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

阿尔茨海默病(AD)是美国的一种公共卫生危机，与非洲人的健康差距越来越大 美国人(AA)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。 努力为穷人的已知中年风险因素确定可改变的早年风险和保护性因素 需要晚年的认知结果来保护中老年AA的健康。我们建议 前瞻性地研究个人和社区层面的压力暴露的轨迹 中年早期是继发性阿尔茨海默病及其相关已知中年风险因素的预测因子 痴呆症(ADRD)在两个主要(~66%)的AA队列中出现，现在年龄在40-44岁之间，并已得到随访 约翰霍普金斯预防干预研究从6岁到32岁的反复调查(2009-2011) 中心(PIRC)。相关的个人和社区层面的压力暴露，从早期生活到 中年包括：1)不利的生活环境和创伤(即极端贫穷、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 以及他们的症状；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受到的影响不成比例。我们的目标是确定~35年的轨迹 在中年早期使用痴呆症测量的压力暴露与晚年ADRD的风险相关 风险指数，以及中青年生理衰老的指标(端粒长度、p16、甲基化年龄)， 表观遗传修饰、炎症和认知能力。我们还将检查这些是否 相关性受性、种族和AD风险基因的调节，并探索暴露在 生活课程，以及其他潜在的主持人(即，儿童学业成就， 教育/职业成就、酗酒/吸毒、吸烟、行为问题、社会支持、 感觉到的控制)，影响这些联系。此外，我们将探索两个早期生命(6-8岁)的影响 PIRC对我们中年早期研究结果的干预。为了做到这一点，我们将重复流血和 对遗传和表观遗传物质进行口腔采样，并完成两次家庭访谈，包括一次 认知电池和活动睡眠评估，有1150名参与者。这是一项罕见的研究 有机会澄清早年压力暴露与中年痴呆症风险的联系，识别易受伤害的人 有针对性的ADRD预防分组，阐明社会不平等在决定种族方面的作用 AD痴呆的差异，并为这些异常情况的未来随访建立中年认知基线 特征良好的纵向，主要是AA队列。

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.