The Germ of an Idea

by Women's Brain Health Initiative:The idea that infectious agents (such as viruses, bacteria, or fungi) may play a role in dementia is not new. Alois Alzheimer – the man who first described a “peculiar disease” in 1906 that would later become known as Alzheimer’s disease – first proposed that infection might be involved in the disease process. Over the years, various researchers have uncovered findings that support potential links between different infectious agents and neurological disorders.Recently, a wave of new research has been published related to herpes viruses in particular, and their role in dementia. This research adds to the existing evidence that herpes is a strong risk factor for dementia, outlines theories that might explain the relationship between herpes and dementia, and suggests potential directions for new dementia drug research.Links Between Herpes Viruses and DementiaHerpes simplex virus type 1 (HSV-1) is the infectious agent that has been most strongly linked to Alzheimer’s disease to date. Over 150 research publications directly or indirectly support this association.One study – conducted by Dr. Ruth Itzhaki and colleagues, published in The Lancet in 1997 – found that when HSV-1 is present in the brains of individuals with a particular gene variant, apolipoprotein E epsilon 4 (APOE e4), those individuals have a strong risk of developing Alzheimer’s disease. “We estimate that the likelihood of APOE e4 carriers with HSV-1 in the brain developing Alzheimer’s disease is 12 times greater than for people with neither factor,” said Dr. Itzhaki, a professor at the University of Manchester in the U.K. “Our research suggests that it is the combination of these two factors together that are damaging the brain, not either factor on its own.”Later research conducted by Dr. Itzhaki’s research team showed that infecting human cell cultures with the herpes simplex virus causes the accumulation of amyloid-beta and abnormal tau proteins – both characteristic traits of Alzheimer’s disease.In the April 2018 issue of Neurotherapeutics, Dr. Nian-Sheng Tzeng and colleagues shared findings from their study involving more than 33,000 people in Taiwan (8,362 of whom were diagnosed with severe herpes simplex virus – either HSV-1 or HSV-2 – and the rest randomly-selected controls). Utilizing data from the National Health Insurance Research Database, they found that the risk of developing dementia was 2.56-fold greater in the HSV-infected group than in the control group. However, when the researchers compared those in the HSV-infected group who had been treated with antiviral drugs versus those in the group who had not, they discovered a dramatic impact on incidence of dementia; the relative risk of developing dementia was reduced by a factor of 10 for those treated with antivirals.This was not the first study to examine the impact of HSV-antiviral agents on Alzheimer’s disease. Dr. Itzhaki’s team conducted a study (published in PLOS ONE in October 2011) to examine the effects of antiviral drugs on cell cultures acutely infected with HSV-1. The researchers found that the antiviral agents acyclovir, penciclovir, and foscarnet reduced the accumulation of amyloid-beta and abnormal tau proteins in the cell cultures.These findings suggest that antiviral drugs for herpes infections might be used for preventing or treating dementia, although more research is needed. It is important to note, though, that the aforementioned studies focused on severe herpes infections, which are rare. Additional research is needed to learn about the effects of antivirals on other populations – for instance, individuals without dementia who have the herpes virus but are only experiencing mild symptoms or are asymptomatic, and those who already have dementia.While much research has focused on HSV-1 (as it appears to be the most abundant type of herpes virus present in the brains of elderly people), other herpes viruses have also been linked to dementia. In a recent study from the Icahn School of Medicine at Mount Sinai, researchers found that two strains of human herpes virus – human herpes viruses 6a and 7 (HHV-6a and HHV-7) – are present in the brains of individuals with Alzheimer’s at levels up to twice as high as in the brains in those without the disaese. The researchers also identified previously unknown networks in which viruses operate and influence known Alzheimer’s genes. Their findings could potentially translate to the identification of virus or virus-related biomarkers that could be used for improved diagnosis. The findings also suggest a potential new direction for the search for drugs to prevent or treat Alzheimer’s disease. This research was published in Neuron in June 2018.What Might Explain the Herpes-Dementia Link?In a 2018 review paper published in Frontiers in Aging Neuroscience, Dr. Itzhaki proposes a “viral concept of Alzheimer’s disease” as a possible explanation for the herpes-dementia link. As our immune systems weaken with age, the herpes virus makes its way into the brain where it remains in a mostly dormant state. “The viral concept proposes that the dormant HSV-1 virus is reactivated intermittently and leads to direct viral damage in infected brain cells and to viral-induced inflammation,” explained Dr. Itzhaki. “Repeated activation causes cumulative damage, leading eventually to Alzheimer’s disease in people who carry the APOE e4 gene allele. Our theory is that in APOE e4 carriers, there is more herpes-induced formation of toxic products in the brain or less repair of the damage, compared to non-APOE e4 carriers.”An immune response to infections, including ones that are mild and do not induce symptoms, may be at the root of the formation of toxic products – the plaques and tangles associated with Alzheimer’s disease. Research has shown that amyloid-beta (Aβ) is a natural antimicrobial that works to protect the brain from infection, and is not just a functionless, abnormal substance that sometimes appears and accumulates with age, as previously thought. So, when an infectious agent makes its way into the brain, the body’s defense system activates and uses Aβ to surround the invader, which subsequently dies inside the Aβ “cage.” The cage – which is essentially the plaque associated with Alzheimer’s disease – gets left behind. This process has been confirmed in brain cells growing in the laboratory, as well as in simple organisms and mice. More research is needed to determine if a similar process occurs in human brains.A group of Harvard Medical School researchers at Massachusetts General Hospital have recently proposed that the role of Aβ starts out as protective but then, in cases of Alzheimer’s disease, becomes overactivated, causing neuroinflammation and widespread death of neurons. They refer to their theory as the “antimicrobial response hypothesis.”In their 2018 research paper published in Neuron, the research team (Eimer et al.) suggest that several factors might be involved in mediating a shift of Aβ from protective to pathological: strength and persistence of the infectious agent, genetics, and environmental factors. With respect to genetics, for instance, individuals with a gene variant called APOE e2 have brains that seem to be successful at removing Aβ plaque, and have a low risk of developing Alzheimer’s disease. Conversely, individuals with the APOE e4 gene variant have brains that appear to be inefficient at sweeping out Aβ plaque.No need to worryDr. James Pickett, Head of Research at the Alzheimer’s Society in the U.K., emphasizes the need for more research, and urges the public not to be worried about the latest findings regarding a herpes-dementia link. “Herpes is a hot topic in dementia research right now. Our researchers are hard at work to understand more about the diseases of the brain that do cause dementia, but there is still a lot to learn.It’s important to remember that most people who carry the herpes virus – which is most of us by the time we retire – will not develop dementia, said Dr. Pickett. “So, the link between herpes and dementia isn’t something that we feel people should worry about, although it’s sensible general advice to seek treatment for persistent cold sores. Dementia is not contagious and should not be thought of as an infectious disease.”There are more than 100 known herpes viruses. Eight of these routinely infect only humans:

• herpes simplex virus type 1;
• herpes simplex virus type 2;
• varicella-zoster virus (chicken pox, shingles);
• cytomegalovirus;
• Epstein-Barr virus;
• human herpesvirus 6 (variants a and b);
• human herpesvirus 7; and
• human herpesvirus 8 (Kaposi’s sarcoma).

Herpes simplex virus type 1 (HSV-1) usually causes sores around the mouth, commonly referred to as cold sores. HSV-1 can also cause genital herpes, resulting in sores around the genitals or rectum, although most cases of genital herpes are caused by herpes simplex virus 2 (HSV-2). Both HSV-1 and HSV-2 are common, lifelong infections that frequently have no symptoms. Many people acquire HSV-1 early in life, and it is estimated that more than 9 in 10 people have been exposed to the virus by the time that they reach old age. HSV-2 is thought to affect 1 in 6 U.S. adults.Human herpesviruses 6 and 7 are common viruses best known for causing roseola, a skin rash experienced by children.Herpesviridae are so common that infection in the general population of one type or more is estimated to be close to 100%. In other words, almost all people carry at least one type of herpes virus, irrespective of whether or not they have ever experienced symptoms.Source: MIND OVER MATTER V8