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

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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.