Alzheimer’s disease (AD), the most common cause of dementia, is a neuro-degenerative disease that causes cognitive decline affecting memory and executive function. While rarely due to genetic mutation, the cause of most cases of Alzheimer’s disease is not known. However, new research indicates that the virus that causes cold-sores (fever-blisters) may also cause or contribute to the development of Alzheimer’s disease.

According to the “viral hyypothesis,” which has been around for about three decades, viruses may be causative agents in the development of Alzheimer’s disease.  In a recent paper published in the journal Current Neurology and Neuroscience Reports, researcher Dr. Devanand compiles evidence supporting the hypothesis, and suggests that antiviral treatment trials are needed to explore whether antiviral medication can be used to treat Alzheimer’s disease.

Herpes Simplex Virus (HSV) and Alzheimer’s Disease (AD)

The hallmark sign of Alzheimer’s disease (AD) is the formation of plaques and tangles in the brain. Plaques form in the tissue spaces between nerve cells and are composed of aggregates of amyloid fibrils, while tangles form within nerve cells and consist of abnormal tangles of tau protein. HSV DNA has commonly been found in amyloid plaques and the virus can trigger amyloid-beta aggregation. Reactivation of the virus is associated with abnormal activation of tau protein known as hyperphosphorylation, and tau hyperphosporylation has been implicated in the pathogenesis of AD and neurodegeneration.

Two-thirds of the global population has been estimated to be infected with HSV1 according to the World Health Organization (WHO), as the infectious virus is easily transmitted via oral-oral contact. Infection is life-long and characterized by recurrent episodes of viral shedding. Shedding frequency varies and can be asymptomatic. So, an infected person may not know that they are infected or when they are experiencing viral reactivation, as not all people infected with HSV1 develop cold-sores.

Herpes Simplex Virus (HSV) and Neuronal Damage

Cold–sores are caused by Herpes Simplex Virus 1 (HSV1) which is related to the Herpes Simplex Virus 2 (HSV2) that primarily causes genital herpes. HSV1 is an enveloped double-stranded DNA virus.  Upon initial infection the virus attaches to the surface of the cell and fuses its viral envelope with the cell membrane in order to enter the cell. Once inside the cell, the virus transports to the nuclear pores and releases its DNA into the cell nucleus. There, it replicates, and using the infected host cell, produces more virus.  This process causes lysis of the host cell, and shed virus can either infect new epithelial cells or enter into latency. During latency the virus occupies nearby sensory neurons and may occasionally reactivate.  Reactivation of HSV in the neuron may cause nerve damage.

When HSV1 binds to the membrane of neurons it can increase calcium ion entry into the cell which can trigger the cell to die from hyperexcitability. Calcium ion signaling activation is also responsible for HSV1 induced amyloid-beta accumulation. This is a result of amyloid precursor protein interacting with the HSV1 capsid proteins to allow migration of new virion inside of infected cells. In addition, HSV1 binds to components of plaques and tangles that are involved in cell death and DNA and protein processing.

Who gets HSV associated AD

While clinical studies in humans found cognitive impairment in patients with HSV1, not all infections lead to AD. Factors such as genetic disposition, frequency of viral reactivation, development of HSV encephalitis, and inflammation all play a role in determining whether HSV1 infection leads to the development of AD.

Genetic factors

Genetic defects in Toll-like Receptor 3 (TLR3) gene and Fas gene polymorphism (found in South-African women) increases the risk of HSV infection. Also Apolipoprotein E 4 is a risk factor for AD and may be associated with increased viral load of HSV in the brain. Carriers of the Apolipoprotien E 4 genotype with AD  are more commonly seropositive for HSV1 infection than those who do not carry the gene.

HSV Encephalitis and Inflammation

Inflammation can occur in the CNS or throughout the body. Encephalitis is inflammation of the brain, which is commonly caused by viruses. Encephalitis indicates viral entry into the brain via blood-borne transmission or via the virus moving along nerves.  Herpes virus encephalitis is rare, but recurrent activation of HSV in infected person is common. Reactivation leads to elevated antibody tithers.  Anti-HSV IgG  and IgM antibodies are produced with reactivation or new infection and IgG in particular was found to be associated with incidence of AD.

Viral Reactivation

Subclinal reactivation occurs in most people infected with HSV1, in which viral shedding occurs without signs or symptoms.  Frequent viral reactivation leads to elevated viral antibody tithers, which is associated with AD. Stress and age-related loss of blood-brain-barrier and immune function increase viral reactivation.

Age

Age is also a factor, for as we age the immune system and blood-brain-barrier weaken, allowing for increased viral load and possible viral entry into the brain.

Bottom-line

Infection with HSV1 doesn’t necessarily mean one will develop AD. In an AD study, where the brains of AD sufferer’s were examined during autopsy, 90% of amyloid plaques contained HSV1 DNA, and 72% of the HSV1 DNA found in the brain was plaque-associated. However, in brains from people who were seropositive for HSV1, but did not have AD, only 24% of the HSV1 DNA found in the brain was plaque-associated. Therefore, HSV1 can be found in the brain without inducing AD, but when AD and HSV1 are present they are strongly associated with each other. Also, viral load strongly correlates with plaque formation.

Antiviral Treatment and AD

Animal studies show that anti-HSV drugs decrease the accumulation of amyloid-beta and tau protein in HSV-infected mouse brains. This and other evidence of HSV association with plaques and tangles suggests that antiviral treatment trials are needed.

Antiviral treatment may delay the progress or severity of AD. Antiviral medications Acyclovir, Penciclovir, and Foscarnet commonly used for the treatment of HSV1 and HSV2, were shown to reduce HSV1 particles and amyloid-beta and tau accumulation in cell-culture models. So the less virus there is, the less amyloid-beta protein that is produced. The same results were seen in the brains of HSV-infected mice.

Anti-viral drug Valacyclovir (the pro-drug of acyclovir) has been used successfully for the treatment of herpes simplex virus 1 and 2 for over a decade. It is generally safe with relatively no negative side effects, and can readily penetrate the central nervous system. Currently, the first ever anti-viral treatment trial for Alzheimer’s disease, using Valacyclovir, is being conducted in humans.

Reference

Devanand, D. P. (2018). Viral Hypothesis and Antiviral Treatment in Alzheimer’s Disease. Current Neurology and Neuroscience Reports, 18(9). doi:10.1007/s11910-018-0863-1