PROJECT SUMMARY Social isolation, loneliness, and social environment continue to emerge as important factors in Alzheimer’s disease and related dementias (ADRD), more so with the COVID-19 pandemic and observed trends in the prevalence of social isolation, loneliness, and ADRD. Although there is increasing recognition these factors can impact the aging brain, represent early expression of ADRD neuropathological changes, and influence health behaviors and resource access, less is known about the biological mechanisms involved. Our overarching hypothesis is that social isolation, loneliness, and social environment are distinct factors that alter brain biology and influence trajectories of healthy neurocognitive aging and ADRD vulnerability. Because understanding causal pathways and the cumulative role of these critical psychosocial factors through decades-long human experimental trials is infeasible, here we propose a unique and innovative approach to comprehensively assess these psychosocial determinants and temporally relate them to dynamic profiles of ADRD vulnerability, leveraging one of the largest biologically well-characterized community-based cohorts in the US, the Framingham Study (FS). Since 1948, FS has enrolled 3 generations of participants (ages 20-50) and 2 multi- ethnic cohorts, examined them regularly for cognitive decline and dementia, and collected an exquisite array of in-depth and cutting-edge “multi-omic”, imaging, and other data over their lifespan and before clinical ADRD onset. The FS has a 70-year legacy of unique contributions to public health, and will continue make breakthroughs in ADRD through its Brain Aging Program (3U19AG068753-02S1). We seek to leverage these resources through the following specific aims: AIM 1 is to examine and explain associations of social isolation, loneliness, and social network structure with ADRD vulnerability over a lifetime. Our prior work in FS suggests a molecular pathway related to neural plasticity/repair and cognitive resilience might be involved in these mechanisms. We will collect a new wave of data on these factors—partially harmonized with the NIH Toolbox and integrate this data with relevant psychosocial information at multiple previous exams. AIM 2 is to identify and validate these biological pathways using causal inference analyses and machine-learning methods on the extensive multi-omics data available. AIM 3 is to characterize social environment’s cumulative role in psychosocial mechanisms of ADRD risk across the adult lifespan by developing a latent social environment index with a validated geocode-based method and conducting sophisticated analyses. We will validate our findings with other multi-ethnic cohort datasets and share all data through dbGaP and bioLINCC. We expect to meaningfully evaluate whether and how these psychosocial factors influence the biology of healthy neurocognitive aging and ADRD vulnerability and identify new pathways that may serve as targets for intervention in the preclinical stage of ADRD. This will advance our understanding of the long-term effects of psychosocial determinants, ADRD prevention, and how to address the root causes of disparities in ADRD.

PUBLIC HEALTH RELEVANCE Although social isolation, loneliness, and social environment are increasingly recognized as important factors in Alzheimer’s disease and related dementias (ADRD), less is known about the biological processes by which these factors impact brain health and ADRD. We plan to study these relatively novel associations in detail by adding social isolation, loneliness, and social environment information to ongoing ADRD surveillance in the biologically well-characterized Framingham Study cohorts, relating these measures to extensive preclinical ADRD data from dementia-free Framingham participants of diverse racial/ethnic and socioeconomic backgrounds (neuropsychological and state-of-the-art omics and brain imaging—amyloid/tau-PET and volumetric/connectivity/perfusion-MRI), and using advanced computational analysis to characterize the cumulative biological role of these factors in ADRD. This would complement studies of the COVID-19 pandemic’s long-term population health impacts, help us better understand observed trends between psychosocial determinants of health and ADRD risk, clarify the magnitude of change needed in these factors for a meaningful improvement in health, advance health equity by supporting quantitative methods development to address root causes of disparities in ADRD, and, if validated, identify new treatment targets that may also strengthen individual and group psychosocial functioning.