There are few more devastating diagnoses than dementia. Alzheimer disease robs people of their memories, their personalities and their ability to care for themselves. It is often a torturous decline that impacts friends and families in life-shattering ways. Despite billions of dollars spent on research and drug development, scientists have made little progress against Alzheimer’s. A fascinating new study published in the Journal of Alzheimer’s Disease (Aug. 2, 2022) suggests that the herpes virus (HSV-1) that causes cold sores could be a culprit, especially if another herpes virus, varicella zoster, reactivates it. Could the shingles vaccine and/or antiviral herpes drugs reduce the risk for Alzheimer’s disease? Read on to find out!
A Reader Shares a Story About Antivirus Herpes Drugs:
Q. I’ve had herpes for over 35 years and taken acyclovir to suppress it for nearly that long. When I miss my medication, I can perceive cognitive impairment. It clearly makes a difference in how alert I am and how well I can perform.
My mother-in-law is suffering from Alzheimer’s. Her doctor agreed to put her on daily acyclovir, and she has improved. Is there any research to support antiviral drugs against Alzheimer’s disease?
A. Thank you for sharing your story. For decades, the predominant theory has been that Alzheimer’s disease is caused by a buildup of amyloid plaque in the brain. But most of the drugs created to reduce amyloid have been disappointing. The latest failure was reported by the Eli Lilly company on March 8, 2023. Its experimental anti-amyloid drug solanezumab did not prevent cognitive decline.
Some scientists believe that beta amyloid may actually be how the brain protects itself from infection (the “pathogen hypothesis of Alzheimer’s”). Herpes was proposed as one possible culprit over four decades ago (Canadian Journal of Neurological Sciences, Aug. 1982).
Epidemiological data from Taiwan show that people with a history of herpes are more likely to develop dementia. Those who took antiviral medications had a “decreased risk of dementia” (Neurotherapeutics, April, 2018). Two studies are currently underway to test whether the anti-herpes drug valacyclovir (Valtrex) can delay or prevent the development of dementia.
Herpes Simplex Virus 1 and Alzheimer’s Disease:
Almost 50 years ago, Swedish researchers reported a connection between herpes virus infections and dementia. They noted that people with severe depression or “atherosclerotic dementia had a significantly higher incidence of herpes simplex virus” than was found in healthy controls (British Journal of Psychiatry, March, 1974).
Dr. Ball’s Radical Theory: Herpes and Dementia
Melvyn J. Ball, MD, was a pathologist at the Oregon Health and Science University. He is now retired. In 1982 he suggested that HSV1 (the herpes simplex virus that causes cold sores) might be contributing to the brain pathology of Alzheimer’s disease.
Dr. Ball knew that the herpes virus hibernates in the trigeminal ganglia in the brain. In its dormant state it doesn’t do much damage. Every once in awhile, it travels down a nerve pathway to the lips or face and causes a cold sore outbreak. This can happen after exposure to bright sun at the beach or on the ski slopes. People under stress may also have an attack.
Most neuroscientists assumed that the virus only traveled downward. Dr. Ball proposed the virus could travel up and into brain tissue Canadian Journal of Neurological Sciences, Aug. 1982). A few other scientists began pursuing this radical concept.
Dr. Ruth Itzhaki Continues the Research:
Ruth Itzhaki, PhD, is a British neuroscientist. She is Professor Emeritus of Molecular Neurobiology at the University of Manchester. In 1991, her team reported that the cold sore virus (HSV-1) was prevalent in the brains of senior citizens (Journal of Medical Virology, Apr. 1991).
By 1997, Dr. Itzhaki and her colleagues reported that the combination of HSV-1 plus the gene APOE-e4, was a strong risk factor for Alzheimer’s disease (Lancet, Jan. 25, 1997).
Writing about her research in The Conversation (Oct. 19, 2018), Dr. Itzhaki states:
“The virus can become active in the brain, perhaps repeatedly, and this probably causes cumulative damage. The likelihood of developing Alzheimer’s disease is 12 times greater for APOE4 carriers who have HSV1 in the brain than for those with neither factor.”
“We believe that HSV1 is a major contributory factor for Alzheimer’s disease and that it enters the brains of elderly people as their immune system declines with age. It then establishes a latent (dormant) infection, from which it is reactivated by events such as stress, a reduced immune system and brain inflammation induced by infection by other microbes.”
HSV1 Reactivated By Varicella Zoster?
The latest chapter in this unfolding story was published in the Journal of Alzheimer’s Disease (Aug. 2, 2022). This research was a collaboration between Dr. Ruth Itzhaki at the Institute of Population Ageing, University of Oxford, Oxford, UK and David Kaplan and Dana Cairns in the Department of Biomedical Engineering, Tufts University. What they did is simply stunning.
Complexity vs. Simplicity:
I have long been a believer in the multifactorial model of complex conditions such as cancer and/or Alzheimer’s disease. What I mean is that these illnesses are often brought on by several factors working together to cause mischief.
Historically, medicine prefers simple cause and effect explanations. A classic example is heart disease. Cardiologists love the LDL-cholesterol model. Too much LDL-C is supposed to cause clogged coronary arteries. This in turn is supposed to trigger heart attacks. Statins lower LDL-C and are supposed to be the solution. But heart disease is far more complex. And lots of people taking statins still get heart attacks.
In the case of Alzheimer’s disease, neuroscientists wanted to blame the condition on beta amyloid plaque buildup in the brain. Billions have been spent developing drugs to rid the brain of beta amyloid (or amyloid beta, if you prefer). Doing so was supposed to end Alzheimer’s disease. Sadly, that has not happened.
The Viral Complexity Theory:
Dr. Itzhaki has been studying a viral contribution to Alzheimer’s disease for decades. Her latest research suggests that it might be the combination of infection with varicella zoster virus (chickenpox) and the herpes virus that causes cold sores (HSV-1). By the way, the varicella zoster virus (VZV) that causes chickenpox is also a human herpes virus known as HHV-3.
People who catch chickenpox in their youth can develop a painful skin condition later in life called shingles. It is thought that the dormant VZV that has been hibernating in the brain for decades is reactivated and starts migrating down nerves to manifest as nasty skin lesions.
The new research published in the Journal of Alzheimer’s Disease (Aug. 2, 2022) suggests that the varicella zoster virus (VZV) does not itself lead to amyloid formation in the brain. But it could well pose “an indirect effect: reactivation of HSV-1.”
In the latest experiment, Dr. Itzhaki and her colleagues added VZV to neural stem cells “harboring quiescent HSV-1.” Doing so turned the “hibernating” HSV-1 virus into an active virus. This in turn led to the formation of amyloid beta plaques and tangles. There were also other cellular changes (gliosis and the formation of pro-inflammatory cytokines). The authors describe these outcomes as:
“all features characteristic of the AD [Alzheimer’s disease] brain.”
In Vitro vs In Vivo Research:
Investigators conducted the latest study in vitro. That means they developed an experimental model of the brain for the experiment. In contrast, scientists do in vivo research on intact animals or humans.
To explain this further, the authors write:
“Presumably, the cytokines elicited by VZV infection cause the reactivation of quiescent HSV-1. This striking result would be totally consistent with the suggestion that in vivo, infections such as VZV cause an increase in neuro-inﬂammation, leading to reactivation of latent HSV-1 and consequent damage in brain, so that repeated infections—causing recurrent reactivation—would lead eventually to the development of AD/dementia. These proposed events would explain the fact that many studies have found that peripheral infections lead not only to cognitive decline but also to an increased risk of AD/dementia.”
Long COVID and Brain Fog:
One need look no further than the COVID pandemic to discover a relationship between viral infection and cognitive impairment. Many long COVID patients complain of brain fog, lapses in memory and brain “dysfunction.” Will this lead to a new pandemic of Alzheimer’s disease and dementia? No one knows, but the prospect is super scary.
Dr. Itzhaki and her colleagues write that:
“It is noteworthy and probably significant that a number of studies on COVID-19 have shown that HSV-1 and VZV are reactivated during or after SARS-CoV-2 virus infection, especially in older subjects and in those with weakened immune systems; and sometimes both are reactivated together.”
Some Good News About Preventing AD:
An article in Lancet Infectious Diseases (Nov. 2021) offers a ray of hope amidst the gloom and doom. The authors point out that preventing infections and/or prompt treatment may delay the development of dementia or slow its decline.
An article published in the journal Frontiers in Aging Neuroscience (July 22, 2021) also reinforces the idea that infections can lead to inflammation within the brain. They refer to this process during aging as “inflammaging.”
They note that this could be the underlying cause of Alzheimer’s disease:
“The features of inflammaging consist of enhancement of microglial activation and pro-inflammatory molecule production, which deteriorates inflammation in aging people and AD.”
Can We Reduce the Risk of Alzheimer’s Disease with Vaccines and/or Antiviral Herpes Drugs?
Dr. Itzhaki and her colleagues note that:
“Three of the studies on VZV and its relevance to AD/dementia examined the effect of vaccination against shingles on risk of dementia and all discovered that it reduces the risk considerably.”
In other words, the shingles vaccine may be protective against Alzheimer’s disease by preventing the reactivation of varicella zoster and ultimately HSV-1.
The researchers conclude:
“One of our aims now is to investigate the effects of other viruses, both herpesviruses and non-herpesviruses, as well as other common infectious pathogens, on cells of various types quiescently infected with HSV-1, to find if they too cause reactivation of the HSV-1. The results should help to elucidate the pathways whereby infections increase the risk of AD/dementia and the ways this disease could be combatted by appropriate antivirals for treatment, or just possibly, for prevention.”
Antiviral Herpes Drugs to the Rescue?
In a recent article Dr. Itzhaki makes a crucial point:
“It’s important to note that all studies, including our own, only show an association between the herpes virus and Alzheimer’s – they don’t prove that the virus is an actual cause. Probably the only way to prove that a microbe is a cause of a disease is to show that an occurrence of the disease is greatly reduced either by targeting the microbe with a specific anti-microbial agent or by specific vaccination against the microbe.
Antiviral Herpes Drugs:
Dr. Itzhaki goes on to note:
“Excitingly, successful prevention of Alzheimer’s disease by use of specific anti-herpes agents has now been demonstrated in a large-scale population study in Taiwan. Hopefully, information in other countries, if available, will yield similar results.”
Actual Research with Antiviral Herpes Drugs Against Alzheimer’s:
A review in Frontiers in Aging Neuroscience (Oct. 19, 2018) offers another glimmer of hope that antiviral herpes drugs might help attenuate the decline into dementia.
Antiviral herpes drugs like acyclovir (Zovirax), famciclovir (Famvir) or valacyclovir (Valtrex) have been available for many years. (Zovirax was first marketed by Burroughs Wellcome as an ointment in 1982 and in capsule form in 1985.) These antiviral medications are prescribed to treat herpes infections such as shingles (herpes zoster), chickenpox (varicella), genital herpes (HSV-2) and herpes labialis (cold sores caused by HSV-1).
In one study antiviral treatment of herpes virus infections with drugs like acyclovir, famciclovir or valacyclovir dramatically reduced the likelihood of developing dementia (Neurotherapeutics, Apr. 2018). In that epidemiological study, roughly 28 percent of HSV patients developed dementia during the 10-year follow-up. Among similar patients treated with antiviral drugs, fewer than 6 percent progressed to dementia.
Dr. Itzhaki describes the research this way:
“Even more strikingly, a group of HSV-infected patients (N= 7, 215) who had been treated with one of various anti-herpes agents (acyclovir, famciclovir, ganciclovir, idoxuridine, penciclovir, tromantadine, valaciclovir (VCV—the biodrug of ACV, which is better absorbed) and valganciclovir), showed a dramatic reduction of almost 10 fold in the later incidence of SD [senile dementia] compared with those who received no treatment.”
From the Researchers Themselves:
The Taiwanese investigators recruited 33,448 people:
“8,362 with newly diagnosed HSV [herpes simplex virus] infections and 25,086 randomly selected sex- and age-matched controls without HSV infections…”
The study was described this way:
“This retrospective cohort study is to investigate the association between herpes simplex virus (HSV) infections and dementia, and the effects of anti-herpetic medications on the risk involved, using Taiwan’s National Health Insurance Research Database (NHIRD).
“The usage of anti-herpetic medications in the treatment of HSV infections was associated with a decreased risk of dementia. These findings could be a signal to clinicians caring for patients with HSV infections.”
Final Thoughts About Antiviral Herpes Drugs and Alzheimer Disease:
Dr. Itzhaki and her colleagues bemoan the fact that scientists have been overlooking research data linking infections and Alzheimer’s disease for three decades.
“Surely, now is the time to rectify the situation by determining and then using the best means of treatment at hand.”
Frontiers in Aging Neuroscience, Oct. 19, 2018
We suspect that most health professionals have never heard of the herpes virus theory of Alzheimer disease. Fewer still have read about the study from Taiwan demonstrating benefit from antiviral herpes drugs.
Not surprisingly, readers would like to know if antiviral herpes drugs might be helpful. Here is an article we wrote on this topic based on just such a question.
Other Anti-Alzheimer Disease Resources:
We have interviewed two neuroscientists who are at the cutting edge of Alzheimer disease research. You may find our one-hour interview of great interest. These scientists discuss the role of infection in dementia and talk about the anti-viral activity of amyloid beta. Here is a link to that show.
You can listen to the streaming audio or download an mp3 file.
You can also listen to Dr. Ruth Itzhaki wrestle with the question:
“Do Cold Sores Boost Your Risk for Dementia?”
She is the second guest (after our interview with Dr. Eran Elinav) at this link.
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