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Commentary on causal link between herpes and Alzheimer's

The first strong population evidence for a causal link between herpes virus infection (HSV1) and Alzheimer's disease, from a recent groundbreaking Taiwanese study, is taken up in a commentary in the Journal of Alzheimer's Disease.

A new commentary by scientists at the Universities of Manchester and Edinburgh on a study by Taiwanese epidemiologists supports the viability of a potential way to reduce the risk of Alzheimer's disease.

When the Taiwanese authors looked at subjects who suffered severe herpes infection and who were treated aggressively with antiviral drugs, the relative risk of dementia was reduced by a factor of 10.

Manchester's Professor Ruth Itzhaki and Edinburgh's Professor Richard Lathe say the paper, by Tzeng et al. also shows that herpes simplex virus type 1 (HSV1) leads to an increased risk of developing the disease. "This article and two others by different research groups in Taiwan provide the first population evidence for a causal link between herpes virus infection and Alzheimer's disease, a hugely important finding," said Itzhaki.

They argue that they provide the strongest evidence yet for a causal link between herpes infection and Alzheimer's disease, backing 30 years of research by Itzhaki. Itzhaki said: "I believe we are the first to realise the implications of these striking data on this devastating condition which principally affects the elderly. No effective treatments are yet available.

"Almost 30m people worldwide suffer from it and sadly, this figure will rise as longevity increases. But we believe that these safe and easily available antivirals may have a strong part to play in combating the disease in these patients. It also raises the future possibility of preventing the disease by vaccination against the virus in infancy. Successful treatment by a specific drug, or successful vaccination against the putative microbe, are the only ways to prove that a microbe is the cause of a non- infectious human disease."

Most Alzheimer's disease researchers investigate its main characteristics – amyloid plaques and neurofibrillary tangles; however, despite the vast amount of research, the causes of their formation are unknown.

HSV1 infects most humans in youth or later and remains lifelong in the body in dormant form within the peripheral nervous system. From time to time the virus becomes activated and in some people it then causes visible damage in the form of cold sores.

The Taiwanese study identified 8,362 subjects aged 50 or more during the period January to December 2000 who were newly diagnosed with severe HSV infection. The study group was compared to a control group of 25,086 people with no evidence of HSV infection. The authors then monitored the development of dementia in these individuals over a follow-up period of 10 years between 2001 and 2010.

The risk of developing dementia in the HSV group was increased by a factor of 2.542. But, when the authors compared those among the HSV cohort who were treated with antiviral therapy versus those who did not receive it, there was a dramatic tenfold reduction in the later incidence of dementia over 10 years.

Lathe added: "Not only is the magnitude of the antiviral effect remarkable, but also the fact that – despite the relatively brief duration and the timing of treatment – in most patients severely affected by HSV1 it appeared to prevent the long-term damage in brain that results in Alzheimer's.

Itzhaki said: "It was as long ago as 1991 when we discovered that, in many elderly people infected with HSV1, the virus is present also in the brain, and then in 1997 that it confers a strong risk of Alzheimer's disease in the brain of people who have a specific genetic factor. In 2009, we went on to show that HSV DNA is inside amyloid plaques in Alzheimer's patients' brains. We suggested that the virus in brain is reactivated by certain events such as stress, immunosuppression, and infection/inflammation elsewhere. So, we believe the cycle of HSV1 reactivation in the brain eventually causes Alzheimer's in at least some patients."

Abstract 1
Three articles have very recently appeared that are of especial relevance to the causes of dementia and its potential treatment. The first two (Tsai et al., published in PLoS One in November 2017; Chen et al., published in the January/February 2018 issue of Journal of Clinical Psychiatry) demonstrate an increased risk of subsequent senile dementia (SD) development in patients with acute varicella zoster (herpes zoster) infection. These articles present data highly relevant to the third, and most important, paper—by Tzeng et al., published online in the journal Neurotherapeutics at the end of February 2018. These authors report that infection with a different herpes virus, herpes simplex virus type 1 (HSV1), leads to a similarly increased risk of later developing SD. Further, when the authors looked at patients treated aggressively with antiherpetic medications at the time, the relative risk of SD was reduced by a factor of 10. It should be stressed that no investigations were made on subjects already suffering from SD, and that those treated were the few rare cases severely affected by HSV. Nonetheless, antiherpetic medication prevented later SD development in 90% of their study group. These articles provide the first population evidence for a causal link between herpes virus infection and senile dementia.

Authors
Ruth F Itzhaki, Richard Lathe

Abstract 2
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). We enrolled a total of 33,448 subjects, and identified 8362 with newly diagnosed HSV infections and 25,086 randomly selected sex- and age-matched controls without HSV infections in a ratio of 1:3, selected from January 1, to December 31, 2000. A multivariable Cox proportional hazards regression model was used to evaluate the risk of developing dementia in the HSV cohort. This analysis revealed an adjusted hazard ratio of 2.564 (95% CI: 2.351-2.795, P < 0.001) for the development of dementia in the HSV-infected cohort relative to the non-HSV cohort. Thus, patients with HSV infections may have a 2.56-fold increased risk of developing dementia. A risk reduction of dementia development in patients affected by HSV infections was found upon treatment with anti-herpetic medications (adjusted HR = 0.092 [95% CI 0.079-0.108], P < 0.001). 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. Further research is, therefore, necessary to explore the underlying mechanism(s) of these associations.

Authors
Nian-Sheng Tzeng, Chi-Hsiang Chung, Fu-Huang Lin, Chien-Ping Chiang, Chin-Bin Yeh, San-Yuan Huang, Ru-Band Lu, Hsin-An Chang, Yu-Chen Kao, Hui-Wen Yeh, Wei-Shan Chiang, Yu-Ching Chou, Chang-Huei Tsao, Yung-Fu Wu, Wu-Chien Chien

[link url="http://www.manchester.ac.uk/discover/news/new-study-highlights-alzheimers-herpes-link-experts-say/"]University of Manchester material[/link]
[link url="https://content.iospress.com/articles/journal-of-alzheimers-disease/jad180266"]Journal of Alzheimer’s Disease abstract[/link]
[link url="https://link.springer.com/article/10.1007%2Fs13311-018-0611-x"]Neurotherapeutics abstract[/link]

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