Earlier-Life Predictors of Midlife Risk Factors for Dementia: A 35-Year Follow-up

中年痴呆症风险因素的早期预测因素：35 年随访

• 批准号: 10596295
• 负责人: GEORGE W. REBOK
• 金额: $ 130.25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596295
• 关键词: Academic achievement; Address; Adult; Affect; African American; African American population; Age; Aging; Alcohols; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Attention; Baltimore; Behavior; Biological; Biological Markers; C-reactive protein; CDKN2A gene; Child; Childhood; Chronic stress; Cognition; Cognitive; Communities; Crime; Cyclin-Dependent Kinase Inhibitor; Data; Dementia; Diabetes Mellitus; Diagnosis; Drug usage; Early identification; Education; Elderly; Epigenetic Process; Exposure to; Future; Genetic; Genetic Materials; Health; Health protection; Home; Hyperlipidemia; Hypertension; Impaired cognition; Imprisonment; Individual; Inequity; Inflammation; Inflammatory; Interleukin-6; Intervention; Intervention Studies; Interview; Length; Life; Life Cycle Stages; Link; Measures; Mental disorders; Methylation; Modification; Not Hispanic or Latino; Obesity; Occupational; Outcome; Outcome Study; Participant; Pathway interactions; Physiological; Police; Poverty; Prevention; Prevention trial; Psychopathology; Public Health; Race; Risk; Risk Estimate; Risk Factors; Risk Marker; Role; Sampling; Sleep; Sleep disturbances; Social support; Stress; Subgroup; Symptoms; TNF gene; Trauma; Wrist; achievement test; actigraphy; cognitive performance; cohort; community violence; conduct problem; dementia risk; disorder risk; early life stress; first grade; follow-up; health disparity; inflammatory marker; middle age; modifiable risk; poor sleep; prevent; preventive intervention; prospective; protective factors; racial discrimination; racial disparity; risk variant; second grade; sex; stressor; substance use; telomere; traumatic event; universal prevention; young adult

Alzheimer’s disease (AD) and related dementias (AD/ADRD) are a public health crisis in the US marked by growing racial disparities, with African Americans (AAs) two to three times more likely to be diagnosed than non-Hispanic Whites. Efforts to identify modifiable earlier-life risk and protective factors for known midlife risk factors for poor cognitive outcomes in later life are needed to protect the health of middle-aged and older AAs. We propose to prospectively examine trajectories of stress exposures from childhood to early midlife as predictors of known midlife risk factors for subsequent AD/ADRD in two primarily (~66%) AA cohorts that are now ages 41-45 and have been followed repeatedly from age 6 to age 32 (2009-2011) by the Johns Hopkins Prevention Intervention Research Center (PIRC). Relevant individual- and community- level stress exposures that occur from early life to middle adulthood include: 1) adverse life circumstances (i.e., extreme poverty, residential instability, crime, incarceration, racial discrimination, traumatic events); 2) mental disorders and their symptoms; and 3) poor sleep (e.g., abnormal duration, fragmentation). Additionally, these stress exposures have been linked to other risk factors for AD/ADRD, including obesity, hypertension, and diabetes, by which AAs are disproportionately affected. We aim to determine the extent to which ~35-year trajectories of stress exposures are associated with estimated midlife risk for later-life AD/ADRD, physiological aging (telomere length, p16, methylation age), epigenetic modification, and inflammation, and cognitive performance—all measured in early midlife—and if these associations are moderated by sex, race, and AD/ADRD risk genes. We will also explore how the timing of exposures in the life-course affects these associations, and if other potential moderators (e.g., childhood academic achievement, educational/occupational attainment, alcohol/drug use, conduct problems, social support, perceived control) affect these associations. We will further explore effects of two early-life (ages 6-8) PIRC interventions on midlife study outcomes. To accomplish this, 1,150 PIRC participants will complete two in- home interviews including a cognitive battery and actigraphic sleep assessments, and we will collect biospecimens for genetic and epigenetic material and physiological aging measures. This study is a rare opportunity to clarify links of earlier-life stress exposures with estimated midlife dementia risk, identify vulnerable subgroups for targeted AD/ADRD prevention, elucidate the role of social inequities in determining racial disparities in AD dementia, and establish a midlife cognitive baseline for future follow-up of these unusually well-characterized longitudinal, primarily AA cohorts.

阿尔茨海默病（AD）和相关痴呆症（AD/ADRD）是美国的一种公共卫生危机， 种族差异日益扩大，非裔美国人（AA）被诊断出的可能性是普通人的两到三倍 非西班牙裔白人努力确定已知中年的可改变的早期生活风险和保护因素 老年人认知能力差的风险因素是保护中年人健康所必需的， 年长的AA我们建议前瞻性地研究从童年到早期的压力暴露轨迹 在两个主要（约66%）AA中，中年作为随后AD/ADRD的已知中年风险因素的预测因子 现在年龄在41-45岁之间的队列，从6岁到32岁（2009-2011年）， 约翰霍普金斯预防干预研究中心（PIRC）。相关个人和社区- 从生命早期到成年中期的水平压力暴露包括：1）不利的生活环境 (i.e.,赤贫、居住不稳定、犯罪、监禁、种族歧视、创伤事件）; 2） 精神障碍及其症状;以及3）睡眠不佳（例如，异常持续时间、碎片化）。 此外，这些压力暴露与AD/ADRD的其他风险因素有关，包括肥胖， 高血压和糖尿病，其中AA受到不成比例的影响。我们的目标是确定 其中，约35年的压力暴露轨迹与估计的晚年中年风险相关 AD/ADRD、生理老化（端粒长度、p16、甲基化年龄）、表观遗传修饰和 炎症和认知能力--所有这些都是在中年早期测量的--如果这些关联是 受性别、种族和AD/ADRD风险基因的调节。我们还将探讨如何在曝光的时间， 生命过程影响这些关联，并且如果其他潜在的调节者（例如，儿童学术 成就，教育/职业成就，酒精/药物使用，行为问题，社会支持， 感知控制）影响这些关联。我们将进一步探讨两个早期生命（6-8岁）PIRC的影响， 对中年研究结果的干预。为了实现这一目标，1,150名PIRC参与者将完成两个- 家庭访谈，包括认知电池和活动记录睡眠评估，我们将收集 生物标本的遗传和表观遗传物质和生理老化措施。这项研究是罕见的 有机会澄清早期生活压力暴露与估计的中年痴呆风险之间的联系， 有针对性的AD/ADRD预防的脆弱亚组，阐明社会不平等在以下方面的作用： 确定AD痴呆的种族差异，并为未来的随访建立中年认知基线 这些异常良好的纵向特征，主要是AA队列。