Editor – Neuroinflammation is a chief common characteristic of both coronavirus disease 2019 (COVID-19) and Alzheimer disease1,2 and can play a vital role in the development of COVID-19 to Alzheimer disease.3,4 Severe acute respiratory disease coronavirus 2 (SARS-CoV-2), which is responsible for the COVID-19 pandemic, imposes a high neuroinvasive potential on the central nervous system (CNS), and neurological consequences can be expected.3,4
SARS-CoV-2-mediated cytokine storms, blood-brain barrier endothelial dysfunction, and microglial activation2,5,6 take part in neuroinflammation in COVID-19 patients.3,4,7-9 These processes lead to increased levels of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, which are mainly secreted by activated microglia,3,4,10 aggravating neuroinflammation and enclosing the potential to supply to neurodegenerative pathologies implicated in the progression of Alzheimer disease.2,11
As neuroinflammation is a critical feature in Alzheimer disease pathogenesis, abnormal immune reactions and the resulting neuroinflammation caused by SARS-CoV-2 infection may progress to degenerative endings and augment vulnerability to Alzheimer disease.12 These pathological processes may be shared by considerable commonalities between COVID-19 and Alzheimer disease, including angiotensin-converting enzyme 2 (ACE2) receptors and a variety of inflammatory mediators (e.g., IL-1, IL-6, and the APOE4 allele).2,13
The resulting neuroinflammation caused by SARS-CoV-2 infection, which is the result of the activation of microglia and astrocytes secreting pro-inflammatory cytokines (i.e., IL-1β, IL-6, IL-12, and TNF-α), could become uncontrolled, particularly in the elderly, who have a less productive immune system reaction.3,4,14,15 These inflammatory mediators can be responsible for synaptic malfunction, causing neurodegeneration, which can convincingly result in Alzheimer disease.16,17 Neuroinflammation is also coupled with extreme oxidative stress production, causing neurodegeneration and credibly directing the progression of neurodegenerative diseases, such as Alzheimer disease.17
The association between COVID-19 and Alzheimer disease through inflammatory pathways can be described by several inflammatory mediators, such as IL-6, IL-1, and galectin-3 (Gal-3).
For example, increased circulating levels of IL-6, as a common prognostic biomarker of worse prognosis for both COVID-1918,19 and Alzheimer disease,20 are linked to a high possibility of advancing severe SARS-CoV-2 infection, mortality, and with the advancement of Alzheimer disease and poorer cognitive attainment.2,17,18,20 Elevated levels of IL-6 were also found to be interrelated with the increased viral load and severity in seriously ill COVID-19 patients.18,21 Changes in IL-6 and IL-6R genes were found to be responsible for the initiation and development of a number of diseases, including infectious diseases (i.e., COVID-19) and neurodegenerative diseases (i.e., Alzheimer disease).2,17,22-25 For example, IL-6 and IL-6R were reported to be responsible for neuroinflammation, synaptic injury, microglial activation, and cognitive deficits in the pathogenesis of Alzheimer disease.25
The increased level of IL-1 as a prognostic biomarker of worse prognosis in COVID-19 patients26,27 has also been reported to be amplified in the brains of patients with Alzheimer disease.28 In addition to its action on neuronal death, IL-1 is imperative for physiological control of hippocampal plasticity and memory mechanisms.17 In this regard, both increased and decreased IL-1 levels have been linked to defective memory performance.17 Therefore, the elevated levels of IL-1 reported in COVID-19 patients can cause cognitive impairment, resulting in the progression of Alzheimer disease.2,17,29
Increased levels of Gal-3 in patients with severe SARS-CoV-2 infection can also cause COVID-19 development via promoting hyper-inflammatory responses and lung fibrosis adjoining alveolar damage, hypoxia, and progression of infection.30 Since amplified levels of Gal-3 have also been reported in the serum of patients with Alzheimer disease,31 and based on animal models of Alzheimer disease that found Gal-3 responsible for amyloid-beta (Aβ) aggregation and amyloid plaque creation,32 the amplified levels of Gal-3 in COVID-19 patients could also be responsible for the injury, resulting in the progression of Alzheimer disease. Therefore, as GAL-3 has been shown to be involved in viral inflammatory reactions33 and microglial-mediated neuroinflammation,34 COVID-19 patients can be at a prominent risk for the progression of Alzheimer disease.
Inflammasome activation is another common pathway in both COVID-19 and Alzheimer disease due to the malfunctioning microglial clearance of Aβ.35-37 Therefore, neuroinflammation and progression of neurodegeneration may eventually lead to an increased risk of Alzheimer disease.38
Acknowledgements
The author would like to express his honest gratitude and high respect for the lifetime support of his father, Mohammad Nouraeinejad.
Footnotes
Disclosures
The author received no financial support for the research, authorship, and/or publication of this article; and the author declares no conflict of interest.
- Received April 7, 2023.
- Accepted August 1, 2023.
References
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