A common complication of coronavirus infection is neurocognitive impairment similar to dementia (dementia). The mechanisms of this complication remain unclear.

Scientists from the Institute of Genomic Medicine (USA) investigated what causes coronavirus infection to develop neurological complications and cognitive dysfunction. Scientists have compared the biochemical parameters of patients with different types of dementia and patients with COVID-19.

Study Design

Scientists conducted a networked multimodal study to identify all possible relationships between COVID-19 and brain disorders. Experts proceeded from the assumption that there are two possible pathways for the neurological impact of coronavirus infection on the brain:

  • proteins of the SARS-CoV-2 coronavirus directly target human proteins associated with neurological diseases;
  • proteins of the SARS-CoV-2 coronavirus indirectly affect brain damage through a sequence of protein interactions.

To identify possible associations between the proteins of the SARS-CoV-2 coronavirus and human proteins associated with neurological diseases and conditions, the scientists used an analysis of the network proximity of protein interactions.
Scientists analyzed whether there are common biochemical mechanisms and pathways between COVID-19 and the following diseases and conditions:

  • Alzheimer’s disease;
  • amyotrophic lateral sclerosis (motor neuron disease);
  • dementia;
  • decrease in cognitive functions;
  • frontotemporal dementia;
  • multisystem atrophy;
  • neuronal ceroid lipofuscinosis;
  • Parkinson’s disease;
  • spinal muscular atrophy (loss or damage to motor neurons);
  • spinocerebellar ataxia.

Scientists have compared experimentally validated genome profiles to uncover potential mechanisms of protein-protein interactions.

Research Results

Most likely neurological complications of coronavirus infection

Scientists have found that the SARS-CoV-2 coronavirus activates the same genes and protein-protein interactions as neurological diseases. Most likely neurological complications of COVID-19: Parkinson’s disease, cognitive decline, Alzheimer’s disease.

The network landscape of coronavirus disease and neurological diseases is shown in the figure. The degree of network proximity is best seen on a heatmap – the brighter the red, the higher the network proximity:

In COVID-19 and Alzheimer’s disease, the activity of proteins responsible for mental functions changes

Scientists have focused on the link between Alzheimer’s and COVID-19. Experts have investigated the complete set of interactions between protein molecules. Many proteins have been discovered that play an essential role in both Alzheimer’s disease and COVID-19.

The vascular cell adhesion protein VCAM1 is found on the surface of endothelial cells. Elevated levels of this protein are associated with the severity of dementia and structural changes in the brain’s white matter. This protein is a marker for Alzheimer’s disease.

In severe patients with COVID-19, the amount of VCAM1 protein is increased compared with patients with mild coronavirus infection and healthy people from the control group. As you recover, the level of this protein will return to normal. Scientists note that the VCAM1 protein plays a vital role in vasculitis (vascular inflammation) caused by COVID-19.
RAB7A protein is a potential biomarker of Alzheimer’s disease. Its high blood content improves results in-memory testing.

Genome decoding and subsequent comparison showed that one of the proteins of the SARS-CoV-2 coronavirus directly inhibits RAB7A.

The signaling protein TGFB1 is a potential biomarker of Alzheimer’s disease, and low blood levels of this protein are found in patients. The TGFB1 protein has neuroprotective and anti-inflammatory functions in Alzheimer’s disease.

With COVID-19, the TGFB1 protein level is reduced in all groups of patients: mild, moderate, severe, in need of intensive care. The analysis was based on the RNA decoding from the blood of patients with COVID-19.

The findings prompted scientists to identify all possible pathological pathways by which coronavirus infection can lead to dementia, similar to Alzheimer’s.

Protein markers of neuroinflammation are similar in COVID-19 and Alzheimer’s

The researchers wondered if neuroinflammation is a common mechanism in these diseases. A list of protein markers of blood and cerebrospinal fluid in pathologies associated with Alzheimer’s disease was compiled. Scientists have compared the activity of the genes of these markers in patients with COVID-19 and without COVID-19.

A large number of common protein markers of neuroinflammation have been found in the cerebrospinal fluid. However, there were significantly fewer of them in the blood. The degree of network affinity between markers was also more significant in the cerebrospinal fluid. A comparison of the activated genes also confirmed this result.

Scientists note that network and multidisciplinary data analysis indicates that coronavirus infection affects genes and immune pathways that can lead to neuroinflammation characteristic of Alzheimer’s disease.

COVID-19 and Alzheimer’s Disease Link is Confirmed Clinically

Patients with Alzheimer’s disease are at increased risk of contracting COVID-19. On the other hand, coronavirus affects the nervous system and can cause long–term neurological complications (for more information, see the article “COVID-19 influence on brain and nervous system“). One of the causes of neurological complications of coronavirus is neuroinflammatory processes, which also play a leading role in the pathogenesis of Alzheimer’s disease.

American scientists have investigated whether COVID-19 can cause Alzheimer’s disease or accelerate its occurrence. The study involved more than 6 million older adults over 65 years of age:

  • 7% – transferred COVID-19;
  • 93% – did not have COVID-19.

COVID-19 increased the risk of Alzheimer’s disease by 1.7 times within a year after infection with the coronavirus. The risk is exceptionally high in patients over 85 years of age and in women.

Increased Susceptibility of Endothelial Cells to SARS-Cov-2 Coronavirus Stimulates Microvascular Brain Damage

Scientists assessed the risk of microvascular damage by examining the entry factors for coronavirus into different types of brain cells.
6 types of cells were studied:

  • excitatory neurons;
  • inhibitory neurons;
  • astrocytes;
  • microglia;
  • endothelial cells;
  • oligodendrocytes.

Compared to other tissues of the body, brain cells contain significantly fewer proteins through which SARS-CoV-2 enters the cell. However, if you look at individual types of brain cells, endothelial cells are most susceptible to infection.

The proteins used by the coronavirus in endothelial cells are much larger than, for example, in neurons. The coronavirus spike protein can penetrate the blood-brain barrier and cause inflammation in endothelial cells and, as a result, inflammation in microvessels.

Activation of genes for antiviral defense in endothelial cells can also lead to damage to brain microvessels. RNA decoding of these cells revealed increased activity of antiviral genes:

  • a gene for interferon type I receptor (IFNAR1), which is used to trigger all antiviral functions of the cell;
  • lymphocytic antigen LY6E, which prevents the fusion of membranes where there is a spike protein;
  • a gene of interferon-stimulated protein IFIT3, which suppresses the infection of the cell with the virus.

Network analysis also revealed several additional proteins involved in antiviral defense. For example, the transcription activation protein STAT3 and Janus-kinase JAK1 are required to form the antiviral state of the cell.

Comparison of protein bonds in Alzheimer’s patients and patients with COVID-19 has revealed many common biochemical mechanisms that focus on pathways of neuroinflammation and microvascular damage.

Conclusions

COVID-19 causes neuroinflammation and damage to the microvessels in the brain. It increases the likelihood of developing dementia, cognitive impairment, and other neurological diseases. Thus, COVID-19 increases the risk of Alzheimer’s disease by 1.7 times within a year after infection with coronavirus, especially in patients over 85 years of age and in women.

The results of this study will help to understand better the neurological manifestations associated with COVID-19. Based on this study, scientists will develop protein tests to identify patients at high risk of neurological complications. The data obtained can be used to reduce the risk of potential cognitive impairment in patients with coronavirus infection.

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