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.

痴呆症影响着全球超过 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障碍。 死亡前 ADRD 的后果 三分之一的痴呆症病例可能归因于可改变的因素， 由于 AD 治疗的益处尚不明确，因此需要确定预防 ADRD 的干预目标 由于这两种情况之前都可能出现认知和身体表现不佳的情况。 十多年来，认知-身体双重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并告知治疗目标，以预防 ADRD 和身体残疾。 老年科学假说认为，针对衰老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，确实是平行的研究。 表明反映衰老潜在生物学的生物标志物与认知和身体衰退有关 作为单独的终点，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、细胞通讯改变、表观遗传变化、端粒磨损、营养信号传导、 然而，严格的流行病学研究尚未充分调查是否具有生物学意义。 衰老机制影响认知和身体衰退（ADRD）和身体衰退之间的关系和动态 随着时间的推移，身体残疾开始出现，因此，识别生物衰老机制的早期生物标志物。 与双重认知-身体衰退和联合ADRD-残疾最初在健康老年人中发病有关是一个关键 实现这一目标的一个主要障碍是纵向研究。 认知和身体终点很容易受到生存偏差和无法测量的现有混杂因素的影响。 统计方法克服这一障碍的能力有限；因此，共享的生物机制 认知和身体终点的数量尚不完全清楚，需要新的统计方法。 填补这些知识空白的障碍，该提案的具体目标是：1）测试生物标志物的关系 衰老与纵向双重认知-身体衰退的关系；2) 测试衰老生物标志物与时间的关系； 突发性关节痴呆（即 ADRD）-残疾发作；以及 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，我们建议扩展多种统计方法。 确定纵向和事件发生时间结果，并将其应用于 8 项队列研究的统一数据 >11,000 名年龄至少 65 岁的社区居住成年人。 并部分解释已知风险因素之外的认知和身体终点之间的关系。 作为共同研究认知和身体终点的重要工具而开发的统计方法将被共享 该项目对公共健康的最终影响是新型生物标志物的潜力。 老龄化为老年科学策略提供信息，以预防和预测老年人 ADRD 和身体残疾。