PROJECT SUMMARY/ABSTRACT The growing prevalence of Alzheimer’s disease and Alzheimer’s related disorders (ADRD) is a critical public health concern, potentially exacerbated by the COVID-19 pandemic. Infectious diseases may increase ADRD risk by causing neuroinflammation and oxidative damage in the central nervous system, promoting atherosclerosis and endothelial dysfunction, or via other inflammatory, immune-response, and vascular mechanisms. Despite intriguing links between several infectious and neurodegenerative conditions, whether and how infectious diseases influence ADRD risk remains underexplored. This question is urgent especially during the COVID-19 pandemic, where the widespread SARS-CoV-2 infection has heavily impacted global public health. Mounting evidence suggests a significant fraction of those infected with SARS-CoV-2 may experience substantial and long-lasting sequelae, including cognitive decline and neurologic deficits. Many unknowns remain, including long-term outcomes and the role of COVID-19 vaccination and viral variants in modifying the effect of SARS-CoV-2 infection on cognitive decline and ADRD risk. This proposed F99/K00 project seeks to address these gaps with two specific aims using complementary longitudinal datasets and rigorous, advanced epidemiological and statistical methods. Aim 1 (F99 dissertation phase: 2023-2025) will use the previously identified COVID-19 brain magnetic resonance imaging (MRI) signature region to infer the long-term effects of infection on ADRD risk via brain structure changes. The COVID-19 MRI signature region comprises brain regions where cortical thickness and gray-white matter contrast was reduced after SARS- CoV-2 infection (identified in a longitudinal MRI study). The candidate will quantify the association between the COVID-19 MRI signature region and future ADRD risk among UK Biobank participants. Aim 2 (K00 postdoctoral phase: 2025-2029) will evaluate the effects of vaccination status and timing of SARS-CoV-2 infection on cognitive outcomes and ADRD among COVID-19 survivors. The candidate will use data from electronic health records (EHR) and a nationally representative cohort. Methodological innovations include the use of neuroimaging, causal survival analysis, machine learning methods for classification algorithms, as well as multiple data sources (i.e., clinical data from EHR and survey data from cohort studies). This proposal directly responds to the call to study the impact of COVID-19 on risk of ADRD and cognition from the National Alzheimer's Project Act (NAPA). The proposal extends the candidate’s quantitative expertise with advanced training in clinical and biological perspectives on ADRD as well as causal inference methods for aging research. Strong interdisciplinary mentorship teams and outstanding supportive training environments at the University of California, San Francisco (F99) and the Massachusetts General Hospital (K00) provide a foundation for the candidate to fill an important scientific gap on infectious disease and immune-related determinants of cognitive aging and ADRD, including infection with SARS-CoV-2.

PROJECT NARRATIVE This proposed research will determine the effect of SARS-CoV-2 infection on Alzheimer’s disease and related dementias (ADRD) risk via brain structure changes and evaluate how vaccination status and timing of SARS- CoV-2 infection affect cognitive outcomes and ADRD risk among COVID-19 survivors. The findings from this research could improve knowledge of ADRD in the post-COVID-19 era, and facilitate planning and appropriate resource allocation to care for an aging population and reduce the burden of ADRD. The long-term goal of this line of research is to decrease the global burden of ADRD by advancing our understanding of how major infectious diseases influence long-term ADRD risk.