Can COVID-19 aggravate Alzheimer’s Disease?

By Emmeleia Psyllaki

Coronavirus disease 2019, widely known as COVID-19, is a very infectious disease that is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 or SARS-CoV-2 for short¹. 

The intensity of symptoms of infection can vary from those of a mild to moderate respiratory illness and relatively quick recovery without medical attention to those of a more serious illness requiring hospitalization and special treatment. This is especially prevalent in older people and those with underlying medical conditions, such as chronic respiratory diseases that COVID infection can exacerbate. The terrifying part is that irrespective of age, race, sex or medical condition, patients can become seriously ill and even die. The disease’s high infection rate led to its rapid spreading around the world and its characterization as a pandemic; one that is extremely devastating and with ascending mortality rates¹.

Alzheimer’s disease (AD) is the most prevalent kind of dementia in the elderly population worldwide and its clinical features include neuronal loss in the hippocampus and cortical regions resulting in cognitive impairment, behavioral changes, mood swings, and memory loss. These symptoms can progress and grow even more serious, reaching the point where they interfere with patient’s daily tasks and activities, such as eating and sleeping².

Neuropathological hallmarks for AD are amyloid plaques and neurofibrillary tangles. The former are formed due to deposits of misfolded beta-amyloid protein between nerve cells, while the latter appear due to the twisting of the hyperphosphorylated tau protein inside cells. These are believed to occlude communication between nerve cells resulting in the blockage of multiple processes that cells need to survive, eventually leading to the damage and death of the nerve cells³.

As described, both COVID-19 and Alzheimer’s are very devastating, continuously affecting millions of people worldwide, together with their loved ones who must suffer their dramatic journeys and in many cases their passing as well. Could these two somehow be related? What happens when an Alzheimer’s patient gets infected with SARS-CoV-2? Can it aggravate Alzheimer’s disease?

Although SARS-CoV-2 mainly affects the respiratory tract, increasing evidence and emerging studies suggest that there is a very close relation between COVID-19 and the central nervous system (CNS) ⁴. In agreement with this finding, SARS-CoV-2’s involvement in the CNS was confirmed by magnetic resonance imaging (MRI), which revealed brain structural abnormalities linked to COVID-19 in both surviving patients and non-survivors⁴.

The presence of viral RNA and protein in the brains of COVID-19 patients with neurological symptoms has been connected to an infection of human neurons by a virus. According to a neurochemical study, patients with severe SARS-CoV-2 infections have high plasma levels of the glial fibrillary acidic protein (GFAP) and neurofilament light chain protein (NFL), which are biochemical markers of neuronal injury and glial activation, respectively³. 

Presence of viral RNA and protein in the brains of COVID-19 patients with neurological symptoms led to scientists suggesting that a viral infection of the human neurons has occurred. According to a neurochemical study, patients experiencing severe SARS-CoV-2 symptoms have very high plasma levels of neurofilament light chain protein (NFL) and glial fibrillary acidic protein (GFAP) which are known to be biochemical markers of neuronal injury and glial activation respectively³. The findings of this research, thus support the idea that SARS-CoV-2 brain infection and neurological disorders are directly related.

The study also suggested multiple ways with which a virus can enter and infect the brain. Firstly, it was discovered that the virus may enter the olfactory bulb, which is located in the forebrain, directly without having to first get involved with the lungs, in both human and animal subjects ⁵. Angiotensin-converting enzyme 2 (ACE2), which is abundantly expressed in glial cells and neurons, interacts with the viral S1 spike protein to enable this. Additionally, it was found that both excitatory and inhibitory neurons as well as non-neuronal cells such as oligodendrocytes, astrocytes, and endothelial cells have ACE2. These findings support the hypothesis, that in patients with COVID-19 a brain infection by SARS-CoV-2 may enhance symptoms in the CNS⁶. Furthermore, this may suggest some possible novel routes with which a virus enters and propagates into the cerebral tissue. Lastly, the same study found that SARS-CoV-2 may infect the brain through the blood-brain barrier which becomes damaged as a result of neurodegenerative diseases, especially in Alzheimer’s disease⁶.

Neuroinflammation, which is caused by the activation of microglia cells and the production of multiples cytokines, plays a pivotal role in the advancement of the neuropathological alterations seen in Alzheimer’s pathogenesis. It is interesting to note that severe outcomes following SARS-CoV-2 infection in older people are frequently linked to a cytokine storm that causes an overactive immunological and inflammatory response, which may speed up  inflammatory neurodegeneration in the brain⁶.

A more recent study revealed that SARS-CoV-2 spike S1 protein can promote the spreading of the twisted hyperphosphorylated tau protein through extracellular vesicles or direct cell-to-cell contact⁶. The virus can actually lend its glycoproteins to neurons and extracellular vesicles, continuing the disease, due to its ability to infect human neurons and use this machinery to replicate. Moreover, astrocytes can also be infected by the virus, altering the metabolic pathways involved which impedes the survival of neurons, resulting in neurodegeneration⁶.

In conclusion, more research needs be carried out to investigate whether SARS-CoV-2 is able to infect neurons directly, replicate within them or just enter nerve cells. Furthermore, it has to be confirmed whether the symptoms and complications described are due to SARS-CoV-2 brain cells’ infection or due to a general systemic illness that the patients are experiencing. The sure thing is that people who have been diagnosed with Alzheimer’s are a vulnerable group and thus more prone to getting COVID-19 and developing more severe symptoms, resulting even in death. Consequently, understanding how COVID-19 and AD are related may facilitate with the identification of COVID-19 early on and the development of targets against both diseases. 

References:

1. Who. Coronavirus disease (COVID-19). [Online]. Available from: https://www.who.int/health-topics/coronavirus#tab=tab_1 %5BAccessed 21 October 2022].
2. Nhs. Alzheimer’s disease. [Online]. Available from: https://www.nhs.uk/conditions/alzheimers-disease/ %5BAccessed 21 October 2022].
3. Villa, C., Lavitrano, M., Salvatore, E., Combi, R. Molecular and Imaging Biomarkers in Alzheimer’s Disease: A Focus on Recent Insights. National Library of Medicine. [Online] 2020;10(3): . Available from: https://pubmed.ncbi.nlm.nih.gov/32664352/ %5BAccessed 21 October 2022].
4. Paniz-Mondolfi, A., Bryce, C. E, Grimes, Z., E Gordon, R., Reidy, J.. Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Natural Library of Medicine. [Online] 2020;92(7): 699-702. Available from: https://pubmed.ncbi.nlm.nih.gov/32314810/ %5BAccessed 22 October 2022].
5. Li, Y.C, Bai, W.Z, Hashikawa, T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. Wiley Online Library. [Online] 2020;92(6): 552-555. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25728 [Accessed 22 October 2022]
6. Villa, C, Rivellini, E, Lavitrano, M, Combi, R. Can SARS-CoV-2 Infection Exacerbate Alzheimer’s Disease? An Overview of Shared Risk Factors and Pathogenetic Mechanisms. Natural Library of Medicine. [Online] 2022;12(1): . Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8780286/#B8-jpm-12-00029 %5BAccessed 23 October 2022].