Does Herpes Cause Alzheimer's Disease?

In June, 2018 we posted about a possible connection between the herpes virus and Alzheimer's disease.  (In February 2019 we posted about a bacterium that might also be implicated.)  As we noted on January 15 of this year, 2019 saw new interest in the possible role of the herpes virus in the etiology of Alzheimer's disease. 

So what are we to make of the role of pathogens in general and herpes in particular in what sparks Alzheimer's disease and what then drives its development?

The answer is that it depends on who you ask.  This week's ALZForum carried an interesting article that attempted to assess where we're at with this question: "Herpes Viruses and Alzheimer's -- the Debate Continues."  As we noted in the June 2018 article, the herpes virus can be found in the brains of people who died of Alzheimer's dementia, suggesting that it was part of the etiology -- although it noted that our brains begin accumulating viruses of many types from when we were children.  But the new article points out that there are different ways of assessing the presence of viruses in an autopsy, and the different ways yield different conclusions.

A problem with the story that's been evolving since the important research in 2018 is that it's not clear that there are more herpes viruses in the brain of a person who died with Alzheimer's dementia than in that of a normal person.  Some studies say there is, but other credible studies (using a different methodology) find that there isn't.  On the other hand, there seems to be a consensus that viruses may well play a role in the development of Alzheimer's disease.

It's not so much about finding the viruses are still active, but rather finding the damage they caused. 

Gene regulatory networks are systems that control how genes are expressed in proteins.  (As a consequence, they control, for example, whether you are a human or a reptile.)  Damaging them won't cause you to turn into a lizard, but damage in a gene regulatory network may cause a gene to express in a manner that promotes Alzheimer's disease.  And damaged networks may focus their influence on the genes we have learned to associate with risk for Alzheimer's disease.

The evidence for a connection between herpes and Alzheimer's disease is strong, based on data used in the study we discussed in June 2018.  Remember that Alzheimer's disease begins years, maybe decades before the first symptoms appear.  So, while there may not be evidence of an unusual presence of herpes at death, it may have been much stronger long ago.  The virus could have done its damage to the gene networks then, and the consequences were realized much later. 

Herpes causes Alzheimer's ... or does it?

It was almost exactly one year ago we posted on the unfolding story of the relationship between Alzheimer's disease and the herpes simplex virus.  What we said then was that the research results have been conflicting.  A year later, more research has been done, but little has changed.  Research results have still been conflicting.

According to an article this week in ALZForum, some new research in European health databases found correlations between herpes infection and Alzheimer's disease in some countries, but much less so in others.  There were also conflicting results regarding anti-viral treatments and their influence on Alzheimer's disease.  In some cases it looked like treating with certain drugs actually helped, but in other places it did not.  And then, is it herpes, or any virus -- like, for example, covid-19?

The manifestation of a herpes infection most easily followed is herpes zoster, or shingles.  Shingles is usually considered to be a late appearance of the virus following its first appearance as a childhood chicken pox infection.  But there was evidence in the research of elevated incidence of Alzheimer's disease from most any virus, not just herpes.  And then, what about bacterial infection?  They found evidence that hospitalization for any infection increased the probability of Alzheimer's disease by a factor of 1.6.  (Correlation is not causation...)

Have there been previous studies of national health databases looking for correlations?  A few years ago, three studies of the Taiwanese national healthcare database found that a severe herpes infection raised the risk of Alzheimer's disease by a factor of 2.5 to 3 times.  Consistent -- and inconsistent -- with the results of the European study, treatment with the drugs acyclovir and valacyclovir dramatically diminished the odds of getting dementia in these situations.

Of course, some to the inconsistencies may be consequences of inconsistencies in research methodologies.

This seems to be a topic of heated discussion.  To resolve the matter, several incentives have been offered.  Most notably, anyone “who provides persuasive evidence that an infectious agent is the root cause of Alzheimer's disease,” will be awarded a $1 million prize by Leslie Norins at ALZgerm.org.   

A Eureka Moment

Yesterday we discussed research at Tufts and Oxford universities that found evidence for a mechanism by which two types of herpes viruses may work together to cause Alzheimer's disease.  Most of our eggs have been in the amyloid research basket, but the amyloid scandal suggests we should be looking harder for causes in other places.  

I sometimes think of Alzheimer's disease as a wound spring waiting to be released.  And so the risk factors set up conditions where the spring can be released.  But what could actually cut it loose?  Pathogens is a good place to start, especially with the two herpes viruses studied in the research.

Yesterday, we also said that I continue to wonder why I developed Alzheimer's disease, when I don't have any of the conventionally identified risk factors.  (Except that I lived a very sedentary lifestyle, and my diet wasn't very good.)  But the question now occurs to me -- could it have been herpes?

As we discussed in Beating the Dementia Monster, the disease begins about 15 years before the first symptoms appear.  And according to the recent research on herpes, episodes of shingles can cut the disease loose, triggering the generation of the characteristic amyloid plaques and tau tangles.  Herpes simplex is resident in the brains of many people, and it is activated during episodes of shingles caused by herpes zoster.  Herpes zoster may be acquired by a childhood chickenpox infection, but the virus then waits in the brain to later cause shingles.  

Maybe that's what happened to me.  I had chickenpox when I was five and then had shingles three time beginning when I was in my early 30s.  But when was my last episode of shingles?  If my disease started then, does it fit the 15 year timeline we described?

So this morning I started shuffling through my old medical records and found when I last had shingles.  It was 2003, 12 years before my first symptoms of Alzheimer's disease.  I'm thinking that's pretty darn close to the 15 years they talk about, and maybe that's the answer to my riddle.  So, eureka.

Herpes continues to interest research

A few weeks ago we wrote about an assessment of thinking on the role of the herpes simplex virus in Alzheimer's disease.  (We have actually been writing about this for some time.)  We noted that the connection is controversial, and it sparks emotional discussion among researchers.  Well, there's some new fuel for the fire coming from Sweden.  

The February 14 issue of the journal Alzheimer's & Dementia (the Journal of the Alzheimer's Association) carried the results of a study of about 265,000 subjects, age 50 and above, who were either diagnosed with either of two herpes simplex infections and/or were otherwise prescribed certain antiviral drugs targeting herpes simplex.  In older adults, herpes simplex is commonly associated with ailments such as cold sores and shingles infection.  The researchers were looking for a link between antiviral treatment and the incidence of Alzheimer's disease, hoping to show that these treatments would have a protective effect.  Of course, the assumption going in was that herpes does have agency in the development of Alzheimer's disease, although not everyone fully embraces this.

Data about the subjects were derived from two Swedish nationwide databases: the National Patient Register and the Swedish Prescribed Drug Register.  Data collected was from 2005 to 2017.  Subjects who had received antiviral treatment had generally received acyclovir or valacyclovir.

The results? "Our findings together with previous reports suggest that antiviral treatment might reduce long‐term risk of dementia. In contrast, untreated herpes infection increases the subsequent dementia risk."  Of course, they called for further study.

Associating Herpes with Alzheimer's Disease

We have written several times in the past about a correlation between herpes infection and Alzheimer's disease.  Correlation is not causation, and no causal relationship has been found.  Nevertheless, the correlation is intriguing.  

A couple of points, most of which we've made before:

• The implicated version of the virus is the Herpes Simplex Type 1, or HSV1.  It's known for causing cold sores.
• Most people contract the virus at some point in their lives, and it often finds a hiding place in the brain.  
• People carrying the APOE4 gene are most likely to show a correlation between a viral infection and Alzheimer's disease in their autopsies.
• There is interest in the possibility that controlling the herpes virus might control at least some forms of Alzheimer's disease.

So will fighting the herpes virus fight Alzheimer's disease?  According to a nationwide study out of Taiwan, the answer is yes.  This was reported in an April 2018 article in the journal Neurotherapeutics.  The study enrolled 33,448 subjects, 8,362 of whom were newly diagnosed with herpes infections.  The infected subjects were treated with antiherpetic medications.  The study concluded, "The usage of anti-herpetic medications in the treatment of herpes simplex virus infections was associated with a decreased risk of dementia."  The risk of dementia was reduced by a factor of 10.

The correlation with the APOE4 gene variant is significant, because it is a factor in many, but certainly not all cases of Alzheimer's disease.  Therefore, treating or preventing HSV1 infection might influence a substantial portion of Alzheimer's cases, but certainly not all.

If not amyloid, let's take another look at the herpes virus

One of the tragedies of the ongoing amyloid scandal is that pursuing the possibly flawed amyloid hypothesis for Alzheimer's disease may have distracted us from other pathways to effective treatments.  One of those pathways might be through the herpes virus and its suspected role in the development of the disease.  

Back in June 2018 and January 2020 we wrote about evidence that the herpes virus may be among several pathogens that spark the development of Alzheimer's disease.  Some studies found more herpes viruses in the brains of people dying of Alzheimer's disease, but this was not confirmed in other studies.  Nevertheless, there has been a longstanding association between herpes infections and the development of the disease, although how this occurs has not been clear.  But maybe there has been a breakthrough.

A recent study at Tufts University and the University of Oxford  developed an hypothesis about how this happens, and it involves two different versions of the herpes virus, herpes simplex (HSV-1) and varicella zoster (VCV).  HSV-1 is known to cause cold sores around the mouth, while VCV first causes chicken pox and later shingles.  Perhaps you're familiar with these.

As we noted in our earlier posts, after an infection, HSV-1 can take up residence in brain cells and remain innocuously dormant there for a long time.  Until VCV shows up. 

Both viruses attack nerve cells and cause inflammation.  If, like me, you've had shingles, you know that it produces a rash-like appearance of tiny red dots on your skin.  Those red dots are the inflamed ends of nerves reaching from the brain to the surface of the skin.  That's why shingles is so painful.  It also indicates that there is inflammation in the brain, and brain inflammation is an important factor in the development and progress of Alzheimer's disease.

What the researchers found was that an infection with VCV may somehow "activate" the HSV-1, causing it to promote inflammation and the development of the amyloid plaques and tau tangles that define Alzheimer's disease.  

But there may be ways of activating HSV-1 other than by VCV.  In Beating the Dementia Monster, we discussed an association between the development of Alzheimer's disease and factors like head trauma, alcohol consumption, and obesity.  The authors of the study suggested that these could promote the disease by activating the HSV-1 virus on their own, since HSV-1 is already resident in the brains of most of us.

So, how about stopping the VCV from activating HSV-1?  The authors of the study say you should get your shingles shot!  There is already an association established between people who get the shingles shot and a reduced risk of Alzheimer's disease, something I didn't know before reading this study.

I have wondered before why I developed Alzheimer's disease, when I don't have any of the commonly associated risk factors, such as the APOE4 gene.  Maybe this is the answer.  I had a serious case of shingles when I was in my early 30s, but I experienced two more episodes in the following decades.  To the best of my recollection, the most recent episode was about 15 years before my diagnosis in 2015.  As we discussed in Beating the Dementia Monster, the disease is thought to begin about 15 years before the appearance of the first symptoms.  So maybe that's the answer I've been looking for to my question, "Why me?"  

(I'm not whining when I say, "Why me?"  The years since my diagnosis have been some of the richest years of my life.)

Viruses and Alzheimer's disease

This week's ALZForums newsletter highlighted an article connecting the herpes virus with AD.  The article reflects the results of a four-year "big data" study of available  information regarding what goes wrong in brains suffering AD.  It found evidence linking viral load (notably herpes) to the molecular, pathological, and clinical manifestations of dementia.  There was a connection between how many herpes viruses were present in the brain with the brain's dementia status.

But, the researchers who made this connection could not determine cause and effect.  Are the viruses driving the disease, or are they opportunistic, taking advantage of the weakened condition of the already diseased brain? 

A couple of points in the article:

• An association between AD and some viruses, especially herpes, has long been recognized.
• The different herpes viruses cause a variety of problems with the nervous system.
• The viruses may be driving the production of amyloid.
• People begin to accumulate these viruses at a young age, but they may only be activated at the time AD pathology begins.  Most people have them hiding in their brains.      

Is it about the Christmas colors? Green tea and red wine continue to attract attention of research.

If you read Beating the Dementia Monster, you know that red wine is considered part of the MIND diet, a diet that appears to be effective in supporting brain health.  As I mentioned in the book, I don't drink, and so I don't turn to red wine as part of my own diet.  (I make an exception for celebration of the Eucharist.)  Red wine contains resveratrol, the chemical component thought to be helping the brain.  Unfortunately, research has not found that extracting the resveratrol and taking it as a supplement will help with brain health.  At least not until recently.

Green tea has also attracted interest for brain health, and I have taken it at times.  However, it has caffeine, and the caffeine and acids in the tea get to be a problem with my insomnia and nocturia.

Recently, my friend Teale sent me this article in Neuroscience News about some research at Tufts University on green tea and resveratrol.  The researchers claim to have found green tea catechins and resveratrol may reduce the formation of amyloid plaques in neural cells.  

What did the resveratrol and the catechins do?  The researchers believe that they acted as antiviral agents against the herpes virus.  As we discussed in Beating the Dementia Monster, the herpes virus is high on the list of suspects for causes of Alzheimer's disease.  Researchers at Tufts have done other work tying herpes to Alzheimer's disease.

But don't get your hopes up too high.  This was not research done in humans or even in brains.  It was done in the laboratory with cells on a sponge simulating a brain.  And lot of work has been done already simply seeing what happens when people consume more resveratrol and green tea.  The benefits have been marginal.  The real value of the research seems to be to support the hypothesis that the herpes virus--the variety that causes cold sores and chickenpox--also causes Alzheimer's disease. 

Shingles Is Still Causing Dementia

We've written before in this blog ... and in Beating the Dementia Monster ... that there is a correlation between episodes of shingles with the development of dementia.  Shingles is caused by the herpes zoster virus which also causes chicken pox.  In fact, shingles is probably caused by the herpes zoster virus living in the body after a childhood chicken pox infection.

This topic is interesting to me because I don't have many risk factors for Alzheimer's disease.  But I did have shingles several times over the years; at least three times.  So maybe that explains my disease.

There was a new study published in August in the journal Alzheimer's Research and Therapy.  It reported on research with almost 150,000 subjects in three large cohorts of medical professionals.  Researchers followed them over decades, beginning as long ago as 1976.  Consistent with other research, they found a correlation between shingles events and the onset of dementia.  Surprisingly (to me, at least) they found that, in the context of shingles infections, carrying the APOE ε4 gene variant affected men much more than women.  (The ε4 variant of the APOE gene is what 23andMe tests for when predicting your risk of developing Alzheimer's disease.  It's the strongest genetic risk factor for Alzheimer's disease, although there are many others.)

But how much did shingles infection affect risk of dementia?  With such a large sample size and such a long period of time, we should see some reliable answers to this question.  So what did they find?

The researchers found that a history of shingles infection raised the risk of dementia by about 20%.  That's actually kind of a lot when you think about it.  

They further wrote, "Findings from these three large independent cohorts of women and men suggest herpes zoster was associated with a higher long-term risk of subjective cognitive decline. The risk may be greater for the APOE ε4 allele carriers among men, but not among women. The relation did not differ among those with potentially immunocompromising conditions. The magnitude of the elevated long-term risk of [subjective cognitive decline] may potentially be reduced by [shingles] vaccination, but further study is needed."

Note that, loosely defined, "subjective cognitive decline" is cognitive decline concerning enough to the patient to cause him or her to seek medical advice.  Statistically, these people are more likely to be diagnosed with actual Alzheimer's disease.

A new virus linked to Alzheimer's disease - this one in your gut

We've written before about the herpes zoster virus as a potential culprit in the development of Alzheimer's disease -- the virus that causes chickenpox and shingles.  So we quoted some authorities who concluded from their research that the shingles vaccine may provide some protection from Alzheimer's disease originating from that source.  But now there's another virus under the Alzheimer's microscope, another member of the herpes family.  But, while herpes zoster inhabits the nervous system, this one lives in your gut.

The virus is called cytomegalovirus, or HCMV.  You may acquire it as a child and experience an apparently innocuous chronic infection in your gut.  Based on autopsy results, about 80% of us show evidence of having had an HCMV infection by age 80.  So it's pretty common. 

But the trouble starts when the virus either escapes the gut into the blood stream or follows the vagus nerve to the brain.  There it comes into contact with the brain's immune cells -- microglia.  In Beating the Dementia Monster we discussed the role that microglia may play in the development of the disease, notably by way of inflammation.  This somehow triggers the syndrome of amyloid plaques and clumps of microtubules with a defective form of tau protein that we associate with Alzheimer's disease. 

I choose my words carefully here.  It's increasingly clear that what we call Alzheimer's disease comes in different flavors which have different causes.  For example (as we explained in Beating the Dementia Monster), "young onset Alzheimer's disease" or "familial Alzheimer's disease" (which often strikes in someone's 40s or 50s) occurs in a different genetic environment from "sporadic Alzheimer's disease."  The latter is the common version, where symptoms begin to appear after the age of 65.  Are familial and sporadic Alzheimer's diseases exactly the same disease but with different causes, or are they distinct but slightly different diseases?  How many forms of the disease are there?  Or how many different disease are there that we label "Alzheimer's disease?"  Opinions vary.

There was a new study conducted by researchers from Arizona State University and Banner Alzheimer’s Institute on the possible role of HCMV in the development of Alzheimer's disease.  The findings were just published (December 2024) in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, with the title, "Alzheimer's disease-associated CD83(+) microglia are linked with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagal nerve, and brain."  The researchers concluded "[HCMV-microglia biochemistry] is consistent with an active HCMV infection, which may indicate an opportunity for the administration of antiviral therapy in subjects with AD."  Translation: "Stopping or preventing HCMV infections may be a way preventing or treating Alzheimer's disease."  But ... more research is required. 

Click here for more of a deep-dive on this topic.

We said here that there may be different varieties of Alzheimer's disease or even different diseases all labeled "Alzheimer's."  But, from everything I've read, they all respond to the lifestyle tools of the Dementia Toolkit.

In the News X2 (#1)

I saw two recent news articles on Alzheimer's disease and dementia research that I found interesting, and I want to discuss them both.  I'll put them in two different posts.

The AP just published an article on the state of Alzheimer's research that echoed what we have been saying here.  The article was entitled "Scientists rethink Alzheimer’s, diversifying the drug search," and it had some interesting photographs of whole and dissected human brains -- if you're into that sort of thing.  The theme was that the search for a silver bullet pharmaceutical intervention appears to have failed, and a drug approach will need to address a variety of causes of memory loss.

The article cheers the success medical science has had in removing amyloid plaques from brains, but then laments that this has not improved cognition or stopped the progress of the disease.  As we have noted previously, autopsies of people who died of Alzheimer's disease very often exhibit evidence of other causes as well, causes such as Lewy bodies and vascular disease.  This is called mixed dementia, and it is more common than has been appreciated.  Therefore, attacking memory loss must simultaneously attack Alzheimer's disease and the other causes of dementia.

The article went on to discuss other areas where our knowledge of the disease is weak.  We know that herpes virus is often found in the brains of people who died from Alzheimer's disease, so the article discusses a possible link to herpes infection.  (We discussed this in June 2018.)  They also discuss the potential role of gum disease as a player in the etiology of AD -- as we did back in February.  These, of course, raises the possibility of a vaccine for Alzheimer's disease.  So you read it here first.

The article discussed the key role of inflammation in the progress of the disease.  It discussed the role of microglia cells, since they are the brain's immune system.  They attack foreign invader in the brain (and they may perceive amyloid as such an invader), and this immune response includes inflammation.  As with other inflammation responses in the body, the inflammation begins by destroying the enemy but then begins to do a lot of collateral damage to the tissue it is trying to protect.

I was disappointed that the article did not mention lifestyle interventions -- the only way that Alzheimer's sufferer's are currently being helped.  The theme of the article was progress with drug interventions (or lack thereof), but lifestyle intervention research has something to say to drug research.  As several articles have pointed out, understanding why lifestyle changes affect the progress of Alzheimer's disease provides a window into how the disease works and what drug interventions might eventually work.  The Scientific American article we reviewed last October suggested that a drug intervention should attempt to recreate in the brain the conditions that exist during physical exercise.

Alzheimer's disease and covid

Throughout the day on Tuesday of this week, I felt a little off.  By evening, I was feeling a little feverish.  My temperature came in at 99, when it's usually about 97.  So many people I know have been coming down with covid, that I wondered if that was what was going on.  About a month ago I became very ill with all the symptoms of covid, but I tested negative.  The doctor said he believed it was strep.  I did recover from that illness and felt well until this week.

Wednesday morning I had a temperature of 100 and was experiencing more "flu-like symptoms."  So I tested for covid again, and this time it came back positive.  I spoke with a friend who had been with me on Sunday, and he said that he was having the same experience. Toward evening, I felt better, and most of the symptoms calmed down by bed time.  I slept unusually well.  In the morning (today) my temperature was normal, and I felt nothing unusual.  But as the day has worn on, the flu-like symptoms have been returning.  Will I continue to worsen, or will the whole thing dissipate in another day or two?  Who knows.

My son points out that the coronavirus has significant neurologic effects, famously loss of taste and smell.  These have not been serious with me so far, but my lunch today tasted differently than in the past.  So maybe those are catching up with me.  But more worrying are reports of "brain fog."  And recently, more attention has focused on hearing loss and balance.  (Remember that hearing loss aggravates social isolation which aggravates Alzheimer's disease.)  Readers of this blog know that balance is at the top of my list of neurologic concerns.  My balance was unusually bad all day Wednesday, but seems to have returned to how it was before the infection.  So far, anyway.

There is a lot of worry about covid-19 and dementia.  We knew early on that the coronavirus caused unusual inflammation in the brain, a condition that could cause and will certainly aggravate Alzheimer's disease.  But recent research finds that the virus has a whole host of ways in which it causes or supports Alzheimer's disease.  This includes lockdowns that force people into social isolation, a major factor in the development of dementia.  In Beating the Dementia Monster, we discussed the likely role of the herpes virus in the development of Alzheimer's disease, and the coronavirus appears to provide a new pathway for the herpes virus in the brain.  But there are other factors.  This article from the journal, Translational Neurodegeneration surveys both the physiological and societal consequences of covid-19 with respect to Alzheimer's disease.

In the end, will my infection have lasting effects on my disease?  Time will tell.

More skeptisicm of the amyloid hypothesis

In Beating the Dementia Monster, we expressed some skepticism about the amyloid hypothesis and the current ideas about the role beta amyloids play in Alzheimer's disease.  The concept is that malformed proteins (actually, peptides) are excreted from the cells and form plaques in the brain.  The plaques stick to brain cells and kill them.  So the driving idea in research and the search for effective treatments was to find ways of removing the plaques and cure, or at least impede the disease.

This hasn't worked out very well.  I was skeptical of the hypothesis, although I toned down my approach following comments by reviewers of the manuscript prior to publication.  Researchers have found they can remove the plaques without curing the disease.  So this hasn't worked out very well.  Aduhelm removes the plaques, but no one is satisfied with how well it alters the course of the disease.  Lecanemab may be a little better, but it's not a cure.  And it might have killed some of the test subjects.  If repeated failures of experimental treatments wasn't enough, we found that fraud had reinforced faith in the amyloid hypothesis.  

In Beating the Dementia Monster, we discussed several alternatives to the amyloid hypothesis.  These included the propagation of gum disease bacteria into the brain as well as infection with the herpes virus.  Environmental considerations, such as air pollution, correlate with increased incidence of the disease.

Science is coming to terms with the fact that this is an extremely complex disease, and there may be far more moving parts than have been anticipated.

I read this fascinating but long article that traces the history of Alzheimer's research up to the present conundrum.  It's main focus is on the amyloid hypothesis and how it may have led researchers astray for many years.  Research was so focused on it as the explanation for Alzheimer's disease, that researchers pursuing other paths were marginalized.  Research money was scarce for anything outside of the amyloid bubble.

The author of the article is a bit biased, and she follows the story of a few iconoclast researchers.  In so doing, she focuses on one particular alternate explanation, the "endosomal-lysosomal hypothesis."  

One appeal of the amyloid hypothesis was that it was simple.  These plaques are forming and killing cells, so just get rid of them.  What could be easier.  Except that it hasn't been working out.

The endosomal-lysosomal hypothesis is a lot more complicated.  It involves autophagy, or how cells reach the end of their lives and recycle their constituent parts.  Aficionados of the Keto diet and the more extreme forms of intermittent fasting will know about promoting autophagy and its benefits. 

One distinction between the two hypotheses is the role of beta amyloid.  In the original amyloid hypothesis, amyloid is excreted from the cell, forms plaques, and the plaques kill cells from outside.  In the endosomal-lysosomal hypothesis, the amyloids kill the cells before they leave.  So cleaning out the amyloid from the brain is like removing the gravestones from the graveyard.  It doesn't make the people come back to life.  

The endosomal-lysosomal hypothesis posits that there is a complex disruption in how the cells die and recycle their constituents.  It's too complicated for this blog, but you can read the article.  And the author says something that I've been hearing for a while.  None of these hypotheses fully explains this incredibly complex disease.  Perhaps they are all playing different roles in a bigger story.  The author subtly recalls the Hindu parable of the blind men and the elephant. 

Some Crazy Stuff about Shingles and Dementia

We've discussed before, both in this blog and in Beating the Dementia Monster, that there seems to be a correlation between people getting their shingle shot and a reduced incidence of developing Alzheimer's disease.  The case for this continues to strengthen, as illustrated in some recent studies in Wales and Australia.  I believe it's likely that my disease stems from my history of three episodes of shingles.

In our book, we noted that some researchers believe that the amyloid plaques we're trying to get rid of are actually part of the body's defense against a variety of microbial pathogens.  The plaques may be trying to encapsulate the pathogens and stop their propagation in the brain.  In our discussion of pathogenic causes of Alzheimer's, we noted researchers have also correlated another pathogen, the bacteria causing gum disease (p. gingivalis), with the advent of Alzheimer's symptoms.  At autopsy, evidence of the presence of the herpes virus and p. gingivalis are usually found in the brains of Alzheimer's victims.

So here's a question.  How does the role of pathogens in the brain correlate with the positive effects of applying The Dementia Toolkit, notably with respect to exercise and diet?  Well, according to one paper, perhaps "environmental factors like stress, diet, sleep, and exercise may influence Alzheimer's risk in part by modulating the innate and adaptive immune responses to [pathogens]."  In other words, the time you spend on the treadmill is regulating the ability of the pathogen to cause damage in your brain.  The paper appeared in the journal, Molecular Psychiatry.  It was entitled, "The viral hypothesis: how herpesviruses may contribute to Alzheimer’s disease."

What's prompting me on this topic is a new study in Australia about a relatively small but consistent correlation between the shingles shot and the advent of dementia.  The study replicated the results of a similar study in Wales.  The Australian study was published in the JAMA Network.  It's a little complicated, but by studying the medical records of more than 101,000 patients with a mean age of about 62 years, there was a 1.8% decrease in the probability of receiving a dementia diagnosis during a 7.4-year period.  That's not a lot, but hopefully most of us will have several more 7.4 year periods after we turn 62.  And the rate of development of the disease increases with age.  So what would that mean for a 7.4-year period beginning at the age of 75?  It might be a lot more than 1.8%

But what may be more important here is the insight this research gives us on the causes and mechanisms of the disease.  As time as gone on, most researchers have migrated away from a simplistic understanding that the disease is fundamentally about the development of amyloid plaques and microtubule tangles.  As a minimum, the amyloid hypothesis has been maturing, and some have abandoned it.

I apologize for being a bit of a slug about posting here.  My wife and I took a trip to a resort area in the Cascades for a few days, and then I was in Seattle for an overnight stay in the hospital while they wired me up to study my sleeping brain.  I'm hoping this will yield a positive outcome for my chronic insomnia.  And, I'll admit it, I have a harder time these days finding the energy to research and write on these topics.  And the YouTube channel is a lot of work.  So I do what I can.

Now Alzheimer's disease is an autoimmune disease? That's a switch!

In the few years that I've spent trying to understand Alzheimer's, one thing has impressed me above all else.  We just don't understand this disease.

Sure, we know that the Alzheimer's brain loses cells and atrophies.  Problems with tau protein cause the microtubules to collapse into tangles.  And we see amyloid plaques accumulate in ways that might impede memory and cognition.  Maybe they too can kill neurons.  Certainly what we notice most about the disease is what happens to people as the disease progresses--the deterioration of their memories, cognition, and even personhood.  That's what we notice, but are those effects central to the disease's dynamic?

We've written before about grave questions with our understanding about how these things happen.  There seem to be several genes involved in many (but not all) cases.  Do these genes cause the disease, or do they just create conditions in the brain that are fertile for the disease?  There is other evidence implicating a role in the disease for the herpes virus, and that seems to be an avenue to pursue.  But there is also evidence that a bacterium causing gum disease plays some kind of role.  Maybe the amyloid plaques are simply the body's defensive action to protect the brain from an invasion of bacteria?  There are many hypotheses.  Some fit together, while others suggest multiple, entirely different mechanisms of the disease.

So now there's another hypothesis.  Alzheimer's is actually an autoimmune disease, and we should be barking up that tree.  Where did that idea come from?

The idea comes from research published in Nature, one of the most prestigious scientific journals.  It was "Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy."  The research was conducted by a team led by Dr. David Holtzman of Washington University, St. Louis.

In Beating the Dementia Monster, we provided a rather simplistic explanation of the brain's immune system.  We said that the brain was isolated from the body's main immune system by the blood-brain barrier, and used its own immune cells, called microglia, to fight off any invading pathogens that succeed in crossing the blood-brain barrier.  It doesn't use T-cells or B-cells.

Or does it?  Dr. Holtzman's team found T-cells and evidence of T-cell activity in the brains of mice bred to imitate Alzheimer's disease.  They further found that they could halt brain atrophy by removing the T-cells.  The thought is that the T-cells are constantly being activated to respond to an antigen and are subsequently exhausted.  But there's a cycle in which the exhausted cells lay dormant for a while and are then reactivated.  But they're not that dormant, and the "dormant" cells can cause injury to surrounding cells.  

And why are they constantly being reactivated?  They weren't sure, but this seems to be where the autoimmune part comes in.

As we've said so many times before, mice are not people, and something we see in mice may not apply to people.  But in samples of brain tissue from people with different stages of Alzheimer's disease, the researchers found higher levels of T-cell presence in the more advanced stages.

So what does this all mean for Alzheimer's disease research?  As a minimum, it gives us a new avenue to pursue for understanding the disease.  But it also may be about to turn everything we think we know about the disease on its head.

Covid Promotes Alzheimer's ... Apparently

The evidence that viruses attacking the nervous system promote Alzheimer's disease is pretty well established.  Think herpes, the virus causing cold sores and shingles.  We've discussed this here before and also in Beating the Dementia Monster.  But what about viruses that don't directly attack the nervous system ... like covid?  There's interesting and troubling news on this front.

In research recently published in Nature Medicine, "Plasma proteomic evidence for increased β-amyloid pathology after SARS-CoV-2 infection," researchers examined a cohort of 1,252 people who had been infected with covid-19.  This was in the UK, and the researchers had access to previous blood test results for Alzheimer's biomarkers for these individuals.  So, for these people, and a for similar cohort of people who had not been infected (a control group), they compared biomarker evidence for Alzheimer's.  Test participants ranged in age from 46 to 80 years of age.  Many of those infected had mild cases, but some had infections serious enough to have been hospitalized.

What did they find?

People who had serious infections, especially serious enough to be hospitalized, showed increased biomarker evidence of Alzheimer's pathology.  They also did less well on cognitive and memory tests.  The specific biomarker they measured was the ratio of two forms of beta amyloid peptide that signal the disease.  The researchers estimated that a serious covid infection was the equivalent of a four-year advance of the disease.

The age of the participants was a factor -- the older, the more vulnerable -- but the presence of high blood pressure was also a factor.

In Beating the Dementia Monster, we discussed the production of a form of beta amyloid that is water soluble and of one that is not.  Both are produced in everyone.  The one that is soluble dissolves innocuously, but the one that is not soluble clumps on to nerve cells and apparently kills them.  Measuring the ratio of these two forms in fluid from a spinal tap or from a blood sample provides strong indication as to whether or not the Alzheimer's pathology is progressing.  So this is what the researchers measured.

Covid-19 is not known to attack nerve cells directly, but it does precipitate "cytokine storms" -- inflammation.  (We discussed this back in 2020.)  Inflammation and oxidation are two fundamental environmental factors in promotion of the disease.  The genetic promoters, notably the APOE4 gene, seem to work by creating an inflammatory environment in the brain.  No one seems to be claiming this with certainty, but it seems likely that any infection that causes inflammation in the brain can promote Alzheimer's.  While it's not yet well understood, there are ways in which inflammation outside the brain can sometimes cross the blood-brain barrier and cause inflammation inside the brain.  So a covid infection in the lungs may precipitate a cytokine storm and cause inflammation in the brain.

The good news is that the varieties of covid now in circulation are not causing the severe disease that covid was causing a few years ago.  Nevertheless, many of us recovered from serious infections a few years ago and may now be more vulnerable to developing Alzheimer's disease.

Another Possible Vaccine for Alzheimer's Disease?

As we discussed in Beating the Dementia Monster, Alzheimer's disease continues to be a black box.  There are so many hypotheses surrounding beta amyloid, tau protein, P. gingivalis, herpes, and others.  When we can finally go to press with the second edition, we will note that cancer research began in earnest in 1913, but Alzheimer's research only got going in the 1980's.  So it's not surprising that we still struggle to get a handle on the basic disease mechanisms. This has implications for progress in both disease prevention and treatment.

In two earlier posts (this one and this one) we considered the possibility of a vaccine for Alzheimer's disease.  The first article considered the possible role of P. gingivalis in the genesis of the disease, and the idea that a vaccine against this pathogen might work.  The second article concerned trials for a vaccine that might work against beta amyloid, training the body to treat it as a foreign intruder.

But what about a vaccine against tau protein?  During the perhaps 15 years of the pre-clinical stage of the disease, abnormal tau is being generated within brain cells.  But at the beginning of the MCI stage, tau is expelled from the cells and spreads throughout the brain.  This produces the tangles that are observed during autopsies.  The spreading tau appears to play a role in the advance of the disease.

This invites another idea for a vaccine.  How about a vaccine that attacks the abnormal tau protein?

At the Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting (AAT-AD/PD), held virtually from April 2 to 5, work on such a vaccine got attention.  (We discussed some other interesting takeaways from the conference on April 12 and 13.)

Presenters addressed several initiatives to develop tau vaccines.  In one case clinical trials had not gone well, and others were still trying to get off the drawing board.  But one showed promise in clinical trials. 

The most promising candidate is called "Axon peptide 108 conjugated to KLH" or AADvac1.  Basically the vaccine prompts the generation of antibodies that target one of several abnormal tau proteins.  AADvac1 has completed its phase 2 clinical trial and should -- hopefully -- go into phase 3.  The first two phases of a drug trial look for efficacy of a new drug, but they are first intended to demonstrate safety.  Phase 1 trials are fairly small, and phase 2 will involve more subjects.

In the case of AADvac1, the test subjects had "mild Alzheimer's disease."  (I don't know if that meant they had MCI or were in the mild (first) stage of Alzheimer's dementia.)  After some people dropped out, the phase 2 trial for AADvac1 had 100 subjects on the study drug and 63 on the placebo.  The trial ran for two years.

There were no problems with safety, but does the vaccine work?

Unfortunately, in the two trials there was no evident effect on cognition.  (A subset of younger test subjects may have shown some improved cognition.  "Younger" means ~65-67 years.)  On the other hand, there was pretty good evidence that the process of neurodegeneration was actually slowed.  This was evaluated through changes in blood that are associated with neurodegeneration.

The biotech company Axon Neuroscience plans to move ahead with a phase 3 clinical trial, but they believe they first need to find an international partner.

So what do we make of the fact that the drug slows neurodegeneration but does not appear to improve cognition?  We've found that we can remove amyloid plaques from Alzheimer's brains without improving cognition.  But it appears that cognition will improve somewhat if people stay on a drug long enough after removal of the amyloid to allow healing of the brain.  Will the same apply when removing the abnormal tau protein? 

Looking back, looking ahead

This week's issue of the ALZForum carried a long but very interesting article on the state of affairs in Alzheimer's research.  It reviewed important things that happened during 2019 with implications for what's ahead in 2020.  A few highlights:

• In the United States, government funding for Alzheimer's research was increased to $2.8 billion.  This is close to what the National Institute of Health believes is required to find an effective cure for the disease.  (The US is spending more than any other country on Alzheimer's research, but someone at a conference I attended said that China is #2.  I haven't been able to corroborate that because information on Alzheimer's funding internationally seems to be pretty scant.)
• The article reviewed the aducanumab drama.  Excitement around aducanumab raised hope that it and several other drugs will clean the brain of amyloid plaques and  in so doing may improve cognition and slow the progress of Alzheimer's disease -- if administered in large enough doses.  Will the FDA approve it?  Do we really understand how well it works?  What additional trials will be required?  Stay tuned.
• The article sought to dispel the common belief that Alzheimer's research is focused on the amyloid hypothesis we discussed in Beating the Dementia Monster.  The article listed several other strategies that researchers are pursuing.  It thus emphasized the broad fronts in this war.
• The article discussed new insights in the role of genetics in identifying those susceptible to Alzheimer's disease.  When we think of the role of genetics in the disease pathology, we first look for genes, like Apoe4, that can be directly linked and implicated.  But there is a whole host of other genes for which Alzheimer's may be a secondary consequence.  For example, genes that predispose to heart disease or diabetes can indirectly lead to Alzheimer's disease through these other diseases.  Researchers are finding ways to more accurately profile someone's risk by analyzing a person's whole genome.
• The relationship between beta amyloid and pathological tau protein was clarified.  For a long time it was thought that an important cause of cognitive impairment was amyloid plaques interfering with the flow on information between neurons.  However, after several years of steady buildup of the plaques, there is a sudden explosion of amyloid which appears to prompt the appearance of the famous tau tangles.  It is now thought that it may be the tau tangles that are impairing cognition.
• Microglia got a lot of attention this year.  The brain exists largely outside the body's immune system, so microglia are the brain's own immune system.  One idea pursued this year and into 2020 is that a role of properly functioning microglia is to rid the brain of both amyloid plaques and tau tangles.  So some kind of failure of the microglia may be part of the Alzheimer's pathology.
• There was a lot of progress in finding new biomarkers for Alzheimer's disease, such as by using blood tests.  We discussed this several times, including September 2018 and February 2019.  These blood tests measured traces of amyloid in the blood, but new research last year explored blood tests for pathologic tau protein.  This might give evidence of Alzheimer's disease well before there's any evidence amyloid.
• There were some breakthroughs in brain imaging in which PET scans could more clearly identify buildup of tau protein and beta amyloid -- and distinguish between them.
• There was new interest in the role that infection might play in the genesis of Alzheimer's disease, notably with the herpes virus.  We discussed this in June 2018.
• Exercise.  Yes, the idea that vigorous physical exercise protects against and treats Alzheimer's disease got new momentum.
• As we discussed in November 2019, there is a new understanding developing about the role of sleep, especially deep sleep, in Alzheimer's disease.  Apparently the type of brain waves seen in deep sleep can cause rhythmic pulses in the brain that prompt the movement of cerebrospinal fluid (CSF).  The movement of the CSF likely sweeps beta amyloid and tau tangles out of the brain.  This may be why poor sleep plays a prominent role in Alzheimer's pathology.

Leqembi / lecanemab / BAN2401 approved by the VA

In Beating the Dementia Monster, we discussed the promise of the monoclonal antibody treatment BAN2401.  Since then, it has become more widely known generically as lecanemab, and then commercially as Leqembi.  When administered to patients with early stage Alzheimer's disease, it appears to be more effective than Aduhelm.  Aduhelm is generally priced at $28,200 per year, while Leqembi is priced at $26,500 per year.  Aduhelm is administered intravenously every four weeks, while Leqembi is received intravenously every two weeks.  Both require regular MRIs to check for brain swelling and microhemorrhaging.  We mentioned before that three patients died during the lecanemab trials, although there is dispute over cause of death for at least two of these cases.

I recently received an email from James, one of the subscribers to this blog, noting that the Veterans Administration has now approved Leqembi for some veterans with early stage Alzheimer's disease.  The news was reported in this article from Military.com.   The article acknowledges that drug trials so far have found that, like Aduhelm, Leqembi effectively removes amyloid plaques, but testing to determine how well it improves memory and cognition is still in progress.  Trials for both treatments are incomplete, but, so far, there are better results with Leqembi than with Aduhelm. 

Looking more broadly at the pharmacological approach to treating Alzheimer's disease, the question still remains whether treating amyloid plaques is addressing the actual disease mechanism or a just a symptom.  Removing the plaques doesn't cure the disease, although it improves memory and cognition.  As we discussed before, some researchers propose that the plaques are actually a defense mechanism against the real culprit(s), certain microbes that have entered the brain.  As we discussed in Beating the Dementia Monster, these may be the herpes virus or the p. gingivalis bacteria.