PROJECT SUMMARY Coronavirus Disease 2019 (Covid-19) is a devastating worldwide pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). In the United States alone, there have been over 35 million confirmed cases and Covid-19 has claimed more than 600,000 lives, and the pandemic is still rampant around the globe. While SARS-CoV-2 can infect people at all ages, senior populations are at greatest risk of severe disease and worse outcomes. Although Covid-19 is initially a respiratory disease, it subsequently causes damage to multiple organ systems, including the brain. Clinical findings indicate that neurological symptoms are widely observed in patients with Covid-19 and approximately 33% of Covid-19 survivors suffer from persistent neurological impairment. Emerging evidence also shows that people carrying the apolipoprotein (APO) E4 gene, the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), are more susceptible to SARS-CoV-2 infection with higher severity and mortality than people carrying the APOE3 gene. In addition, older adults with AD or other dementias are at a higher risk of contracting Covid-19 and experiencing more severe outcomes than are people without dementia. These findings suggest that age, APOE genotype, and AD/dementia status modify the risk, severity, and outcomes of SARS-CoV-2 infection, although the underlying mechanisms are unclear. Further, while the acute effects of Covid-19 on brain functions are well documented, the long-term impact of SARS-CoV- 2 infection (“long-Covid”) is currently unknown. We hypothesize that the interactions of SARS-CoV-2 with age, APOE genotype, and the context of AD-type neuropathology at the blood-brain and blood-CSF barriers modulate both systemic and neuroinflammation, dictating the effects of SARS-CoV-2 infection on brain function. Three independent yet interrelated specific aims are proposed to test the hypothesis, using multiple mouse models and a combination of virology, immunology and neurobehavioral approaches, coupled with innovative targeted and unbiased cellular, molecular technologies, including single cell/nucleus transcriptomics, spatial genomics, and 3D brain clearing and imaging. Aim 1 is to assess the acute and long-term impact of SARS-CoV-2 infection on neuropathophysiology in normal aging in WT mice. Aim 2 is to define the interaction of SARS-CoV-2 with different APOE isoforms and its impact on the temporal onset and severity of cognitive impairment and neuropathology in human APOE4/4 and APOE3/3 mice. Aim 3 is to evaluate the impact of SARS-CoV-2 infection on the progression of cognitive deficits and AD neuropathology in APP/PS1 transgenic mice. Results from these proposed studies are expected to define the short- and long-term impact of SARS-CoV-2 infection on cognitive function and pathogenic processes in aging and AD, and provide novel insights into the underlying cellular and molecular mechanisms so that effective interventions may ...