Understanding the Connection Between COVID-19 and Neurodegeneration
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Chapter 1: The Overlooked Impact of COVID-19 on Brain Health
As a researcher who has explored the often-neglected influence of viruses on brain health, I was both pleased and concerned by a recent article published in The Lancet Neurology titled "SARS-CoV-2 Infection as a Cause of Neurodegeneration," authored by Bonherry et al. from Europe and Australia. This piece underscores an essential message that specialists in this field have been advocating: infectious diseases, including the relatively new COVID-19, are not merely transient ailments; they contribute to the cumulative infection burden one faces over a lifetime. A higher infection burden correlates with an elevated risk of neurodegenerative conditions.
Bonherry et al. provide several compelling arguments regarding the role of COVID-19 in neurodegenerative diseases, which I believe are too critical to overlook and should be shared with a wider audience.
Section 1.1: Understanding Risk Factors
Bonherry et al. highlight that neurodegenerative diseases like dementia are shaped by both genetic and modifiable environmental risk factors. According to the Lancet Commission's 2020 report, factors such as limited education, social isolation, smoking, physical inactivity, and brain injuries can be altered and are associated with dementia risk. Moreover, the growing recognition of infections as a potential dementia risk factor is becoming increasingly important.
The Lancet Commission tackles urgent global health issues by assembling expert panels to conduct thorough reviews and formulate evidence-based recommendations. Dementia, a condition that strips individuals of their memories and identity, is a pressing concern, with a new diagnosis occurring every three seconds worldwide. It ranks as the seventh leading cause of death globally.
Understanding dementia's risk factors is essential for addressing the disease effectively. While various risk factors can interact and amplify overall risk, determining the synergistic risk is complex. Typically, the individual contribution of each risk factor is assessed separately rather than attempting to calculate their combined effects.
As Bonherry et al. noted, "Risk factors can interact, but calculating synergistic risk is complicated, so the standard practice is to present marginal risks attributed to individual causative factors."
This article aims to clarify the extent to which infections contribute to the risk of developing neurodegenerative diseases like dementia while also acknowledging other known risk factors.
Section 1.2: The Role of Infection as a Risk Factor
Prior to the COVID-19 pandemic, there was already substantial evidence linking infectious diseases with neurodegenerative conditions. For example, Bonherry et al. referenced a significant study published in The Lancet Infectious Diseases in 2021, which analyzed data from three large Finnish cohorts to assess whether hospitalization due to infections could elevate future dementia risk.
Key findings from this study include:
- Previous hospitalization for infections increased the risk of dementia by 1.5 times across three Finnish cohorts, a correlation also observed in a UK cohort.
- The heightened risk of dementia persists even a decade after the infection, indicating lasting negative effects.
- Infections that affect the brain showed the highest risk, with a threefold increase in dementia risk, while even non-brain infections were linked to a 1.5-fold increase, suggesting that general inflammation may be enough to encourage neurodegenerative diseases.
- The risk of dementia appears to be dose-dependent, with a 1.5–2-fold increased risk associated with one infection, 2.5–4.5-fold with two infections, and 2.5–7-fold with three or more infections compared to those with no infections.
Numerous other studies support the connection between infections and neurodegenerative diseases. I elaborated on some of these in previous articles, such as "The Viral Origin of Alzheimer's Disease Remains Undecoded" and "The Case for Virus Origin of Neurodegenerative Diseases Is Getting Stronger and More Important."
The underlying mechanisms through which infections may lead to neurodegenerative diseases can be categorized into two main pathways:
- Neuronal Invasion: Certain pathogens can breach the blood-brain barrier or spread via olfactory neurons into the brain's olfactory bulb. This can lead to inflammation and neurodegeneration in brain cells.
- Systemic Inflammation: Severe infections can intensify inflammation throughout the body, compromising the blood-brain barrier and allowing immune cells and inflammatory substances to enter the brain, which can result in neuroinflammation and the buildup of neurotoxic proteins.
Figure 1. Mechanisms by which infections, including SARS-CoV-2, harm the brain. Source: Verkhratsky et al. (2020), Biology Direct.
This issue is particularly relevant for chronic infections, where pathogens can persist in the body over extended periods. Notable examples include herpesviruses, HIV, hepatitis virus, Borrelia burgdorferi (the bacterium responsible for Lyme disease), Treponema pallidum (the syphilis bacterium), and SARS-CoV-2, all of which have been associated with neurodegenerative diseases.
Chapter 2: COVID-19 as a Risk Factor for Neurodegeneration
The first video titled "Here's what we know about COVID-19's impact on the brain" explores current findings on how the virus affects cognitive health and the potential long-term consequences.
Despite widespread exposure to SARS-CoV-2 over recent years, longitudinal data on its long-term effects or risks related to neurodegenerative diseases—which typically develop gradually and often affect individuals over 60—remains limited. However, shorter-term data (≤2 years) is available, and Bonherry et al. argue that this is sufficient to establish a causative link between SARS-CoV-2 and increased risks of neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD).
AD is the most prevalent form of dementia, characterized by memory loss, while PD is marked by loss of motor control. Here’s a summary of current evidence:
- Zarifkar et al. (2022) studied a cohort of approximately 3 million individuals, covering half of Denmark's population, with 0.9 million tested for COVID-19. Findings indicated that those who contracted COVID-19 had a 3.5-fold and 2.6-fold increased risk of AD and PD, respectively, compared to non-infected individuals over a 12-month follow-up.
- Wang et al. (2022) analyzed a cohort of 6.2 million older adults in the U.S., concluding that COVID-19 infection was associated with a 1.7-fold increased risk of AD within a year of diagnosis.
- Rahmati et al. (2023) conducted a meta-analysis of 12 studies, encompassing over 33 million people globally. The results indicated increased risks of 1.5, 1.7, and 1.4-fold for AD, dementia, and PD, respectively, within up to 2 years post-infection.
Bonherry et al. also highlighted that SARS-CoV-2 poses unique risks as it can damage blood vessels. The virus binds to ACE2 receptors, which are prevalent in endothelial cells. Consequently, COVID-19 is associated with vascular complications, including thrombosis, heart diseases, and strokes—issues that can lead to vascular dementia.
What's particularly intriguing is that Bonherry et al. applied the updated Bradford Hill criteria to evaluate causality. These criteria, established in 1965, help determine whether an observed association between an exposure (e.g., COVID-19) and an outcome (e.g., dementia) is indeed causal. This approach is invaluable for observational studies where establishing causality is challenging.
For example, the Bradford Hill criteria were instrumental in proving that smoking causes lung cancer, as it would be unethical to conduct a clinical trial requiring participants to smoke. Similar applications have confirmed the harmful effects of air pollution and trans fats.
Figure 2. Original and updated Bradford Hill's criteria for causation. Source: Howick et al. (2009).
So, how does COVID-19 measure up against these causative criteria?
- Direct Evidence: Numerous studies have shown that COVID-19 elevates the risk of neurodegenerative diseases significantly (up to threefold) within a reasonable timeframe (about a year) and this association persists even after accounting for confounding factors.
- Mechanistic Evidence: Various animal and cell culture studies have detailed the biochemical pathways through which SARS-CoV-2 may contribute to neurodegeneration.
- Parallel Evidence: Multiple studies from diverse research teams and countries support both the direct and mechanistic evidence linking COVID-19 to neurodegenerative diseases.
The broader context reveals that a consistent finding is a 1.5-fold increase in the risk of AD following COVID-19 infection. To contextualize this:
- Men (65 years): The lifetime risk of AD is estimated at 6%, rising to 10% for those over 65. A 1.5-fold increase raises these probabilities to 9% and 15%, respectively.
- Women (65 years): The lifetime risk is estimated at 12%, increasing to 20% for those over 65. A 1.5-fold increase raises these risks to 18% and 30%, respectively.
- All Ages: Estimating the lifetime risk for all ages is more complex, but it is likely around 1%. A 1.5-fold increase would elevate this to 1.5%.
While these calculations are estimates and can vary based on additional risk factors, including genetics and lifestyle, they underscore the significant implications of COVID-19 for brain health.
It is crucial to note that, despite fulfilling Bradford Hill's criteria for causation, distinguishing the nature of this causation remains a challenge. As Bonherry et al. stated, "Direct evidence should show an appropriate temporal sequence, which is contentious: it remains difficult to distinguish between dementia cases hypothetically triggered by SARS-CoV-2 infection and those merely accelerated by it."
I contend that COVID-19 primarily acts as an accelerator for those predisposed to neurodegenerative diseases. If COVID-19 were a major trigger, we would likely see a notable surge in neurodegenerative disease cases, which has not been reflected in the 2024 annual report of Alzheimer's Disease Facts and Figures.
In previous discussions, I raised the pressing question of whether we will witness a rise in neurodegenerative diseases following the pandemic. This remains difficult to ascertain, especially since these diseases are typically age-related, and the pandemic has diminished life expectancy in various regions.
Thus, these effects might counterbalance each other—COVID-19 may shorten life spans before age-related diseases can manifest. However, given that neurodegenerative conditions like AD often take decades to develop, it may still be premature to observe any long-term impacts.
In conclusion, the evidence presented strongly supports considering COVID-19 as a causative risk factor for neurodegenerative diseases. "In light of this evidence, SARS-CoV-2 infection should be regarded as a risk factor for Alzheimer's disease," stated Bonherry et al., "despite the ambiguity surrounding causation versus disease acceleration."
This remains true even as COVID-19 variants continue to evolve. Bonherry et al. noted that while the severity of COVID-19 may differ among viral strains, the rate of neurological outcomes post-infection remains constant due to the inherent neuroinflammatory damage associated with the viral life cycle.
Ultimately, neurodegenerative diseases are multifaceted, influenced by a myriad of risk factors that often interact synergistically. It is time to acknowledge the critical role of infections as one such risk factor. By doing so, we can allocate more resources toward exploring preventive measures like antiviral therapies or vaccines to mitigate the risk of neurodegenerative diseases.
Interestingly, there is robust evidence suggesting that a herpesvirus vaccine can lower dementia risk, which I previously discussed in "An Unexpected Ally In Dementia Prevention: Shingles Vaccination."
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The second video, "The Science Behind How the Coronavirus Affects the Brain," delves into the mechanisms by which COVID-19 may influence cognitive function and the broader implications for brain health.