# 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

> **NIH NIH RF1** · UNIVERSITY OF MINNESOTA · 2022 · $2,172,765

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10466413
- **Project number:** 1RF1AG077772-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** MAXIM CHACKO-JOSEPH CHEERAN
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,172,765
- **Award type:** 1
- **Project period:** 2022-06-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466413

## Citation

> US National Institutes of Health, RePORTER application 10466413, 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 (1RF1AG077772-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10466413. Licensed CC0.

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