Risk Factors: A Brief Overview

The authors recognize that neurodegenerative diseases, such as dementia, are shaped by a mix of genetic and modifiable environmental risk factors. The latter are within our control.

According to the Lancet Commission in 2020, modifiable dementia risk factors encompass low educational attainment, limited social interaction, tobacco use, physical inactivity, brain injuries, and more. They also highlight the rising importance of infections as a dementia risk factor.

The Lancet Commission tackles significant global health challenges by assembling expert panels to conduct thorough reviews and develop evidence-based recommendations. One such concern is dementia, a condition that strips individuals of their memories and identity. A new case of dementia arises every three seconds globally, making it the seventh leading cause of death worldwide.

Understanding dementia risk factors is vital for combating the disease. While various risk factors can interact and heighten overall risk, calculating this synergistic effect is intricate. Therefore, the standard practice is to evaluate the individual risk contributed by each factor separately.

As Bonherry et al. noted, “Risk factors can interact, but calculating synergistic risk is complex, so the common approach is to present the marginal risk for each individual causative factor.”

This article aims to elucidate the extent to which infections contribute to the risk of developing neurodegenerative diseases, such as dementia, while also acknowledging the significance of other well-established risk factors.

Infection as a Risk Factor

Prior to the emergence of Covid-19, strong evidence existed regarding the relationship between infectious diseases and neurodegeneration.

For instance, Bonherry et al. referenced a notable study published in The Lancet Infectious Diseases in 2021, which analyzed data from three large Finnish cohorts to determine whether hospitalization for infections increased future dementia risk.

Key findings from this study include: - Hospitalization for any infectious disease led to a 1.5-fold increase in dementia risk across the three Finnish cohorts, a finding corroborated by another UK cohort. - The heightened risk of dementia persisted even ten years post-infection, indicating long-term negative consequences of infections. - Infections targeting the brain resulted in a threefold increase in dementia risk, while non-brain infections also showed a 1.5-fold increase, suggesting that general inflammation may contribute to neurodegenerative diseases. - The risk of dementia is dose-dependent: a single infection leads to a 1.5–2-fold increase in risk, while two infections elevate this to 2.5–4.5-fold, and three or more infections can raise it to 2.5–7-fold compared to no infections.

Numerous other studies support the role of infections as risk factors for neurodegenerative diseases. I have previously discussed some in articles like “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 mechanisms by which infections may initiate neurodegenerative diseases boil down to two widely recognized processes (Figure 1): - Neuronal Invasion: Certain pathogens can breach the blood-brain barrier or travel along olfactory neurons into the brain's olfactory bulb, potentially infecting brain cells and causing inflammation and neurodegeneration. - Systemic Inflammation: Severe infections can exacerbate inflammation throughout the body, affecting blood vessels and the blood-brain barrier. This allows immune cells and inflammatory substances to enter the brain, leading to neuroinflammation and the accumulation of neurotoxic proteins.

This issue is particularly relevant for chronic infections—pathogens capable of persisting in the body long-term, such as herpesviruses, HIV, hepatitis virus, Borrelia burgdorferi (Lyme disease), Treponema pallidum (syphilis), and notably, SARS-CoV-2 (the virus responsible for Covid-19)—all of which have been linked to neurodegenerative diseases in various ways.

SARS-CoV-2 as a Causative Factor

In recent years, nearly everyone has been exposed to SARS-CoV-2. However, longitudinal data to assess its long-term impact on neurodegenerative disease development—conditions that typically evolve over decades, particularly in individuals over 60—is still lacking.

Nonetheless, short-term data (approximately two years) is available, and Bonherry et al. assert that this evidence is sufficient to support the notion that SARS-CoV-2 increases the risk 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 associated with loss of motor control. Both represent the two most common neurodegenerative diseases globally.)

Here’s a summary of the existing evidence: - Zarifkar et al. (2022) analyzed a cohort of around 3 million individuals, representing half of Denmark's population, with 0.9 million tested for Covid-19. Findings indicated that those who contracted Covid-19 (regardless of hospitalization) had a 3.5-fold and 2.6-fold increased risk of AD and PD, respectively, compared to those who did not contract the virus, within 12 months of follow-up. - Wang et al. (2022) studied 6.2 million older adults in the U.S., revealing that those who had Covid-19 (regardless of hospitalization) faced a 1.7-fold increased risk of AD within a year of their diagnosis. - Rahmati et al. (2023) conducted a meta-analysis of 12 studies—including the two aforementioned studies—covering over 33 million individuals globally. Their results indicated that Covid-19 (regardless of hospitalization) was associated with increased risks of AD (1.5-fold), dementia (1.7-fold), and PD (1.4-fold) within two years of follow-up.

Additionally, Bonherry et al. highlighted that SARS-CoV-2 poses particular threats as it can inflict damage on blood vessels. This is due to the receptor ACE2—targeted by SARS-CoV-2—being abundantly expressed on the endothelial cells lining blood vessels.

Consequently, Covid-19 is associated with vascular issues—such as thrombosis, cardiovascular diseases, and stroke—both in the short and long term (long Covid). Various studies indicate that Covid-19 increases stroke risk by approximately 2–3-fold. Stroke often leads to vascular dementia—a subtype of dementia known as post-stroke dementia, albeit less common than Alzheimer’s dementia.

Interestingly, Bonherry et al. employed the updated Bradford Hill criteria to assess causality (Figure 2). Established in 1965, these criteria facilitate the evaluation of whether a correlation between an exposure (e.g., Covid-19) and an outcome (e.g., dementia) is causative.

This methodology is essential in observational studies, where establishing causality is often challenging. In clinical settings, demonstrating cause and effect typically requires randomized clinical trials, which are sometimes impractical due to ethical concerns.

For example, the Bradford Hill criteria were instrumental in establishing the link between smoking and lung cancer, as it would be unethical to instruct participants to smoke in a clinical trial. Similar approaches have confirmed the harmfulness of air pollution, the adverse effects of trans fats on heart health, and the role of human papillomavirus (HPV) in cervical cancer.

How does Covid-19 meet these causation criteria? - Direct Evidence: Numerous studies indicate that Covid-19 elevates the risk of neurodegenerative diseases significantly (up to threefold) within a reasonable timeframe (e.g., one year). This association remains robust even after controlling for confounding factors (e.g., gender, socioeconomic status, lifestyle choices, and pre-existing conditions). - Mechanistic Evidence: Various animal (in vivo) and cell culture (in vitro) studies have elucidated the biochemical pathways and mechanisms through which SARS-CoV-2 may instigate neurodegeneration. - Parallel Evidence: Multiple studies conducted by different research teams across various countries have corroborated both the direct and mechanistic evidence linking Covid-19 to neurodegenerative outcomes.

The Broader Context

As previously mentioned, the most consistent statistic seems to be a 1.5-fold increase in the risk of AD post-Covid-19 (as per Rahmati et al.’s meta-analysis). To provide perspective, let’s clarify the lifetime risk of AD based on widely accepted figures: - Men (aged 65): The lifetime risk of AD is approximately 6%, rising to 10% for those over 65. A 1.5-fold increase would elevate these figures to 9% and 15%, respectively. - Women (aged 65): The lifetime risk of AD is about 12%, increasing to 20% for individuals over 65. A 1.5-fold increase would raise these to 18% and 30%, respectively. - All Ages: Estimating the lifetime risk of AD across all ages is more complex, as the disease primarily affects older adults, but it likely hovers around 1%. A 1.5-fold increase would raise this risk to 1.5%.

(I focus on AD as it is the most common form of dementia and the most prevalent neurodegenerative disorder.)

It is important to note that calculating synergistic risks is intricate. The figures presented here are approximations and will fluctuate based on other risk factors, including genetic predisposition, lifestyle choices, and environmental conditions.

However, even though Covid-19 meets the Bradford Hill criteria for causation, pinpointing the exact nature of this causation remains challenging.

As Bonherry et al. noted, “Direct evidence should show an appropriate temporal sequence, which is contentious: it remains difficult to distinguish between dementia cases that were hypothetically triggered by SARS-CoV-2 infection and those that were merely accelerated by it.”

I believe Covid-19 predominantly acts as an accelerator for individuals predisposed to neurodegenerative diseases. Otherwise, we would expect to see a significant surge in neurodegenerative disease cases if Covid-19 primarily acted as a trigger. This has not been reflected in the 2024 annual report from Alzheimer’s Disease Facts and Figures.

In a previous article, I raised the question of whether we will witness a wave of neurodegenerative diseases following the pandemic, a query that remains difficult to answer. This uncertainty is compounded by the fact that neurodegenerative diseases typically correlate with age, and the Covid-19 pandemic has reduced life expectancy in several countries.

Therefore, these two effects might counterbalance each other—Covid-19 could shorten lifespans before age-related diseases can take hold. However, since neurodegenerative diseases like AD often require decades to manifest, it may still be too soon to observe any lasting effects.

Despite this, the evidence presented above strongly supports the inclusion of 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,” Bonherry et al. concluded, “even though the distinction between causation and disease acceleration remains unclear.”

This assertion holds true, even as Covid-19 variants continue to evolve. Bonherry et al. acknowledged that while the severity of Covid-19 may differ across various strains, the rate of neurological outcomes following infection remains steady. This consistency arises because neuroinflammatory damage is a fundamental aspect of the viral lifecycle.

Ultimately, neurodegenerative diseases are multifactorial, involving a multitude of risk factors that often work together synergistically. It is essential to recognize the role of infections as one such risk factor. By doing so, we can allocate more resources toward investigating preventative measures, such as antiviral therapies or vaccines, to mitigate the risk of neurodegenerative diseases.

There is compelling evidence indicating that a herpesvirus vaccine can reduce dementia risk. I previously discussed this in “An Unexpected Ally In Dementia Prevention: Shingles Vaccination.”

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