On the infectious etiology of Alzheimer's disease (AD)
When I was a third-year undergraduate student, one of my neurobiology assignments was writing a literature review. As I scoured the literature for a compelling issue to write about, I came across the uncanny link between herpes simplex virus type 1 (HSV-1) and Alzheimer’s disease (AD), the most common form of neurodegenerative disease that involves memory loss.
I was so engrossed in the topic that I ended up publishing a paper on it in a Q1-ranking journal in 2021, a year after I graduated. So, with my familiarity with the topic, let me tell you the story about the infectious etiology of AD, and how Covid-19, the virus that concerns us all, is also involved.
In 1982, Melvyn J. Ball, MD, a neuropathologist, published a paper noting that brain regions affected in herpes simplex encephalitis are also the ones affected in AD, namely the limbic system and temporal lobe.
Dr. Ball then hypothesized that the reactivation of HSV-1 — which stays latent or dormant in the body for life once infected — might spread to the brain and trigger sub-clinical neuronal damage that, when accumulates over time, leads to AD. And his hypothesis is impressively accurate.
Fast forward to 2017, after decades of research, the International Association of Gerontology and Geriatrics (IAGG) Congress was held in San Francisco to understand the intricacies between microbes and AD. Therein, it was acknowledged that HSV-1 plays a major role in AD, with over 130 publications from different labs supporting such a role.
Studies have found the genetic material of HSV-1 in amyloid aggregates in the brain of deceased AD patients, as well as brain regions involved in AD, which are typically absent or rare in non-AD brain tissues (Figure 1). (Brain amyloid aggregates are the key hallmark of AD pathology.)
*Figure 1. Top left: arrows point to HSV-1 genetic material (dark purple) in the brain tissue of an AD patient. Top right: HSV-1 genetic material was not detectable in the brain tissue of a non-AD patient. Bottom left: arrows point to HSV-1 genetic material (dark green) in the temporal lobe of an AD patient. Each dot may represent one copy of the HSV-1 genome. Bottom right: HSV-1 genetic material was not detectable in the temporal lobe of a non-AD patient.
When lab-cultured neurons and lab-bred rodents (mice/rats) were infected with HSV-1, they developed amyloid aggregates in the brain, as well as other AD-related pathologies like neuroinflammation and neuronal loss. The HSV-1 infected rodents even developed memory loss, showing a cause (HSV-1) and effect (AD) relationship.
While HSV-1 normally stays latent in the trigeminal ganglion nerve (besides the brainstem) of over 60% of the world population, it can occasionally reactivate during immunosuppression or stress.
And reactivated HSV-1 can spread not only to the lips (to cause cold sores) but also to the brain (to cause clinical encephalitis or subclinical brain impairments, such as neuroinflammation or amyloid aggregation).
As follows, multiple reactivations of HSV-1 would continue accumulating amyloid in the brain, ultimately leading to AD.
Convincing epidemiology evidence also exists to support this notion.
For example, in a 2018 nationwide study of over 33,000 people in Taiwan, those who had HSV-1 infection (e.g., displaying cold sores) had a 2.5-fold increased risk of dementia. (Dementia takes many forms, the most common one being AD). More importantly, antiherpetic medication lowered such a risk by 90% compared to no medication.
More recently, in a 2021 cohort study of over 250,000 people in Sweden, those who had HSV-1 or other herpes infections but did not take antiherpetics had a 1.5-fold increased risk of dementia. This risk was not only nullified in those who took antiherpetics but also fell by 10%.
If HSV-1 is indeed facilitating AD progression in certain ways, then anti-HSV-1 medications should halt AD progression.
That’s why an ongoing clinical trial is testing the efficacy of valacyclovir, an antiherpetic, in treating mild AD patients. Results are expected in 2023. This clinical trial is the first to test if antiviral works for treating AD, which, if successful, would revolutionize how we treat near-untreatable AD.
“Given the failure of the 413 trials of other types of therapy for AD carried out in the period 2002–2012, antiviral/antimicrobial treatment of AD patients…could rectify the ‘no drug works’ impasse,” stated Ruth F. Itzhaki, Ph.D., emeritus professor, one of the pioneers in the field. “We propose that further research on the role of infectious agents in AD causation, including prospective trials of antimicrobial therapy, is now justified.”
Intriguingly, lactoferrin — an antimicrobial peptide capable of inhibiting HSV-1 infection — improved memory function and disease biomarker status in patients with mild-to-moderate AD in a 2019 clinical trial.
And here is where antimicrobial peptides come in. As it turns out, amyloids also have antimicrobial properties, where amyloid aggregation in the brain actually traps microbes, thus hindering the spread of brain infections.
For instance, a 2018 study showed that infecting mice with HSV-1 resulted in amyloid aggregation in the brain. But such amyloids bound and neutralized HSV-1, prevented potentially fatal encephalitis, and prolonged the mice's lifespan but at the cost of increased brain amyloids.
This finding has also initiated a paradigm shift in how we view amyloids. We thought they are purely sinister in nature, toxic to neurons, and cause AD. But it seems that amyloids may be a defense mechanism against brain infections.
Amyloids first evolved about 400 million years ago in vertebrates and, since then, have remained mostly the same without drastic evolutionary changes. The evolutionary-conserved amyloids may, therefore, serve a crucial function over eons, probably pathogen defense.
The story doesn't end with HSV-1, however.
Another common herpesvirus, varicella-zoster virus (VZV) — also known as chickenpox virus that stays latent in the body permanently once infected and may reactivate to cause shingles — plays a role in AD too.
A new study published a few months ago discovered that VZV infection alone did not trigger any amyloid or tau aggregation in neurons, but HSV-1 infection did. However, the catch is that in the presence of HSV-1 latency, VZV infection actually causes HSV-1 reactivation, resulting in more amyloid aggregation and neuroinflammation than HSV-1 infection alone.
“It’s a one-two punch of two viruses that are very common and usually harmless, but the lab studies suggest that if a new exposure to [VZV] wakes up dormant herpes simplex virus, they could cause trouble,” said Dana Cairns, Ph.D., a biomedical engineer, and the study’s lead author.
Interestingly, one nationwide study in the U.K. found that VZV vaccination diminished the risk of dementia by 28%. This finding is consistent with a smaller cohort study reporting lower rates of cognitive loss in VZV-vaccinated than non-vaccinated individuals. (No vaccine exists for HSV-1.)
And the study doesn’t end with HSV-1 and VZV either.
Other viruses, bacteria, and fungi have also been found to contribute to AD, albeit not as extensively studied as HSV-1. Examples include Epstein-Barr virus, hepatitis C virus, Chlamydophila pneumonia, Spirochetes bacterial species, and Candida fungal species, which can induce brain abnormalities reminiscent of AD via mechanisms such as amyloid aggregation, blood-brain barrier disruption, neuroinflammation, and oxidative stress.
Given the undeniably growing evidence on the infectious role in AD, the National Institute of Health has deemed “Infectious Etiology of Alzheimer’s Disease” a high-priority topic with increased funding in 2019. Before that, scientists struggled to get funding for such a topic, which, in fact, was once thought controversial and incredulous.
All that said, however, the direction of causation remains elusive.
Scientists think that because AD is mainly a disease of old age, old age alone may make one susceptible to HSV-1 and other microbial invasions. After all, old age comes with declining immunity and a more permeable blood-brain barrier, both of which encourage brain infections.
Then again, it’s hard to deny the lab evidence that deliberate microbial infection, most notably HSV-1, causes AD. So, the most plausible scenario is that old age and microbes, as well as other factors such as genetics, lifestyle, and environment, all work sophisticatedly in instigating AD.
In this manner, there might not be a single cause of AD, making it an unsolvable disease. But what we’ve seen so far on the role of viruses in advancing AD is highly concerning.