It may start with forgetfulness, lapses in memory and confusion.
As time goes on, one may no longer be able to make plans, solve problems or communicate like they once did. Their personality may change, pieces lost as they struggle to recognize themselves and the world around them.
It's a harrowing picture and stark reality for the tens of millions of people around the world living with dementia-an umbrella term for various neurological conditions, including Alzheimer's disease (AD), in which brain function declines over time. This decline is devastating to those experiencing it, and the loved ones witnessing its effects.
Why dementia happens is a complicated question with answers embedded in genetic, environmental and lifestyle factors. Increasingly, scientists are finding that infections-particularly viral infections-may play a role in dementia development, and that vaccination may reduce the risk. While much of the evidence underlying these links is associative, and the mechanisms are still a bit hazy, it underscores that the impacts of infections can be felt both outside and inside the brain.
Infections Are Associated With Dementia
The intersection between infection and brain function has become broadly apparent over the last several years, due to a preponderance of foggy brains and cognitive impairments arising from the COVID-19 pandemic. However, this relationship has been explored in the context of dementia for decades.
A spate of studies has shown that infections with herpesviruses-including herpes simplex virus (HSV) 1 and 2, which cause oral and genital herpes, and Varicella-zoster virus (VZV), the cause of chickenpox and shingles-are associated with an increased risk of dementia (though the magnitude of this increase differs between studies).
Herpesviruses are neurotropic, meaning they invade and persist in central nerve cells and sometimes the brain. Non-neurotropic viruses have also been linked with dementia, including influenza and HIV, as have bacteria and parasites, such as the oral bacterium Porphyromonas gingivalis and Toxoplasma gondii, respectively. While the data do not explicitly show that infection causes dementia, they have prompted exploration into the potential mechanisms underlying the connections, with the immune system emerging as a key culprit.
How Might Infection Spur Neurodegeneration?
Infections can directly activate immune cells living in the brain, and/or promote infiltration of peripheral immune cells and inflammatory molecules into the brain and spinal cord (the central nervous system, or CNS). The result in either case: inflammation.
Neuroinflammation protects the CNS by fighting off pathogens and helping to heal injuries. But it also has a dark side-namely, as neuroinflammatory processes rev up to manage a threat, they can also damage or kill neurons. The hurt or dying cells release molecules that then trigger more neuroinflammation. Such prolonged or excessive immune-mediated havoc is implicated in various types of dementia, including AD, the most common form. It's a double-edged sword: the responses that protect the brain can also contribute to its demise.
For instance, researchers discovered that amyloid-β peptide (Aβ)-a protein that accumulates in plaques (clumps) between neurons in AD patients, contributing to cognitive decline-is an innate immune protein that helps fight infection. Experiments in vitro and in mice demonstrated that Aβ binds to glycoproteins on the surface of herpesviruses, forming a network of small fibers that traps and sequesters viral particles. While helpful for inhibiting the ability of viruses to adhere to and infect host cells, this process also promotes Aβ deposition in the brain to potentially accelerate plaque formation.
Infection-associated neurodegeneration may be sparked by a new infection or reactivation of a virus that has lain dormant in a host's cells (think shingles, which occurs when VZV acquired during a case of chickenpox reactivates years later to cause a new round of painful symptoms). Moreover, though such processes can originate in the CNS, they don't have to. Systemic inflammation triggered by an infection or condition elsewhere in the body could contribute to cognitive decline, as inflammatory mediators may disrupt or cross the blood-brain-barrier (BBB) and induce inflammation in the brain. Microbes that don't normally infect the CNS, like Klebsiella pneumoniae, can also directly breach the BBB to cause inflammation, as can products they release (e.g., bacterial membrane vesicles).
Is it possible to detect or treat neuroinflammation early to prevent its long-term cognitive effects? While there are currently no routine clinical tests for this purpose, it is an active area of investigation. Advances in brain imaging technologies and fluid biomarkers are opening the door for new diagnostic strategies and therapeutic approaches targeting neuroinflammation.
Vaccines May Reduce Dementia Risk
If infection is associated with dementia, vaccination-which prepares the immune system to face microbial threats-appears to tip the scales in the opposite direction. That is, in individuals aged ~65 and older, many routine vaccines have been tied to a reduced risk of dementia/AD.
For example, a retrospective cohort study comparing vaccinated to unvaccinated individuals aged 65 and older found that those who received Tdap/Td, herpes zoster (shingles) or pneumococcal vaccines on or after onset of the study period had a 30%, 25% and 27% decreased risk of developing AD over 8 years, respectively. In another recent analysis, researchers examined the electronic medical records of thousands of individuals in Wales, showing that people who received the zoster vaccine when they were ~79-80 years old showed a 20% reduced probability of a new dementia diagnosis over 7 years, particularly among women (perhaps, in part, because of sex-associated differences in immune response or dementia pathogenesis). Influenza vaccination has also been associated with reduced AD risk.
Why might vaccines protect against dementia, whereas infections are bad news? The answers likely tie back to the same processes. By preventing infection/viral reactivation-or limiting disease severity-vaccines may minimize neuroinflammation and subsequent neurodegeneration. Some vaccine-triggered responses are specific to the pathogen targeted by a vaccine. However, because several vaccines against diverse microbes have all been linked to a reduced dementia risk, scientists posit that more general modulation of immune responses may be at play. Indeed, vaccines keep the immune system poised to deal with various infectious threats, which can include those they aren't specifically designed to address.
What Don't We Know?
Though there is plenty of evidence for the infection-vaccination-dementia relationship, not all studies point to an association. Of those that do, there are variations in results (i.e., 1 study may find a vaccine reduces dementia risk by a certain amount, another not as much). These discrepancies highlight the need for continued investigation-and there is no shortage of questions to keep the ball rolling.
How much do pathogens contribute to dementia risk? How many years before dementia diagnosis does viral exposure matter? That is, does an infection early in life influence risk later on, and can treatment at an early stage of infection ward off future complications? What is the effect of vaccine type (i.e., live-attenuated, mRNA, etc.), if any? In what ways do infections and vaccines interact with other factors underlying dementia, like genetics? One study found that individuals carrying a genetic susceptibility factor for AD (a variant of the APOE gene, known as APOE4) and with frequent reactivations of HSV-1 had a roughly 3x higher risk of AD. In APOE4-negative individuals, there was no association between HSV-1 and AD, emphasizing the multifaceted aspect of dementia development.
The more researchers continue to build on existing data, the clearer the answers to these and countless other questions will become.
The Takeaway
Not everyone who becomes infected with HSV, VZV or any number of pathogens will develop dementia, the same way vaccines are not the end-all be-all for mitigating risk. Nothing about health is ever so simple; it is the cumulative product of our genes, the microbes that live in and on us, our environment and how we go about our lives that shapes our well-being.
Nevertheless, there are a lot of reasons why minimizing infections and getting routine vaccinations are good ideas, especially given the lasting impacts infections can have on the body. Vaccines are effective tools for managing infectious diseases-that they may also protect against cognitive decline is an emerging benefit worth keeping in mind.
How do microbes pass through the blood-brain-barrier? This next article explores these mechanisms, and how they are informing neurotherapeutic design.
