More Evidence Herpes Virus Strongly Tied to Alzheimer's

Pauline Anderson

October 19, 2018

Mounting research is helping to cement a proposed link between the herpes virus and Alzheimer's disease (AD).

Dr Ruth Itzhaki

The researcher who got the ball rolling nearly 30 years ago by first uncovering the herpes-AD relationship believes it's time to investigate the use of antivirals in mid-life with the view of preventing AD later on.

Ruth F. Itzhaki, PhD, professor emeritus, University of Manchester, United Kingdom, reviews her own research and that of others that examines the viral concept of AD in an article published online October 19 in Frontiers in Aging Neuroscience.

Causal Link?

Over the past few decades, research has shown that individuals who are infected with herpes simplex virus type 1 (HSV1) are at increased risk for dementia and that use of antiviral drugs decreases this risk.

Results of more recent studies suggest the link is more than a mere association.

"Some very important epidemiological work is being done that suggests that it's not just an association but that it's causal," Itzhaki told Medscape Medical News.

Most of the population is infected with HSV1 by age 70. Researchers believe the virus travels to the brain, where it remains in a latent state. Reactivation occurs intermittently, caused by events such as immunosuppression, peripheral infection, and inflammation.

Data suggest that HSV1 may cause amyloid beta plaques, and Itzhaki and others have shown that abnormal tau protein accumulates in HSV1-infected cell cultures.

In addition, the APOE-ε4 allele appears to boost the risk. HSV1 is present in the brain of APOE-ε4 carriers in approximately about half of dementia cases, said Itzhaki.

She and others estimate that the risk for AD is about 12 times greater for those who have both the virus in the brain and the APOE-ε4 allele than for those who have neither.

"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 development of Alzheimer's," she said.

In her article, Itzhaki reviews three recent "very significant" studies from Taiwan, a country that is unique in that records are available for more than 99% of the population through the National Health Insurance Research Database.

The database is being extensively mined for information on microbial infections and disease, said Itzhaki.

In the Taiwan articles, the word "infection" is used for people who show overt signs of the disease, such as shingles (herpes zoster [HZ]), cold sores (herpes labialis), or genital sores. The term "senile dementia" (SD) is used rather than AD because in some cases, the diagnosis was uncertain.

Two of the studies investigated varicella zoster virus (VZV) infection in relation to long-term neurocognitive changes and development of dementia. VZV causes chickenpox. After acute infection, it remains in the body in latent form, and in some individuals, it reactivates later, causing shingles.

Antivirals Preventive?

The first study included 846 patients (mean age, 62.2 years) who were diagnosed with herpes zoster ophthalmicus (HZO) in 2005 and who developed dementia in the following 5 years.

The patients who developed dementia were compared with an age-matched control group of 2538 persons during the same 5-year period.

Of the patients with HZO, 4.16% developed SD, compared to 1.65% of the control persons (P < .001). The crude hazard ratio (HR) of developing SD within 5 years of HZO diagnosis was 2.97 after adjustment for patient characteristics and comorbidities.

In the second study, 39,205 patients with HZ were followed for an average of 6.2 years. The incidence of dementia was compared with that among 39,205 control persons (mean age of both groups, 63.5 years).

At 1.11, the HR was small. However, for HZ patients who were treated with antivirals, including acyclovir, valacyclovir, tromantadine, and famciclovir, the incidence of dementia was about half that of untreated persons (adjusted HR, 0.55; 95% confidence interval [CI], 0.40 - 0.77; P < .0001).

Itzhaki noted that although antiviral treatment seemed to prevent dementia, the mechanism is unclear. She speculated that such treatment may not prevent the onset of dementia, but it may stop further deterioration, which is still a "very valuable result.

"Even if the effects were merely a delay in onset of the disease, this would still be enormously beneficial for patients, carers, and the economy," she said.

Itzhaki noted that the study did not provide data on the effect of antivirals on those already suffering from dementia.

The third study was the "most striking," said Itzhaki. That study investigated 8362 patients aged 50 years or older who were newly diagnosed with HSV infections. The control group of 25,086 age- and sex-matched persons was not infected with HSV.

The risk of developing SD in the HSV group during a 10-year period was 2.56-fold greater than in the control group (95% CI, 2.351 - 2.795; P < .001).

Itzhaki acknowledged that the results of the Taiwanese studies apply only to severe herpes infections, which are rare.

"Ideally, we would study dementia rates amongst people who have suffered mild HSV1 infection, including cold sores or mild genital herpes, but these are far less likely to be documented," she said.

No Cause and Effect

Commenting on the research for Medscape Medical News, James A. Hendrix, PhD, director of global science initiatives, Alzheimer's Association, pointed out that although the studies demonstrate an association between herpes and AD, they do not show cause and effect.

In the antiviral trial, the worse outcome for those not taking the antiviral could be due to a number of factors, including simply having poorer health overall, said Hendrix.

"We know that people who don't get state-of-the-art healthcare have higher rates of dementia," he said.

He was also concerned that the trials investigated senile dementia, which is not necessarily AD.

Itzhaki said the increasing research she outlined in her article suggests that it might be time to test whether antiviral treatment may prevent cognitive deterioration. Such treatment would be more likely to succeed if it was initiated before middleage, even if the treatment were for only a relatively short period.

In the United Kingdom, the proportion of 30- to 40-year-olds who are HSV1 seropositive is estimated to be at most about 70%, and the proportion of those who are carriers of the APOE-ε4 allele is about 25%. So overall, only about 18% of the persons in that age group would be most at risk and would be most likely to benefit from antiviral treatment, said Itzhaki.

She emphasized that antivirals are "harmless" and are relatively inexpensive. "They are probably less expensive than taking a statin, which a lot of people are taking, at least in the UK," she said.

The types of antiviral used to treat AD should be "carefully chosen," said Itzhaki. The exact stage at which the drug would be most effective and how long it should be used should also be closely calculated, she added.

Treatments would probably be more effective if combined with an anti-inflammatory, she said. The herpes virus, she noted, causes inflammation as well as direct damage.

Itzhaki and her colleagues hope to secure funding to test a "double treatment" of an antiviral and an anti-inflammatory in patients with mild AD to see whether this prevents further deterioration.

She sugggested that clinicians keep a note in the patient record of cold sores and other signs of herpes infection. This would make it easier to track whether they were more likely to develop dementia later on, should they be treated in mid-life with an antiherpes agent.

Not Enough Direct Evidence...Yet

For Hendrix, it's still "way too early" to recommend that adults take antivirals for the primary prevention of AD. "We don't have enough direct evidence to even go there yet," he said.

Vaccination against HSV1 would be ideal to prevent the disease, but unfortunately, there's currently no such vaccine. Developing a vaccine would be expensive and would take years to complete, said Itzhaki.

Although there have now been upwards of 150 studies investigating the link between herpes and dementia, Itzhaki said the accumulating data "have been ignored or dismissed."

She said she and others have been battling for years to draw attention to research linking herpes to AD, to little avail.

This, she said, has been "very unfortunate" for patients who developed the disease. "Surely, now is the time to rectify the situation," she said.

She has two theories as to why this area of research has been all but dismissed.

One is that "people have very entrenched views," and the prevailing view and the focus of research is that beta amyloid and tau cause Alzheimer's.

"We think amyloid is involved; we just don't think it's a cause or primary cause," she said.

Hendrix acknowledged that although the Alzheimer's Association funds "a whole range" of different topics and "doesn't pick the winners and losers," past budget limitations forced it to focus more on "mainstream" areas.

But now that more federal funding has been secured, the association will be able to take a more diverse approach, he said.

And that approach should include the role of viruses. He noted that research on the immune system in AD is "exploding."

"Whether herpes or other viruses are actually having an impact on the immune system is a very important area and probably one of the hottest areas of AD research today," he said.

Compelling Evidence

Hendrix referred to a "very important" article published earlier this year, funded in part by the Alzheimer's Association, in which researchers conducted genetic studies of brain tissue from individuals with AD and found compelling evidence of the presence of herpes.

Another reason Itzhaki believes this area of research has not been taken more seriously is that "very few people in the Alzheimer's field know anything about microbes, particularly virology."

That's changing, too, said Hendrix. The increased dedicated funding that the Alzheimer's Association now has will likely "bring in experts" from this and other fields.

"The situation is changing by the week, month, and year," he said.

Dr Itzhaki and Dr Hendrix have disclosed no relevant financial relationships.

Front Aging Neurosci. Published online October 19, 2018. Full text

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