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Review 1: "SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer’s-like neuropathology"

This preprint evaluates SARS-CoV-2 neurotropism in COVID-19 infected brains and hypothesizes inductions of Alzheimer’s-like neuropathology upon infection. Reviewers found this study potentially informative with limitations that prevent a strong generalization of authors' results.

Published onFeb 24, 2022
Review 1: "SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer’s-like neuropathology"
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key-enterThis Pub is a Review of
SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer’s-like neuropathology

AbstractMajor cell entry factors of SARS-CoV-2 are present in neurons; however, the neurotropism of SARS-CoV-2 and the phenotypes of infected neurons are still unclear. Acute neurological disorders occur in many patients, and one-third of COVID-19 survivors suffer from “brain diseases”. Here, we show that SARS-CoV-2 invades the brains of five patients with COVID-19 and Alzheimer’s, autism, frontotemporal dementia or no underlying condition by infecting neurons and other cells in the cortex. SARS-CoV-2 induces or enhances Alzheimer’s-like neuropathology with manifestations of β-amyloid aggregation and plaque formation, tauopathy, neuroinflammation and cell death. SARS-CoV-2 infects mature but not immature neurons derived from inducible pluripotent stem cells from healthy and Alzheimer’s individuals through its receptor ACE2 and facilitator neuropilin-1. SARS-CoV-2 triggers Alzheimer’s-like gene programs in healthy neurons and exacerbates Alzheimer’s neuropathology. A gene signature defined as an Alzheimer’s infectious etiology is identified through SARS-CoV-2 infection, and silencing the top three downregulated genes in human primary neurons recapitulates the neurodegenerative phenotypes of SARS-CoV-2. Thus, SARS-CoV-2 invades the brain and activates an Alzheimer’s-like program.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.


Shen and colleagues have reported brain pathological findings of five COVID-19 patients with or without pre-existing neurological disorders, such as Alzheimer’s dementia or autism. First, the authors have supported SARS-CoV-2 neurotropism, showing the direct viral invasion of cerebral hubs involved in cognitive functions by means of ACE2 and neuropilin-1-dependent mechanisms typical of mature neurons. Second, SARS-CoV-2 infection has been found to be able to trigger or enhance β-amyloid pathology underlying Alzheimer’s neurodegeneration as well as to increase neuroinflammation and induce several cell death pathways, such as apoptosis. Third, the authors replicated SARS-CoV-2-induced neurodegenerative changes by silencing the top three downregulated genes in human neurons.

The study is very interesting, well-written, and potentially informative since it could pave the way towards putative mechanisms underlying neuropathology associated with SARS-CoV-2 infection. However, the small number of examined brains and the impossible evaluation of within-patient changes induced by SARS-CoV-2 infection (i.e. assessing brain samples before COVID-19) are major limitations that prevent a strong generalization of the authors’ results. For example, a higher number of extracellular β-amyloid plaques in Alzheimer’s patients with COVID-19 compared to the control group of Alzheimer’s subjects may derive from a selection bias of a cohort of Alzheimer’s patients with COVID-19 casually characterized by a more relevant Alzheimer’s β-amyloidopathy before SARS-CoV-2 infection. Moreover, a detailed report of clinical features (e.g. history and symptoms) of COVID-19 patients and control subjects is lacking.

Given their results showing no effect on the increase of intracellular neurofibrillary tangles (as evident from panel H of Figure 4), how do the authors explain the Alzheimer’s-like behavior of SARS-CoV-2 infection, which apparently would only act on BACE-1-dependent β-amyloid cascade?

The authors should discuss and comment on several studies that have suggested an indirect effect rather than a direct invasion of SARS-CoV-2 infection in determining brain pathology abnormalities.

Furthermore, I have some concerns regarding some statistical analyses. Indeed, in the legends of Figures 4, 6, 7, and S4, the authors have declared that the Mann-Whitney test was used after confirming a normal distribution. This statement deserves a proper explanation since the Mann-Whitney test is a non-parametrical test, which is applied to data that is not normally distributed. Also, in Figures 6 and 7, when more than two groups are compared, the authors should use the Kruskal-Wallis test as a non-parametrical analysis followed by a posthoc test, instead of a Mann-Whitney test (similarly to ANOVA with posthoc Tukey as parametrical analysis).


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