Life-Course Contexts, Biological Aging, and AD/ADRD Risk: Evidence from a Nationally Representative, Longitudinal Study of Early Midlife Adults - Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD) are on the rise in the United States, with a projected 40% increase in AD among older adults by 2025. Substantial variation exists in AD/ADRD and AD/ADRD risk across populations driven by differential exposure to modifiable contextual factors and resulting dysregulation of biological processes (e.g., cardiovascular, metabolic, inflammatory, epigenetic). These biological processes act as critical pathways to AD/ADRD and potential targets for early prevention prior to disease onset. However, due in part to data availability, longitudinal, prospective studies investigating the effects of contextual factors across multiple domains (e.g., educational, residential, and criminal legal), geographic levels, and life stages on early biological processes linked to AD/ADRD are sparse. Which specific contextual factors (i.e., poverty, school composition, incarceration rates) contribute to biological pathways and the magnitude of risk reduction achievable through targeted interventions therefore remains poorly understood. Moreover, studies adjudicating the salient biological pathways through which specific contextual factors increase AD/ADRD risk are needed to inform mechanistic understandings and intervention strategies. Causal modeling techniques provide strategic opportunities to estimate the magnitude of biological risk reduction achievable under hypothetical targeted interventions using observational data, with direct implications for early prevention to slow the progression of AD/ADRD risk. The overall goals of this project are to: 1) use longitudinal observational data to identify which contextual factors across educational (i.e., school composition, per-pupil spending), residential (i.e., poverty) and criminal-legal (i.e., incarceration rates) domains during the early life course affect cardiovascular, metabolic, inflammatory, epigenetic, and neurodegenerative pathways to AD/ADRD risk; 2) determine how variation in these contextual factors contribute to differences in risk across populations; and 3) estimate the population-level impact of specific hypothetical interventions targeting biological processes of AD/ADRD with careful attention to variation in these pathways across populations. This study will leverage data from the National Longitudinal Study of Adolescent to Adult Health, a nationally representative cohort of individuals followed from adolescence into their early 40s, providing a unique opportunity to track the influence of specific contextual factors on AD/ADRD biological risk across the early life course as risk trajectories are developing. Findings will identify specific life stages and contextual factors that shape salient biological processes underlying AD/ADRD risk, quantify the biological benefits of targeted, hypothetical interventions, and inform evidence-based early prevention strategies.
