Earlier-Life Predictors of Midlife Risk Factors for Alzheimer's Disease: A 35-Year Follow-up

阿尔茨海默病中年危险因素的早期预测因素：35 年随访

• 批准号: 10460376
• 负责人: GEORGE W. REBOK
• 金额: $ 111.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460376
• 关键词: Academic achievement; Address; Adult; Affect; African American; Age; Aging; Alcohols; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Attention Concentration; Baltimore; Behavior; Biological; Biological Markers; Blood; C-reactive protein; CDKN2A gene; Child; Childhood; Chronic stress; Cognition; Cognitive; Communities; Crime; Cyclin-Dependent Kinase Inhibitor; Data; Diabetes Mellitus; Diagnosis; Disease; Drug usage; Elderly; Epigenetic Process; Exposure to; Future; Genetic; Genetic Materials; Health; Home; Hyperlipidemia; Hypertension; Impaired cognition; Imprisonment; Individual; Inflammation; Inflammatory; Interleukin-6; Intervention; Intervention Studies; Interview; Length; Life; Link; Measures; Mental disorders; Methylation; Modification; Not Hispanic or Latino; Obesity; Occupational; Outcome; Outcome Study; Participant; Pathway interactions; Physiological; Police; Poverty; Prevention; Prevention Research; Prevention trial; Psychopathology; Public Health; Race; Risk; Risk Factors; Role; Sampling; Sleep; Sleep disturbances; Smoking; Social support; Stress; Subgroup; Symptoms; TNF gene; Time; Trauma; Violence; Wrist; achievement test; actigraphy; cognitive performance; cohort; conduct problem; dementia risk; disorder risk; early life stress; first grade; follow-up; health disparity; high risk; indexing; 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; universal prevention; young adult

Alzheimer’s disease (AD) is a public health crisis in the US and a growing health disparity, with African Americans (AAs) two to three times more likely to be diagnosed with the disease 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 individual- and community-level stress exposures from childhood to early midlife as predictors of known midlife risk factors for subsequent Alzheimer’s disease and related dementias (ADRD) in two primarily (~66%) AA cohorts that are now ages 40-44 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 and trauma (i.e., extreme poverty, residential instability, crime, police and community violence, incarceration, racial discrimination); 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 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 risk for later-life ADRD measured in early midlife using a dementia risk index, and with early-midlife measures of physiological aging (telomere length, p16, methylation age), epigenetic modification, inflammation, and cognitive performance. We will also examine if these associations are moderated by sex, race, and AD risk genes, and explore how the timing of exposures in the lifecourse, and other potential moderators (i.e., childhood academic achievement, educational/occupational attainment, alcohol/drug use, smoking, conduct problems, social support, perceived control), affect these associations. Further, we will explore the effects of two early-life (ages 6-8) PIRC interventions on our early midlife study outcomes. To accomplish this, we will repeat blood and buccal sampling for genetic and epigenetic material and complete two in-home interviews, including a cognitive battery and actigraphic sleep assessments, with 1,150 participants. This study is a rare opportunity to clarify links of earlier-life stress exposures with midlife dementia risk, identify vulnerable subgroups for targeted 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.

阿尔茨海默氏病（AD）是美国的一个公共卫生危机，也是一个日益扩大的健康差距，非洲 美国人（AAs）被诊断出患有这种疾病的可能性是非西班牙裔白人的两到三倍。 努力确定可改变的早期生活风险和已知的中年风险因素， 需要在晚年的认知结果，以保护中年和老年AA的健康。我们提出 前瞻性地研究从童年到童年的个人和社区层面压力暴露的轨迹， 中年早期作为已知中年危险因素的预测因子， 痴呆症（ADRD）在两个主要（约66%）AA队列中，现在年龄为40-44岁， 约翰霍普金斯预防干预研究（Johns Hopkins Prevention Intervention Research） 中心（PIRC）。相关的个人和社区层面的压力暴露，发生在生命的早期， 中年期包括：1）不利的生活环境和创伤（即，赤贫、居住 不稳定、犯罪、警察和社区暴力、监禁、种族歧视）; 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的其他风险因素有关，包括肥胖、高血压和糖尿病， 哪些AA受影响不成比例。我们的目标是确定~35年的轨迹在多大程度上 的压力暴露与晚年ADRD的风险相关， 风险指数，并与早期-中年生理衰老指标（端粒长度，p16，甲基化年龄）， 表观遗传修饰、炎症和认知表现。我们也会研究这些 相关性受性别、种族和AD风险基因的调节，并探索暴露的时间如何影响AD风险。 生命过程和其他潜在的调节器（即，童年的学业成绩， 教育/职业成就，酒精/药物使用，吸烟，行为问题，社会支持， 感知控制），影响这些关联。此外，我们将探讨两个早期生活（6-8岁） PIRC干预对我们早期中年研究结果的影响。为了实现这一目标，我们将重复血液和 口腔采样遗传和表观遗传物质，并完成两个家庭访谈，包括一个 认知电池和活动记录睡眠评估，1,150名参与者。这项研究是罕见的 有机会澄清早期生活压力暴露与中年痴呆风险的联系， 亚组有针对性的ADRD预防，阐明了社会不平等在确定种族 在AD痴呆的差异，并建立一个中年认知基线，为未来的后续行动，这些异常 充分表征的纵向，主要是AA队列。