Post-Acute Sequelae of SARS-CoV-2 Infection and Subsequent Disease Progression in Individuals with AD/ADRD: Influence of the Social and Environmental Determinants of Health

PROJECT SUMMARY The global pandemic of the 2019 novel coronavirus disease (COVID-19) has severe consequences. Recent studies showed that individuals with COVID-19 had increased risk of an array of postacute incident neurologic sequelae, including cognition and memory disorders, in 12 months after COVID-19 diagnosis. Despite elevated risks of postacute neurologic outcomes of COVID-19 observed in the general population, little is known about Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) in cognitively impaired individuals (e.g., those with mild cognitive impairment [MCI] and Alzheimer's disease [AD]/AD-related dementias [ADRD]) and how it may impact their subsequent disease progression. The rapid adoption of electronic health record (EHR) systems has made longitudinal clinical data available for research, especially for individuals with MCI or AD/ADRD who engage in frequent routine care. However, existing large EHR-based COVID-19 cohorts do not specifically focus on cognitively impaired individuals have several key limitations, including (1) missing or inaccurate information on cognitive impairment, (2) challenges to characterize disease progression in individuals with MCI or AD/ADRD, and (3) robust causal modeling approaches that can account for the complex confounding and selection biases in observational RWD. More importantly, little is known about factors contributing to PASC and subsequent disease progression in cognitively impaired individuals with COVID-19. It has long been recognized that social and environmental determinants of health (SEDH) play important roles in cognitive health. Exposures to multiple SEDH have been associated with MCI and AD/ADRD. Our recent studies (R21ES032762 and the RECOVER Initiative) also found that SEDH are associated with COVID-19 incidence, severity, mortality, and PASC in the general population. Individuals are exposed to multiple SEDH simultaneously, and the exposome is an ideal framework to rigorously examine how SEDH impacts cognitively impaired individuals' susceptibility to PASC and subsequent disease progression. Building upon our prior and ongoing work on COVID-19 and PASC in the general population with the RECOVER Initiative, sub-phenotyping and disease progression modeling, and multiple SEDH, we will (1) understand the epidemiology of PASC in individuals with MCI or AD/ADRD with high-throughput causal inference approaches, (2) examine the impacts of COVID-19 and PASC on subsequent disease progression in individuals with MCI or AD/ADRD with a novel dynamic topic modeling approach, and (3) assess how SEDH contribute to PASC and subsequent disease progression in individuals with MCI or AD/ADRD with the exposome conceptual framework. This project will fill important knowledge gaps on our understanding of, especially SEDH's contributions to, risks of PASC and subsequent disease progression in individuals with cognitive impairment.