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

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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.