Investigating the Potential Link Between COVID-19 Vaccination and Neurodegenerative Diseases

The COVID-19 pandemic has introduced numerous challenges, including concerns about the potential side effects of vaccines. Recently, there has been increasing interest in understanding whether COVID-19 vaccination might be associated with neurodegenerative diseases, particularly Alzheimer’s disease (AD) and its prodromal state, mild cognitive impairment (MCI).

A recent groundbreaking study published by Oxford University Press on behalf of the Association of Physicians has investigated the potential association between COVID-19 vaccination and the onset of Alzheimer’s disease and mild cognitive impairment.

A nationwide, retrospective cohort design was utilized, leveraging data from the Korean National Health Insurance Service. The study focused on determining if there is a significant association between receiving a COVID-19 vaccine and the subsequent development of AD and MCI.

​Conducted in Seoul, South Korea, the study analyzed data from a random 50% sample of city residents aged 65 and above, totaling 558,017 individuals. Participants were divided into vaccinated and unvaccinated groups, with vaccinations including both mRNA and cDNA vaccines. Incidences of AD and MCI post-vaccination were identified using ICD-10 codes. Multivariable logistic and Cox regression analyses were employed to interpret the data, with patients having vascular dementia or Parkinson’s disease serving as control subjects.

​The study found an increased incidence of MCI and AD in vaccinated individuals, particularly those who received mRNA vaccines, within three months post-vaccination. Specifically, the mRNA vaccine group exhibited a significantly higher incidence of AD (odds ratio [OR]: 1.225; 95% confidence interval [CI]: 1.025–1.464; P = 0.026) and MCI (OR: 2.377; CI: 1.845–3.064; P < 0.001) compared to the unvaccinated group. However, no significant relationship was found with vascular dementia or Parkinson’s disease.

Mechanisms of Neurodegeneration

The potential mechanisms underlying these observations involve several pathways. One hypothesis is related to the interaction of the SARS-CoV-2 spike protein with heparin and heparin-binding proteins in the brain, which are prone to self-assembly, aggregation, and fibrillation. Research suggests that the S1 region of the spike protein binds to these proteins, potentially acting as functional amyloid and forming toxic aggregates. These aggregates could seed the aggregation of misfolded brain proteins, leading to neurodegeneration.

Additionally, the spike protein's ability to cross the blood-brain barrier raises concerns. Free spike protein particles have been detected in various organs, including the brain, where they might contribute to pathological processes. The spike protein's interaction with the ACE2 receptor and subsequent cellular entry could disturb protein synthesis machinery, endoplasmic reticulum and mitochondrial function, and increase the accumulation of misfolded proteins. This cascade of events could activate protein aggregation, mitochondrial oxidative stress, apoptosis, and ultimately neurodegeneration.

There is also evidence from studies on other viruses, such as HSV-1, that viral proteins can bind to heparin and increase the aggregation of amyloid β (Aβ42) peptides, a hallmark of Alzheimer’s disease. Given that the receptor-binding domain of SARS-CoV-2's spike protein has several heparin-binding sites, a similar mechanism of neurodegeneration involving the aggregation of proteins like Aβ, α-synuclein, tau, prions, and TDP-43 could be at play in COVID-19.
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Preliminary evidence suggests a potential association between COVID-19 vaccination, especially with mRNA vaccines, and an increased incidence of Alzheimer’s disease and mild cognitive impairment. These findings highlight the need for further research to understand the mechanisms underlying this potential link, particularly focusing on vaccine-induced immune responses and their impact on neurodegenerative processes. Continuous monitoring and investigation into the long-term neurological impacts of COVID-19 vaccines are crucial to ensure comprehensive understanding and safety.

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references

Jee Hoon Roh, et al. “A Potential Association between COVID-19 Vaccination and Development of Alzheimer’s Disease.” QJM, 28 May 2024, https://doi.org/10.1093/qjmed/hcae103. 

Grobbelaar, Lize M, et al. “SARS-CoV-2 Spike Protein S1 Induces Fibrin(Ogen) Resistant to Fibrinolysis: Implications for Microclot Formation in COVID-19.” MedRxiv (Cold Spring Harbor Laboratory), 8 Mar. 2021, https://doi.org/10.1101/2021.03.05.21252960. 

​Idrees, Danish, and Vijay Kumar. “SARS-CoV-2 Spike Protein Interactions with Amyloidogenic Proteins: Potential Clues to Neurodegeneration.” Biochemical and Biophysical Research Communications, vol. 554, May 2021, pp. 94–98, https://doi.org/10.1016/j.bbrc.2021.03.100.