What causes Alzheimer’s disease?
The answer could be right under our noses, says leading expert Professor Ruth Itzhaki.
Her latest paper presents a lifetime of research evidence that the herpes virus responsible for cold sores can also cause Alzheimer’s – and new data which show antiviral drugs drastically reduce the risk of senile dementia in patients with severe herpes infections.
The review in Frontiers in Aging Neuroscience raises the tantalizing prospect of a simple, effective preventive treatment for one of humanity’s costliest disorders.
The HSV1 theory of Alzheimer’s disease
- The herpes simplex virus, or herpes, is categorized into 2 types: herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2).
- HSV-1 is mainly transmitted by oral-to-oral contact to cause oral herpes (which can include symptoms known as “cold sores”), but can also cause genital herpes.
- HSV-2 is a sexually transmitted infection that causes genital herpes.
- Both HSV-1 and HSV-2 infections are lifelong.
- An estimated 3.7 billion people under age 50 (67%) have HSV-1 infection globally.
- An estimated 417 million people aged 15-49 (11%) worldwide have HSV-2 infection.
- Most oral and genital herpes infections are asymptomatic.
- Symptoms of herpes include painful blisters or ulcers at the site of infection.
- Herpes infections are most contagious when symptoms are present but can still be transmitted to others in the absence of symptoms.
- Infection with HSV-2 increases the risk of acquiring and transmitting HIV infection.
Infection with the herpes simplex virus, commonly known as herpes, can be due to either herpes simplex virus type 1 (HSV-1) or herpes simplex virus type 2 (HSV-2). HSV-1 is mainly transmitted by oral to oral contact to cause infection in or around the mouth (oral herpes). HSV-2 is almost exclusively sexually transmitted, causing infection in the genital or anal area (genital herpes). However, HSV-1 can also be transmitted to the genital area through oral-genital contact to cause genital herpes.
Both oral herpes infections and genital herpes infections are mostly asymptomatic but can cause mild symptoms or painful blisters or ulcers at the site of infection.
Herpes simplex virus type 1 (HSV-1)
HSV-1 is a highly contagious infection, which is common and endemic throughout the world. Most HSV-1 infections are acquired during childhood, and infection is lifelong. The vast majority of HSV-1 infections are oral herpes (infections in or around the mouth, sometimes called orolabial, oral-labial or oral-facial herpes), but a proportion of HSV-1 infections are genital herpes (infections in the genital or anal area).
Scope of the problem
In 2012, an estimated 3.7 billion people under the age of 50, or 67% of the population, had HSV-1 infection. Estimated prevalence of the infection was highest in Africa (87%) and lowest in the Americas (40-50%).
With respect to genital HSV-1 infection, 140 million people aged 15-49-years were estimated to have genital HSV-1 infection worldwide in 2012, but prevalence varied substantially by region.
Most genital HSV-1 infections are estimated to occur in the Americas, Europe and Western Pacific, where HSV-1 continues to be acquired well into adulthood. In other regions, for example in Africa, most HSV-1 infections are acquired in childhood, before the age of sexual debut.
Signs and symptoms
Oral herpes infection is mostly asymptomatic, and the majority of people with HSV-1 infection are unaware they are infected. Symptoms of oral herpes include painful blisters or open sores called ulcers in or around the mouth.
Sores on the lips are commonly referred to as “cold sores.” Infected persons will often experience a tingling, itching or burning sensation around their mouth, before the appearance of sores.
After initial infection, the blisters or ulcers can periodically recur. The frequency of recurrences varies from person to person.
Genital herpes caused by HSV-1 can be asymptomatic or can have mild symptoms that go unrecognized. When symptoms do occur, genital herpes is characterised by 1 or more genital or anal blisters or ulcers. After an initial genital herpes episode, which may be severe, symptoms may recur, but genital herpes caused by HSV-1 often does not recur frequently.
HSV-1 is mainly transmitted by oral-to-oral contact to cause oral herpes infection, via contact with the HSV-1 virus in sores, saliva, and surfaces in or around the mouth. However, HSV-1 can also be transmitted to the genital area through oral-genital contact to cause genital herpes.
HSV-1 can be transmitted from oral or skin surfaces that appear normal and when there are no symptoms present. However, the greatest risk of transmission is when there are active sores.
Individuals who already have HSV-1 oral herpes infection are unlikely to be subsequently infected with HSV-1 in the genital area.
In rare circumstances, HSV-1 infection can be transmitted from a mother with genital HSV-1 infection to her infant during delivery.
In immunocompromised people, such as those with advanced HIV infection, HSV-1 can have more severe symptoms and more frequent recurrences. Rarely, HSV-1 infection can also lead to more severe complications such as encephalitis or keratitis (eye infection).
Neonatal herpes can occur when an infant is exposed to HSV in the genital tract during delivery. This is a rare condition, occurring in an estimated 10 out of every 100,000 births globally, but can lead to lasting neurologic disability or death. The risk for neonatal herpes is greatest when a mother acquires HSV infection for the first time in late pregnancy. Women who have genital herpes before they become pregnant are at very low risk of transmitting HSV to their infants.
Recurrent symptoms of oral herpes may be uncomfortable and can lead to some social stigma and psychological distress. With genital herpes, these factors can have an important impact on quality of life and sexual relationships. However, in time, most people with either kind of herpes adjust to living with the infection.
Antiviral medications, such as acyclovir, famciclovir, and valacyclovir, are the most effective medications available for people infected with HSV. These can help to reduce the severity and frequency of symptoms, but cannot cure the infection.
HSV-1 is most contagious during an outbreak of symptomatic oral herpes, but can also be transmitted when no symptoms are felt or visible.
People with active symptoms of oral herpes should avoid oral contact with others and sharing objects that have contact with saliva.
They should also abstain from oral sex, to avoid transmitting herpes to the genitals of a sexual partner. Individuals with symptoms of genital herpes should abstain from sexual activity whilst experiencing any of the symptoms.
People who already have HSV-1 infection are not at risk of getting it again, but they are still at risk of acquiring herpes simplex virus type 2 (HSV-2) genital infection (see below).
The consistent and correct use of condoms can help to prevent the spread of genital herpes. However, condoms can only reduce the risk of infection, as outbreaks of genital herpes can occur in areas not covered by a condom.
Pregnant women with symptoms of genital herpes should inform their health care providers. Preventing acquisition of a new genital herpes infection is particularly important for women in late pregnancy, as this is when the risk for neonatal herpes is greatest.
Additional research is underway to develop more effective prevention methods against HSV infection, such as vaccines.
Several candidate HSV vaccines are currently being studied.
Herpes viruses are the dreaded ‘gift that keeps on giving’.
They remain lifelong in our neurons and immune cells, reactivating and resurfacing in characteristic blisters when we’re run down by stress or illness.
Most people are infected by Herpes Simplex Virus 1 (HSV1) by the time they reach old age.
But what happens to infected neurons in our brain during this reactivation?
“HSV1 could account for 50% or more of Alzheimer’s disease cases,” says Professor Itzhaki, who has spent over 25 years at the University of Manchester investigating a potential link.
HSV1 is better known as the cause of cold sores.
Itzhaki has shown previously that cold sores occur more frequently in carriers of APOE-ε4 – a gene variant that confers an increased risk of Alzheimer’s.
“Our theory is that in APOE-ε4 carriers, reactivation is more frequent or more harmful in HSV1-infected brain cells, which as a result accumulate damage that culminates in the development of Alzheimer’s.”
Proving the theory
Few countries collect the population data required to test this theory – for example, to find out whether antiviral treatments reduce dementia risk.
In Taiwan however, researchers have done just that.
There, 99.9% of the population is enrolled in a National Health Insurance Research Database, which is being extensively mined for information on microbial infections and disease.
In 2017-2018 three studies were published describing Taiwanese data on the development of senile dementia – of which Alzheimer’s is the main cause – and the treatment of patients with marked overt signs of infection with HSV or varicella-zoster virus (VZV, the chickenpox virus).
“The striking results include evidence that the risk of senile dementia is much greater in those who are infected with HSV, and that anti-herpes antiviral treatment causes a dramatic decrease in the number of those subjects severely affected by HSV1 who later develop dementia.”
Previous findings from Itzhaki’s own research group provide a mechanistic link which supports these epidemiological findings.
They found that HSV1 causes protein deposits characteristic of Alzheimer’s: ‘plaques’ between neurons, and ‘tangles’ inside of them.
HSV1 could account for 50% or more of Alzheimer’s disease cases, according to Professor Itzhaki’s research. The image is adapted from the Frontiers news release.
“Viral DNA is located very specifically within plaques in postmortem brain tissue from Alzheimer’s sufferers. The main proteins of both plaques and tangles accumulate also in HSV1-infected cell cultures – and antiviral drugs can prevent this.”
Towards a cure
“It should be stressed that the results of these Taiwanese studies apply only to severe HSV1 (or VZV) infections, which are rare,” admits Itzhaki. “Ideally, we would study dementia rates amongst people who have suffered mild HSV1 infection, including herpes labialis (cold sores) or mild genital herpes, but these are far less likely to be documented.”
Although further work is needed to confirm and define a causal link between HSV1 infection and Alzheimer’s, Itzhaki is enthusiastic about the treatment prospects.
“Considering that over 150 publications strongly support an HSV1 role in Alzheimer’s, these Taiwan findings greatly justify usage of antiherpes antivirals – which are safe and well-tolerated – to treat Alzheimer’s disease.
“They also incentivize development of an HSV1 vaccine, which would likely be the most effective treatment.”
This echoes the growing use worldwide of human papillomavirus (HPV) vaccination to prevent cervical cancer – another virus-disease link which emerged in a similar process of research.
Matthew Prior – Frontiers
The image is adapted from the Frontiers news release.
Original Research: Open access
“Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer’s Disease” Ruth F. Itzhaki. Frontiers in Aging Neuroscience doi:10.3389/fnagi.2018.00324