 认知和物理终点尚不完全了解，需要新的统计方法。克服 填补这些知识空白的障碍，该提案的具体目的是：1）生物标志物的测试关系 纵向双重认知物理下降的衰老； 2）衰老生物标志物的测试关系与时间 入射关节痴呆（即ADRD） - 可见性发作； 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） - 可见性。为此，我们建议扩展多个多的统计方法 延长纵向和事件时间的结果，并将其应用于8个队列研究的统一数据 >至少65岁的11,000名社区居民成年人。我们假设衰老的生物标志物预测 并在某种程度上解释了已知危险因素以外的认知和物理终点之间的关系。新的 将开发为共同研究认知和物理终点的基本工具开发的统计方法将被共享 与科学界。该项目的最终公共卫生影响是新型生物标志物的潜力 衰老以告知Geroscience策略，以预防和预测老年人的ADRD和身体残疾。