Earlier-Life Predictors of Midlife Risk Factors for Dementia: A 35-Year Follow-up (Revision) - Alzheimer’s disease (AD) and related dementias (AD/ADRD) are a public health crisis in the US. marked by growing health 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 adults. We are currently funded to use existing and newly collected data to prospectively examine trajectories of stress exposures—defined here as adverse life circumstances, and trauma (i.e., residential instability, crime, incarceration, traumatic events), mental disorders and their symptoms, and poor sleep—from childhood to early midlife as predictors of known midlife risk factors for subsequent AD/ADRD, based on a midlife dementia risk index, in 1,150 participants in two primarily (~66%) AA cohorts from Baltimore, Maryland who were followed repeatedly from age 6 to age 32 (2009-2011) and are now aged 42-46. In the funded study, we will also determine associations of stress exposures with potential biological pathways—physiological aging, epigenetic modification, and inflammation—and with performance on a neuropsychological battery that will also serve as a midlife cognitive baseline for future follow-up, and we will examine the extent to which these associations differ by sex , race, and AD/ADRD risk genes. This 3-year competing revision would add measures of promising AD/ADRD biomarkers to this funded study visit that are more sensitive to early manifestations of AD/ADRD than cognitive testing, specifically: plasma Aβ42/40, ptau217, NFL, and GFAP assays; olfaction; and gold-standard sleep measures from polysomnography (PSG; i.e., decrements in slow-wave sleep, shorter sleep duration, greater sleep fragmentation, sleep-disordered breathing). The primary goal is to prospectively examine trajectories of stress exposures from childhood to early midlife as predictors of these promising AD/ADRD biomarkers, explore whether these associations differ by sex, race, and AD/ADRD risk genes, and explore the degree to which these associations are accounted for by epigenetic change, inflammation, and physiological aging. We will also examine associations of the promising biomarkers with the midlife AD/ADRD risk index. The availability of self-report sleep data from childhood through midlife and midlife actigraphic sleep data from the funded study, combined with the PSG and plasma biomarkers from the proposed revision will facilitate particularly rich investigations of sleep from childhood through midlife with measures of AD/ADRD risk. The addition of these complementary measures and research questions to our funded study is a rare opportunity to clarify links of earlier-life stress exposures with sensitive AD/ADRD biomarkers, identify subgroups for targeted AD/ADRD prevention, elucidate contributors to AD disparities in dementia, and establish a midlife AD/ADRD biomarker baseline for future follow-up of these unusually well-characterized, longitudinal, primarily AA cohorts.
