Acute and Long-Term Impact of SARS-CoV-2 Infection and its Interaction with APOE on Cognitive Function and Neuropathology in Aging and Alzheimer's Disease

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 be developed to prevent the neurological and neurocognitive sequelae from SARS-CoV-2 infection in aging and AD.