Abstract
BackgroundDementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive and therapeutic interventions.MethodsIn this study, we conducted a network-based, multimodal omics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9-based genetic assay results and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer’s disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2.ResultsWe found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Overall, individuals with the AD risk allele APOE E4/E4 displayed reduced expression of antiviral defense genes compared to APOE E3/E3 individuals.ConclusionOur results suggest significant mechanistic overlap between AD and COVID-19, centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions, although causal relationship and mechanistic pathways between COVID-19 and AD need future investigations.
Highlights
Patients with COVID-19 commonly develop neurologic symptoms and/or complications, such as a loss of taste or smell, stroke, delirium, and rarely new onset seizures [1, 2]
We utilized single-cell/ nuclei RNA-sequencing data from both COVID-19 patients with neurological manifestations and brains of Alzheimer’s disease (AD) patients not infected by SARS-CoV-2, brainregion-specific gene expression data from the GTEx database [77], SARS-CoV-2 virus-host PPIs from mass spectrometry assays, genetic interactions from CRISPRCas9 assays (Table S1), and disease-related genetic data (Table S2)
Neuroinflammation was evaluated by identifying alterations in expression of AD blood and cerebrospinal fluid (CSF) biomarkers in COVID-19 patients using data from peripheral blood mononuclear cell (PBMC) and CSF samples
Summary
Patients with COVID-19 commonly develop neurologic symptoms and/or complications, such as a loss of taste or smell, stroke, delirium, and rarely new onset seizures [1, 2]. COVID-19 patients with dementia have elevated mortality rate [10, 11], and the most frequent symptoms included hypoactive delirium and functional status worsening [11]. COVID-19 may lead to cognitive impairments, such as shown by poor neuropsychological assessments [4, 12] or shown by behaviors or symptoms such as agitation, confusion, inattention, and disorientation [13]. Jaywant et al reported that of 57 recovering COVID-19 patients referred for neuropsychological evaluation before hospital discharge, 81% had cognitive impairment, including mild, moderate, and severe cognitive impairment [16]. Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive and therapeutic interventions
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