Links between COVID-19 and Alzheimer’s Disease

Posted on 2021-10-18


Shared Risk Factors

COVID-19 and Alzheimer’s Disease have been found to have many common risk factors including race, age and the presence of medical conditions such as diabetes, cardiovascular disease and metabolic disorders. Part of this is likely to be related to genetics, for example the presence of the ApoE E4 allele is the highest genetic risk factor for Alzheimer’s Disease and has now been linked to a higher severity of SARS-CoV-2 infection. 

Evidence has been found to suggest that having Alzheimer’s Disease or COVID-19 may predispose people to having the other. Ca2+ dysregulation caused by and inflammation found in Alzheimer’s Disease (even at the beginning of the illness) are thought to facilitate COVID-19 infection and, although the long term effects of SARS-CoV-2 infection are unknown, a study has found neurological damage in 1/3 of those infected with COVID-19 (even those who were asymptomatic) which may predispose patients to neurological decline. 

Ca2+ dysregulation

Aβ oligomers, which are potent neurotoxins causing Alzheimer’s Disease, integrate into the plasma membrane and form pores, which allows for the passage of calcium ions. As they also stimulate N-methyl-D-aspartic acid receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid receptors and L-type voltage-gated calcium channels which increase intracellular Ca2+, this can lead to neurofibrillary tangles, electrophysiological disorder and neuronal degeneration. RNA viruses, including COVID-19, use Ca2+ for infection by disrupting calcium channels and pumps to cause cell death, benefitting viral replication. Therefore, it has been suggested that the dysregulation of Ca2+ from Alzheimer’s Disease may also help viral replication. 

ACE-2

SARS-CoV-2 enters epithelial cells in the lungs by binding to angiotensin-converting enzyme 2 (ACE-2). Patients with a greater quantity of ACE-2 have been seen to have higher severity SARS-CoV-2 infections. Studies of mice and human brain tissue have found an increase in ACE-2 in brains that have undergone neurodegeneration due to Alzheimer’s Disease. This increase has been suggested to make it easier for SARS-CoV-2 in blood to bind to ACE-e in the brain and cause neurological issues, though further long term studies are needed to understand this further. 

ACE-2 binding by COVID-19 may also increase a patient’s chances of developing Alzheimer’s Disease. In vitro studies have shown that SARS-CoV-2 interacts with ACE-2 and infects neurons. ACE2 can hydrolyse Ang II to produce Ang 1-7, which binds to the Mas receptor. This binding regulates various signalling cascades, including the PI3K/Akt/ CREB/BDNF/TrKB pathway, which is involved in the growth, differentiation, plasticity and survival of neurons. Problems in this pathway may accelerate neurodegeneration. 

Cytokine Storm

One of the immune responses to COVID-19 is a cytokine storm, a significant increase in cytokines in the bloodstream. Infected cells release these cytokines as a response to the presence of nucleic acid, which is produced when SARS-CoV-2 invades lung epithelial cells and alveolar macrophages. Heightened cytokine levels in serum have been linked to an increased severity of SARS-CoV-2 illness and are thought to be one of the main causes of acute respiratory distress syndrome and organ failure due to COVID-19. These increased cytokine levels over sustained periods of time have also been proven to negatively impact cognitive function, particularly memory, and to promote neurodegenerative diseases.

 Rapid replication of SARS-CoV-2 triggers a substantial increase in the level of IL-6. An increased serum level of IL-6 has been reported to increase COVID-19 fatality and respiratory dysfunction. Though the mechanism of this in currently not known, it is likely that reduced levels of IL-6 mediate a signalling cascade related to the maintenance and storage of memory. This suggests that an increased level of Il-6 would negatively impact the process of maintaining and storing memory, key features of Alzheimer’s Disease. In fact, preliminary clinical trials have suggested that medications containing antibodies capable of blocking/ reducing the amount of IL-6 can help treat COVID-19 and slow down the progression of Alzheimer’s disease. Similar effects have been reported with IL-1. 

The cytokine storm disrupts the levels of Gal-9 and CKAP4. The increase of the cytokine Gal-9 as part of this cytokine storm is an immune reaction against COVID-19. As it also promotes amyloid-beta oligomerization and toxicity in the brain, this is likely to increase neurodegeneration, though long term studies of the brains of recovered COVID-19 patients are needed to confirm this. CKAP4 has also been identified as one of the most significantly affected proteins affected by the cytokine storm, with a reduction liked to increased COVID-19 illness severity. Reduction of CKAP4 has been shown to increase neuronal precursor cell death through the activation of a p53-PUMA pathway which results in apoptosis. A reduced ability to regenerate brain cells is likely to increase the rate of neurodegenerative diseases such as Alzheimer’s Disease. 

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