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

阿尔茨海默病(AD)和相关痴呆(AD/ADRD)是美国的一种公共卫生危机，其特点是 日益扩大的种族差距，非洲裔美国人(AA)被诊断的可能性是 非西班牙裔白人。努力确定已知中年的可改变的早期生命风险和保护因素 老年认知不良的危险因素需要保护中年人和老年人的健康 年纪较大的美国人。我们建议前瞻性地研究从童年到早期的压力暴露的轨迹。 中年是两个主要(~66%)AA患者随后AD/ADRD的已知中年风险因素的预测因素 现在41-45岁，从6岁到32岁反复跟踪的队列(2009-2011) 约翰霍普金斯预防干预研究中心(PIRC)。相关的个人和社区- 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 (即极端贫困、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，持续时间异常、支离破碎)。 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，这些疾病对氨基酸的影响不成比例。我们的目标是确定 ~35年的压力暴露轨迹与估计的中年风险有关 AD/ADRD，生理性衰老(端粒长度，p16，甲基化年龄)，表观遗传修饰，以及 炎症和认知表现--所有这些都是在中年早期测量的--如果这些联系 受性别、种族和AD/ADRD风险基因的影响。我们还将探索曝光的时间如何 生活过程影响这些联系，如果其他潜在的主持人(例如，儿童学术 成就、教育/职业成就、酗酒/吸毒、行为问题、社会支持、 知觉控制)影响这些联系。我们将进一步探索两个早期(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，1150名PIRC参与者将完成以下两项- 家庭访谈，包括认知电池和动态睡眠评估，我们将收集 用于遗传和表观遗传物质和生理老化措施的生物检疫剂。这是一项罕见的研究 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，确定 有针对性地预防AD/ADRD的弱势亚群，阐明社会不平等在 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 这些不寻常的特征很好的纵向，主要是AA队列。

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.