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.

Alzheimer’s disease is a public health crisis in the US and a growing health disparity, with African Americans at disproportionate risk for the disease compared to non-Hispanic Whites. This project proposes to investigate earlier-life individual- and community-level stress exposures—adverse life circumstances and trauma (i.e., extreme poverty, residential instability, crime, police and community violence, incarceration, racial discrimination), mental disorders and their symptoms, and poor sleep (e.g., abnormal duration, fragmentation)—as determinants of known midlife risk factors for poor cognitive outcomes in later life in two predominantly African American cohorts followed longitudinally for 35 years. Results will help clarify links of stress exposures with estimated risk at midlife for later-life dementia, identify vulnerable subgroups for targeted prevention of Alzheimer’s disease and related disorders, elucidate the role of social inequities in determining racial disparities in dementia, and establish a midlife cognitive baseline for future longitudinal follow-up of this valuable cohort.