Herpes and AD

[stanleypj]

I know this has been discussed at least once before on the forums and most people seemed sceptical. I have read with interest about the research by Professor Ruth Itzhaki of Manchester University. My wife who has early onset dementia was previously investigated by someone, a professional, who had a special interest in viruses. Tests showed that she carried both herpes viruses as well as a number of other viruses that can cause nasty problems. Then I became aware that every so often she had a sore which would break out high up on her buttocks and blister. I found out from the internet that this was herpes and my initially sceptical GP eventually took a swab and had it confirmed. I also started to notice that when she had these outbreaks, her dementia symptoms became worse. I then started to look for links between herpes and dementia and found out about the work of Professor Itzhaki. Since that time her research has made a good deal of progress as I found when I recently emailed her and she sent me a document describing her research and where it was up to. The tragic thing is that, despite the fact that her research results have been confirmed by others around the world, she has always struggled, and continues to struggle, for funding and indeed her research is unlikely to continue unless some millionaire appears on the horizon.

This is her 'lay person's' explanation:

Role of a virus in Alzheimer’s disease, and prospects of treatment with antiviral agents

Almost 18 million people worldwide suffer from Alzheimer’s disease (AD) and unfortunately, this figure will rise as longevity increases. The need for effective treatments is therefore extremely urgent. (Current treatments alleviate symptoms but do not prevent further deterioration.) Most AD researchers investigate the disease’s main characteristics – abnormal structures in brain called tangles and plaques which are probably important features of the disease; however, despite the vast amount of information gathered about the structures, the causes of their formation are unknown.
Our research, which has strongly implicated a common virus in the development of the disease, is completely original and offers a direct route to treatment: very effective and safe antiviral agents are available to combat the virus and thus to treat AD patients. It indicates also the future possibility of preventing the disease by vaccination against the virus in infancy.
The virus implicated in AD, herpes simplex virus type 1 (HSV1), is the one that causes cold sores. It infects most humans in infancy and thereafter remains in the body in latent (i.e., dormant) form within the peripheral nervous system (the part of the nervous system other than the brain and spinal cord). From time to time – for example if the person is stressed – the virus becomes activated and in some people it then causes cold sores..
We found that the virus is present also in brain, in many elderly people, that it confers a strong risk of AD when in the brain of people who have a specific genetic factor (APOE-e4), and that it does become activated, perhaps recurrently, in brain. The likelihood of developing AD is 12 times greater for APOE-e4 carriers with HSV1 in brain than for those with neither factor.
Subsequently, we linked HSV1 directly to AD plaques and tangles. We discovered that the viral DNA is located very specifically in plaques. We found also that the main component of plaques, beta amyloid (Aβ), accumulates in HSV1-infected cell cultures and in the brains of infected mice. Taken together, these results suggest that HSV1 is a cause of toxic amyloid products and plaques. We have shown too that the main component of tangles – hyperphosphorylated tau – accumulates in HSV1-infected cell cultures. Studies by other groups have confirmed the HSV1-induced formation of Aβ and abnormal tau. Possibly, infected cells produce Aβ and abnormal tau as part of their “innate” immune system, in an attempt to protect against HSV1, but eventually these molecules are over-produced and then cause damage. Alternatively, cells may produce them because they are needed by HSV1 for its replication (the virus subverts the cell’s machinery to produce, in general, only such proteins).
We propose that HSV1 enters the brain in the elderly as their immune systems decline, establishes a latent infection from which it is repeatedly reactivated by events such as stress, immunosuppression, and brain inflammation induced by systemic infection, and that repeated activation causes cumulative damage* and eventually AD, in APOE-e4 carriers. (Other studies of ours support the concept that genetic factors can determine the severity of a microbial disease in showing that in the case of several diverse microbes, APOE affects outcome of infection. Probably significantly, we found APOE-e4 to be a risk for cold sores.) The mechanism might involve up-regulation of enzymes involved in Aβ formation and, via the known inhibitory effect the virus has on autophagy, prevention of abnormal protein degradation. Aβ might be produced as part of the cell’s defence response, initially entombing the agent and thereby preventing further damage to the host, but eventually, through overproduction, resulting in toxicity via oligomer formation. Infected cells, after suffering severe structural damage, die and disintegrate, releasing amyloid aggregates which develop into plaques after other components of dying cells are deposited on them. Presumably, in APOE-ε4 carriers, AD develops either as a consequence of greater HSV1-induced formation of toxic Aβ products, or as a direct consequence of virus-induced cell death or inflammation.
Our data suggest that antiviral agents might be used for treating AD. Currently available antiviral agents act by targeting replication of HSV1 DNA, and so we considered that they might be successful in treating AD only if the accumulation of Aβ and P-tau caused by HSV1 occurs at or after the stage at which viral DNA replication occurs. *If these proteins are produced independently of HSV1 replication, antivirals might not be effective.* We investigated this and found that treatment of HSV1-infected cells with acyclovir, the most commonly used anti-HSV antiviral agent, and also with two other anti-HSV antivirals, does indeed decrease Aβ and P-tau, as well as decreasing HSV1 replication (as expected).
We conclude that anti-HSV antiviral agents would be suitable for treating AD to reduce disease progression, with the great advantage that unlike current therapies, only the virus, not the host cell, would be targeted. Also, other viral damage besides Aβ and P-tau production that might be involved in AD pathogenesis would be inhibited. Further, ACV is very safe and relatively inexpensive.

*This is supported by a study by a prominent US virologist who has recently found that repeated activation of HSV1 in infected mice over a long period of time causes the formation of lesions in their brains.

Note that this paper is in no way suggesting that all AD is caused in this way (Professor Itzhaki believes the figure may be around 60%) and also that a genetic link is indicated which helps to explain why, if the herpes hypothesis is correct, there are not even more AD suffferers since 90% or so of the population are herpes carriers.

If this is not research that deserves to be funded, I don't know what is!

Please do not contact Professor Itahaki directly. When I suggested that she should seek more media exposure for her work, to try and obtain more funding, she explained that an article in the times led to a massive number of enquiries from all over the world to which she felt obliged to respond.

You might wish, like me, to ask the various dementia organisations why this research is in danger of coming to an and.

[stanleypj]

I'm bumping this as I feel people may be put off by the length if the original post. I'm sorry about that, but I would be surprised if most people would not find it pretty amazing that such promising research is in danger of running out of funding.

[Saffie]

This is a coincidence as my daughter and I have been having a conversation about the link between cold-sores and AD this morning. She suffers from them as did my husband, who has VD/?AD. My mother alssuffered from them and developed AD in her 60s. My grandson also has cold-sores and he also has Downs Syndrome which can also signify that he might suffer from ADin later life. It's not a happy thought for the future of my daughter nor her son.

[stanleypj]

But important to note that the research does not suggest that everyone who carries the herpes virus will end up with AD - far from it. In any case, if the research is continued and the tentative conclusions prove to be correct it appears there might be relatively simple ways of ensuring that, in these cases, AD does not develop.

[tobermory]

Dear stanleypj.
I read with interest your post and was also aware of the Professor's research. My mother has Vascular Dementia, suffers intermittently from cold sores and is extremely dizzy. No specialist can explain why she is so dizzy other than it's vascular related but it does seem this is her major symptom, other than memory, eyesight, spatial awareness and deafness. Few sufferers we have met at her day centres seem to have dizziness as a main problem. I had previously mentioned to the GP/specialists if there was a link with the cold sore virus but was dismissed.

Anyway, last month she had a really bad outbreak of cold sores under her nose and it went up to her eyes as well. She was in a really bad way, extremely dizzy and we managed to see the GP. He put her on 800mg Aciclovir for a month. She is a bit better now but still dizzy. I fear if the cold sore virus and encephalitis are a factor in this her hearing and neurological problems are beyond repair. Who knows? Nobody unfortunately...

Best regards

[lin1]

I find this very interesting, I knew nothing about this research or possible link with these viruses and AD, tho to be honest it doesnt supprise me

Im sad to say neither does it supprise me about the lack of funding for such research

Perhaps those of us who are able need to jump on the bandwaggon and make our wishes be known that such research needs proper funding, perhaps we could start by contacting the Alzheimers Society , then our mp's

my thoughts are, if such viruses get to the brain then maybe by some action its possible for them to to cause AD or other types of dementia, Im no doc so Im not expressing myself properly, I hope you understand what im trying to say

My mum had mixed dementia AD/VD
since her childhood suffered coldsores often all round her mouth and up her nose

I now have concerns over my dad
and he has had quite bad coldsores since childhood
and shingles once

[lin1]

Ive been browsing and found this
http://en.wikipedia.org/wiki/Herpes_simplex_virus

connections with the virus and AD is about three quarters of the way down the page

and this one
http://www.ncbi.nlm.nih.gov/pubmed/18982063

[stanleypj]

Thanks for these responses. I'm particularly interested in the links lin1 sent. I'd looked at the Wiki page before but failed to note that the link was first suspected in the seventies! It amazes that so little progress has been made.

As a matter of interest, my wife has been having a 'prevention dose' of Aciclovir (an anti-viral) for about 3 months now. During that time we have seen a number of improvements and she has been significantly calmer.

It seems to me that anyone who cares for an AD sufferer who has a history of herpes outbreaks might ask their GP about this kind of approach. Aciclovir seems to be a relatively safe drug.

Phil

[tobermory]

That's interesting about your wife and Aciclovir. I will ask the GP if the course can be continued. Mum's only been taking it a week so far.

[stanleypj]

I'd be interested to hear if your mum's still on Aciclovir and if so whether you have seen any improvements - e.g. calmer? more aware?

My wife is still on it and her improvements have been maintained (though I know there are other things that could have helped with this). Now the doc (who's very supportive) is making it clear that he can only really prescribe it to stop or reduce 'outbreaks' and I'm guessing he won't be able to continue it indefinitely.

I can say if she'd been on Aricept or Memantine during this time I'd be thinling what effective drugs they are.

[stanleypj]

I thought it worth reporting that a year after taking a suppression dose of acyclovir every day my wife's condition remains stable. She is a lot calmer than she was before she started the acyclovir and there has been no worsening of her symptoms.

Everybody who sees her, including the rare professional, has commented on the improvement.

It also interests me that by far the most popular pages on my blog are those which mention herpes.

[Sue J]

Thank you for this stanleypj, it is very relevant to me but I cannot communicate properly at the moment - but am very interested in the low suppression dose - is it one dose a day of 500mg?

[tre]

My mum who had vascular dementia suffered a severe bout of shingles in her mid sixties. My friend's mum who also had a severe bout of shingles ( herpes virus) died aged 92 with no dementia. It would be interesting to know their APOE-04 status.

My husband has PCA which is currently classified as a rare form of AD. However, interestingly for PCA you are more likely to not have APOE-04 which is the reverse of "standard" AD. I know some work has been carried out on this in relation to PCA.

Many illnesses/ conditions are more prevalent for certain tissue types. My dad has rheumatoid arthritis. When I was doing my degree some of us had the chance to be tissue typed but I avoided it as I did not think it would help me to know if I had the right tissue type to develop this as I felt I would think every twinge was the beginning. Even having the vulnerable tissue type did not inevitably result in the disease- you had to meet some other unknown triggering factor but even back then it was thought likely that this may be some type of viral infection so I do not find the possible link with herpes and AD surprising.

I still do not know whether I had the risky tissue type and did not meet the trigger or I have a safer ( for rheumatoid arthritis) tissue type.

If there had been any preventative treatment for those with the vulnerable tissue type I would have found out like a shot but when there is nothing it just feels like another worry.

I am glad to hear for your wife at least that the antiviral medication is proving beneficial

Tre

[stanleypj]

Thank you for this stanleypj, it is very relevant to me but I cannot communicate properly at the moment - but am very interested in the low suppression dose - is it one dose a day of 500mg?

Hi Sue,

The patient information leaflet says 200mg 4 times a day at 6 hourly intervals - not very practicable! We use 200mg 3 times during waking hours. There is some logic in spacing it out as far as possible as it doesn't stay in the body very long apparently. You can also use valacyclovir which is a 'prodrug' that changes inside the body and is supposedly more effective. I've not asked for that as it is more likely to produce side-effects - my wife often has problems with drug side-effects.

Take care

[Sue J]

Hi Sue,

The patient information leaflet says 200mg 4 times a day at 6 hourly intervals - not very practicable! We use 200mg 3 times during waking hours. There is some logic in spacing it out as far as possible as it doesn't stay in the body very long apparently. You can also use valacyclovir which is a 'prodrug' that changes inside the body and is supposedly more effective. I've not asked for that as it is more likely to produce side-effects - my wife often has problems with drug side-effects.

Take care

Thank you, I misunderstood I thought you meant a single dose daily. I had a 5 day course of 200mg x 5 a day for 5 days earlier in the year which helped my very severe prolonged symptoms, surprisingly I managed to take them very regularly - I appreciate it is important but challenging when you're on your own - I too have very bad side effects. I'm pleased your wife seems to have responded well to it.