Herpes Viruses and Dementia Risk: What We Know About This Neuroimmune Stress

Hello, I am Julie Donaldson and I am a clinical nutritionist with functional medicine training. I specialize in restoring balance in complex, chronic and acute health conditions. I welcome you to peruse other articles that may be of interest to you in your health investigation!

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Since 2021, significant studies have been showing us connections between the herpes virus and a doubled risk of developing Alzheimer’s Disease (AD) or dementia. Given that herpes infection rates are at over 50% of the adult population in the U.S., and given that the 2023 statistics showed a 19% rate of occurrence in AD and dementia with continual increases, this is not a small concern. Here, we’ll talk about the risk, where it’s coming from, and what to do to protect yourself.

The herpes simplex virus

There are 2 strains of the herpes simplex virus, HSV-1 and HSV-2. More than 3.7 billion people globally have one or both of the herpes virus strains. Women have higher rates of infection than men (of both strains of the virus), a statistic that increases linearly with age. This creates a magnified risk for cognitive diseases.

HSV infections are most commonly acquired through direct contact with sites of viral shedding, A fascinating aspect of HSV infection and reactivation is that asymptomatic shedding is believed to be the most common cause of horizontal and vertical HSV transmission in “immuno-competent” individuals (those with adequate immune response).

Entry begins with attachment of the virus to the cell surface, followed by interactions between viral glycoproteins and cellular receptors to facilitate capsid penetration. (The virus capsid functions to protect the nucleic acid from the environment, and some viruses surround their capsid with a membrane envelope.) The nucleocapsid is then transported along microtubules to the nuclear membrane, where viral DNA is released, allowing the virus to replicate in the nucleus.

Once the herpes virus enters the body, it stays for life. Herpes viruses are large viruses with substantial genomes. Although it usually infects the body, HSV also has been found in the brain.

Herpes viruses are capable of establishing latency in diverse cell types, allowing for evasion of the host immune system and reactivation of viral replication. In both HSV-1 and HSV-2, sensory neurons and ganglia serve as the reservoirs for latent virus. From my article on chronic viral and methylation responses comes this information:

“They have multiple mechanisms in the immune system by which they are able to avoid cell death. HSVs may persist in a quiescent but persistent form known as latent infection, notably in the neural ganglia. HSV-1 tends to reside in the trigeminal ganglia, while HSV-2 tends to reside in the sacral ganglia, but these are tendencies only, not fixed behavior. During latent infection of a cell, HSVs express latency associated transcript (LAT) RNA. LAT regulates the host cell genome and interferes with natural cell death mechanisms. By maintaining the host cells, LAT expression preserves a reservoir of the virus, which allows subsequent, usually symptomatic, periodic recurrences which are characteristic of non-latency.”

While much remains to be studied about the molecular mechanisms of LAT, if we are “blocked” in killing HSV-infected cells by its function, we must look beyond this to the cells that can kill HSV without requiring antigen presentation. These are NKCs (Natural Killer Cells).

For NKCs to function optimally, the adaptive immune system must be strong and responsive. Some potential substances for this purpose are medicinal mushrooms and their beta glucans, as well as the herbs astragalus and andrographis.

It is the HSV-1 strain that is most commonly associated with neuroimmune and neurodegenerative conditions. This is the strain that most commonly affects tissues of the mouth and lips.

HSV-1 and doubled risk of developing Alzheimer’s disease or dementia

in this study, a doubled risk of cognitive neurodegenerative disease was identified with HSV IgG seroprevalence - in simple terms, this means the presence of antibodies against the virus in the blood. This correlation was tested up against CMV (cytomegalovirus), where no risk or correlation with AD or dementia was found.

One of the main links between HSV-1 and dementia is that HSV-1 DNA has been found within the protein clumps (amyloid plaques) that build up in the brains of AD patients. Aside from this, some researchers think that herpes could cause excess inflammation in the brain. HSV is a huge, double-stranded virus with significant inflammatory effects.

In laboratory-grown brain cells, HSV-1-induced inflammation impairs normal functioning of these cells. This could then potentially trigger or worsen existing trends for Alzheimer's disease development.

Women and Alzheimer’s, special risks

There are approximately 6.9 million people living with Alzheimer’s disease in the U.S. A full 2/3 of this group are women. Women have a 1 in 5 risk for developing AD, while men have a 1 in 10 risk.

Some other staggering statistics on AD:

Approximately 11% of people 65 and older in the U.S. have the disease
AD rates are projected to triple between now and 2050 - this means the requirement also to triple geriatric medical care in that time
11 million people (family, friends) are currently providing unpaid care for AD patients, totaling 18.4 billion work hours worth an estimate $350 billion
Blacks are twice as likely to get AD in older age than whites; Hispanic people are 1.5 times more likely to develop AD than whites

Compounded with the higher rates of HSV infections in females, women are very vulnerable to this disease. While researchers are still digging into the mysteries of why, we do have some possible answers at this point.

Scientists have found that differences in the structural and functional connections of a woman's brain may speed the spread of tau, a protein that clumps into tangles then contribute to cell damage and, ultimately, cell death. The study included healthy individuals (123 men, 178 women) and people with mild cognitive impairment (MCI: 101 men, 60 women) enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. For each group, the tau-connectivity networks were characterized to indicate (1) the overall number of connections, (2) areas within the brain with higher tau connectivity than the rest of the brain (communities), and (3) regions that influenced the spread of tau across different communities.

The researchers found that the tau network of women with MCI looked very different than the other three groups. Women with MCI had the highest network density (0.38 ± 0.03 compared to 0.21 ± 0.02 in MCI-male, 0.11 ± 0.02 in CN-male and 0.12 ± 0. 02 in CN-female) and, at the same time, increased brain-wide tau burden. The researchers found that healthy women in the study had several key brain regions (parahippocampus, superior parietal, insular, superior temporal) that served as hubs and connected different brain areas within the network. They speculate that this may favor an accelerated brain-wide tau spread in women, leading to cognitive decline.

In another study focused on the lifestyle and work patterns of women over the last decades, it was found that cognitive decline occurred more frequently in women who were not in the work force.

Average memory performance between the ages of 60 and 70 declined 61% faster for married women with children who never engaged in waged employment, and average memory performance between ages 60 and 70 years declined 83% faster for women who experienced a prolonged period of single motherhood without waged employment.

Based on these findings, the scientists suggest that participation in the paid labor force may play an important role in late-life cognitive health for women in the United States. This builds on prior research that has found participation in the workforce is associated with higher levels of cognitive stimulation and increase in cognitive reserve.

Neuroimmune looping in the midst of HSV and AD

The interplay between the immune system and the brain/nervous system has been illuminated and it is key to this connection between HSV infection and the risk for development of AD and dementia.

As has already been noted, the herpes family of viruses are large, double-stranded and quite offensive to the body. Their ability to produce inflammation can create susceptibilities for neuroimmune looping and stress.

Body inflammation leads to stress chemistry inciting brain inflammation. What follows is diminished Vagus nerve output which then loops back to more body inflammation.

In such states, we have the potential alteration of the following body processes:

Body inflammation. One of the primary drivers of brain inflammation is body inflammation. Inflammation also causes impaired neuronal metabolic integrity. It is noteworthy that TNFα and IL-1β, two important inflammatory “ON” signals, are both primary pro-inflammatory cytokines that are upregulated in the context of brain inflammation.
Neuroinflammation. Increases in pro-inflammatory cytokines in the body create upregulation of brain inflammation. Systemic IL-1β can cause central nervous system (CNS) inflammation once it enters the brain, linking systemic inflammation and immune activation with brain inflammation
Microglial cell activation: Our bodies produce immune cells called macrophages. The job of the macrophage is to seek out and ingest foreign material. Microglia are the resident macrophages of the CNS. Microglia are exquisitely sensitive to brain injury and disease and are tasked with performing continuous surveillance on neurons . The pruning of synapses by microglia is an essential part of normal brain development. They do this by palpating. Activation of microglial cells is initiated by the movement of phosphatatdyl serine (PS) from the inside of the neuron cell wall to the outside. (PS is a very important phosphate-based lipid which protects the nervous system The phosphate/lipid combination provides fluidity in two dimensions combined with mechanical strength against rupture.) When it leaves the inner membrane of the neuron, however, microglia palpate the substance and initiate consumption of the neuron. Brown and Neher describe several factors that can drive PS to flip to the outside membrane, promoting apoptosis of neurons by microglia. These include ATP depletion, inhibition of phosphatidylserine translocases by oxidative stress, and increased calcium levels (latter may be impacted by heavy metal toxicity and/or thyroid imbalances). (NOTE: The official discovery of the glymphatic system in the brain occurred in 2015 at UVA’s Center for Brain Immunology and Glia. The meningeal lymphatic vessels consist of both interstitial fluid and cerebrospinal fluid which provide a conduit that enables communication between the brain parenchyma and cervical lymph nodes. This deepens the relationship between the immune and nervous systems.) Many clinically modifiable comorbidities have a common thread, in that they all influence neuron-microglial interactions.
Neuronal death. Surveillance by microglial cells of healthy and unhealthy neurons is happening billions of times daily, typically with a high degree of accuracy. But in an inflammatory state, the signaling tips in favor of gobbling vs. leaving neurons alone. The error rate which is naturally inherent in the process also becomes increased and tipped in favor of neuron consumption. This becomes very, very problematic for the overall health of the brain and nervous system, especially when microglial cells think that neurons are dying when they don't fire often enough...Loss of neuronal firing rate will at some point yield a loss of the neuron’s ability to generate enough electrical activity to adequately inhibit its consumption by microglial cells. This can occur as a consequence of impaired neuronal metabolic integrity, when the neuron cannot generate enough ATP to sustain its firing rate. Mitochondrial ATP production is required for all cells to function, including neurons. If the neuron cannot produce ATP, it cannot continue to pump PS from its outer membrane to its inner membrane; nor can it produce adequate neurotransmitters, growth factors, or other microglial “OFF” signals. Microglial activation is implicated in a number of neurodegenerative diseases, including Parkinson’s, MS and Alzheimer’s disease. Neuronal metabolic integrity is maintained by stimulation, oxygen and glucose.

T-cells and immune modulation

The human immune system is a very complex operation. We all have what are called “T-cells” that are a significant baseline for differentiation in the immune system. How they mature from a naïve state is dependent upon the amounts and types of inflammation in the body.

Your thymus gland produces regulatory T cells (called Tregs). This gland lives in the front of your chest, between your lungs and behind your breastbone. Your thymus produces the hormone thymosin, which stimulates the development of regulatory T-cells. Tregs control your body’s immune response to keep it from over-reacting to harmful invaders such as a herpes virus. Once these T-cells mature, they populate in your lymph nodes and spleen to assist with immune responses.

The gland shrinks over the course of adulthood and becomes fat. Remarkably, much of the functional and regulatory aspects of thymus-dependent T cell responses occur early in life and may be largely dispensable thereafter; multiple peripheral mechanisms of homeostasis maintain T-cell numbers and proper immuno-regulation.

In addition to Tregs, Th1 and Th2 cells are differentiated from naïve T-cells.

Th1 cells are the helpful cells that support the body to fight pathogens effectively. Their (sometimes) unhelpful counterpart are Th2 cells. When body inflammation and stress chemistry have a decreasing effect on Th1 cells, the Th2 cells proliferate. This can lead to a lot of histamine and inflammatory-based responses in the body vs. resolution of pathogens (such as herpes viruses). While Th2 cells are necessary to the Bell curve of resolving infection, their proliferation over Th1 cells can be problematic. The body is designed to naturally teeter-totter between Th1 and Th2 activation.

T-cell receptor (TCR) stimulation is a potent and specific means of activating T cells. It appears, however, that the HSV cells have the power to interfere with this process. T cells do not prevent HSV latent infection or reactivation, suggesting that HSV has the potential to modulate T-cell function in its own unique way.

HSV-infected T cells stimulated through the TCR selectively synthesized interleukin-10, an immune cytokine that suppresses cellular immunity and favors viral replication. To achieve selective interleukin-10 synthesis, HSV differentially affected TCR signaling pathways. This creates a unique survival and replication mechanism which contributes to a troublesome latent and chronic infectious state with HSV. Additionally, HSV-infected cells can evade T-cell recognition by interfering with antigen presentation. Antigens are substances in toxins, bacteria and viruses (as well as food compounds in some cases) that combine with a specific antibody (T-cell receptor) having a matched molecular structure. This presentation allows the immune response to be mounted.

A Th1-dominant environment favors recognition and removal of virus-infected cells, and HSV may gain a growth advantage by inhibiting TCR-stimulated Th1 cytokines.

Also importantly, IL-10, a Th2 cytokine, has been shown to suppress Th1 development. As mentioned above, the Th1 cells are key to immune attack and resolution.

The rays of hope with this challenge lie with NKCs (discussed earlier) and STAT3. HSV does not inhibit TCR-stimulated activation of STAT3, a transcription factor involved in interleukin-10 synthesis. This gives us unique therapeutic opportunities to bolster the responses against HSV when we understand how STAT3 works. While STAT3 has a purpose in immune inflammation, it is one more aspect of immune function that must be modulated/kept in check. Adequate vitamin D levels (and synthesis from the liver to the bloodstream) are absolutely crucial to STAT3 support, as are omega 3’s, sulforaphane and potentially special pro resolving mediators (SPMs).

Summations and solutions

The more repetitive and severe HSV outbreaks are, the higher the risk for neuroimmune looping and the development of neurodegenerative diseases like Alzheimer’s and dementia. It is so very important to understand that chronic (and acute) immune stresses create more vulnerability than strictly inside the immune system. As always, let’s discuss what can be done to prevent this dangerous scenario, so you can get back out there and play!

Let us remember that every single cell in the body is dependent upon ATP for its energy source. ATP allows a cell to do its job, no matter what it is, just like gas in a car engine. When ATP is being used to fight a chronic latent virus, it is potentially diverted from other cells working to complete other tasks. The modulation of the immune system and efficient management of HSVs is critical to a person's overall health and ability to maintain successful completion of other physical tasks in the body.

Understand that every immune challenge must complete a successful Bell curve in order for your body to return to homeostasis. If your body remains inflamed (from ANY pathogenic activity) and the natural teeter-totter of your T-cells is disrupted, risks for neurological problems increase.
Work with a skilled practitioner to understand your own personal immune weaknesses and to remodulate the system accordingly. Detailed focus on STAT3 and NKC activity in the immune system is highlighted in order to bypass the immune evasion and manipulation techniques of HSV.
Support the suppression of HSV activation with the right tools/substances.
On a daily basis, practice relaxation, get good sleep, sun exposure, exercise and eat according to your personalized nutrition, MT®. (HSV can hijack lipid metabolism, as well as cholesterol can assist the reactivation of the virus. HSV-1 also results in altered carbohydrate metabolism and glucose uptake. These are key aspects to monitor with infection.)
Balance body and mind with specific types of meditation and processing of life/emotions.
Stimulate the brain with learning on a regular basis. Be curious, inquisitive and challenge your mind with new tasks and information.
If mild cognitive impairment is evident, a full personal workup is advised. Substances such as lions mane and boswellia may be helpful.
Many people have learned to control HSV successfully. Contact me at Julie@truenaturehealthconsulting.com for personalized support. We provide holistic telehealth services.