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. 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.
The infectious etiology of Alzheimer’s Disease (AD)
In 1982, Melvyn J. Ball, MD, a neuropathologist, published a paper noting that brain regions affected by 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 accumulated 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.
*Fig 1. Sources: Top, Zhang et al. (2022); bottom, Morri et al. (2004). 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 efficacious vaccine exists for HSV-1.)
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 not credible.
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.
How Covid-19 might make things worse
With the emergence of SARS-CoV-2, the Covid-19 virus, we now have an additional microbial threat to look out for, among many others.
Initially thought of as purely a respiratory virus only, SARS-CoV-2 is now known to infect blood vessels and neurons as well. As a result, SARS-CoV-2 can cause various cardiovascular and neurological symptoms in both clinical Covid-19 and sub-clinical long-Covid syndrome.
Like HSV-1, SARS-CoV-2 is capable of invading the brain. But instead of via reactivation from the nearby trigeminal nerve, SARS-CoV-2 infects the brain via crossing the blood-brain barrier or olfactory route.
Like HSV-1, SARS-CoV-2 genetic material and protein have been detected in the brain of infected patients. Although SARS-CoV-2 has not been shown to cause amyloid aggregation directly— probably due to the lack of research in this area — amyloid deposits have been detected in brain tissues of Covid-19 patients at a higher rate than non-Covid patients (Figure 2).
*Figure 2. Source: Rhodes et al. (2022). Representative section of the entire neocortex of a deceased Covid-19 patient, stained for beta-amyloid. Numerous amyloid deposits or aggregates were found (brown spots). Some of the amyloids were found within cells (arrowheads).
Like HSV-1, such amyloids probably served as a defense mechanism against SARS-CoV-2 infection in the brain.
Although SARS-CoV-2 can’t switch between latency and reactivation phases like HSV-1, SARS-CoV-2 is capable of virus persistence by switching off immune surveillance to continue replicating. In fact, SARS-CoV-2 genetic material has been detected in brain tissues of Covid-19 patients up to 230-day after symptom onset, i.e., over 7 months of virus persistence.
SARS-CoV-2 persistence is one of the key theories underlying long-Covid, a debilitating post-virus syndrome with multifaceted symptoms, one of which involves cognitive impairment like memory loss.
So, like HSV-1, SARS-CoV-2 may also pose a chronic threat that increases the brain amyloid burden over time, eventually leading to AD.
And epidemiological evidence supports this conjecture.
In a 2022 large cohort study of over 6 million older adults in the U.S., the risk of AD increased by 69% in those who had Covid-19 within a year of diagnosis compared to those without Covid-19.
Similarly, in another 2022 cohort study of nearly 3 million people in Denmark, Covid-19 patients had a 3.5-fold increased risk of AD compared to non-Covid patients at a 12-month follow-up.
Another impactful longitudinal study in 2022 investigated brain changes in 785 older adults in the U.K. They discovered that those who had Covid-19 had reduced grey matter thickness in the cortical and hippocampal brain areas — as well as elevated tissue damage in brain areas that are functionally linked to the olfactory cortex — compared to their baseline brain scans and to non-Covid controls. Covid-19 survivors also showed a greater cognitive decline compared to their baseline scores (taken 38 months ago before Covid-19).
And these brain imaging and cognitive function effects still persist despite excluding hospitalized Covid-19 patients, indicating that even mild Covid-19 could adversely affect the brain, specifically the hippocampal and cortical areas that are also the main regions damaged in AD.
“These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease through olfactory pathways,” the study authors wrote. “The overlapping olfactory- and memory-related functions of the regions shown to alter significantly over time in SARS-CoV-2 — including the parahippocampal gyrus/perirhinal cortex, entorhinal cortex and hippocampus in particular — raise the possibility that longer-term consequences of SARS-CoV-2 infection might in time contribute to Alzheimer’s disease or other forms of dementia.”
You might wonder how olfaction (smell) and AD (memory loss disease) are related. Actually, the olfactory cortex is one of the earliest brain regions to be affected in the pre-AD stage. This is why AD patients often develop smell dysfunction even before full-blown AD.
Ultimately, the key question of whether we might see a wave of AD from the pandemic. But so far, no study has investigated this question. While the prevalence of AD is predicted to rise due to the rising aging population, the Covid-19 pandemic has decreased life expectancy in numerous countries. As such, both effects might even out with each other.
At least in 2022, the incidence of AD doesn't seem to be increasing compared to previous years, probably due to better healthcare and sociocultural situations. But whether the present Covid-19 pandemic will lead to a wave of AD in the future is still unknown.
All in all, we haven’t yet decoded the infectious etiology of AD. But what we’ve seen so far — especially from HSV-1 and potentially from Covid-19 — is worrying. If we somehow decoded it, we might possibly solve AD that was once thought unsolvable.
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