Dementia due to Alzheimer’s disease and related dementias (ADRD) disproportionately impacts racial/ethnic minorities and the socioeconomically disadvantaged. Development of effective interventions require mechanistic understanding of distal fundamental forces, including socioeconomic context (i.e. “neighborhood disadvantage” or the social determinants of health of a given area), that put people at “risk for [more proximal] risks” such as individual-level income, education, health behaviors and comorbidity. Prior research supports that contextual disadvantage is modifiable and interacts with biological processes to produce disease, yet little is known of its impact on ADRD. Towards this, we created validated quantifications of neighborhood disadvantage for the full US. This Area Deprivation Index (ADI) incorporates poverty, education, housing and employment indicators; predicts disparity-related health outcomes; and is freely shared through our public platform (the Neighborhood Atlas). We have validated survey and public data-based residential history tracing methodologies that establish dosage and timing of neighborhood disadvantage exposure across a life-course for both living and deceased persons. We have demonstrated that even after adjustment for individual risk factors, neighborhood disadvantage is strongly associated with cognitive function, neurodegeneration shown on MRI, and post-mortem AD plaque neuropathology. However, our current sample is lacking in geographic diversity and is of insufficient size to conduct a more robust multi-factor phenotypic risk assessment of social-biological interactions and their mechanisms; a necessary foundation towards developing new therapeutic intervention. This proposal employs collaboration with 22 Alzheimer’s Disease Research Centers (ADRC) and their existing cognitive, neuroimaging and neuropathology data. We take on the substantial work to create detailed residential histories for each ADRC subject (N~9,234 living, N~10,469 brain bank) to establish a dosage and timing of neighborhood disadvantage exposure across each life-course. Hypothesis: Larger and earlier exposures to neighborhood disadvantage will predict lower cognitive function, faster cognitive decline and greater disease burden including AD neuropathology among the targeted sample. Aim 1: Determine the impact of the cumulative dose and timing of neighborhood disadvantage exposure (indexed by ADI), on cognitive function and change over time; Aim 2: on AD-specific markers indexed by neuroimaging (amyloid and tau PET) and the secondary outcome of volumetric MRI; and Aim 3: on neuropathologic tissue features and diagnosis. Aim 4: Using existing ADRC data and newly collected survey data, define the extent to which individual race/ethnicity, age, sex, income, education, comorbidity and health-behaviors mediate these relationships. The proposed project, if funded, will be the largest study of its kind on social determinants of health in the context of AD. Successful completion will result in the development of a novel collaborative infrastructure of contextual exposure for future social-biological phenotypic evaluation, providing a potential pathway to new therapeutics, and directly responsive to the NIA mission.

NARRATIVE Dementia due to Alzheimer’s disease and related dementias (ADRD) disproportionately impacts racial/ethnic minorities and the socioeconomically disadvantaged; groups more often exposed to neighborhood disadvantage. Prior research supports that neighborhood disadvantage is modifiable and interacts with biological processes to produce disease, yet little is known of its impact on ADRD. This project leverages data within 22 Alzheimer’s Disease Research Centers across the US to conduct the largest study of its kind on social determinants of health in the context of AD and to develop a novel collaborative infrastructure of contextual exposure for future social-biological phenotypic evaluation-- a potential pathway to new therapeutics directly responsive to the NIA mission.