Difference between revisions of "HSV-1 hypothesis: a personal experiment"

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(Brand name of lovastatin is Mevacor (not Lipitor).)
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by CrashTestDummy
by CrashTestDummy


WORK IN PROGRESS, NOT FINISHED YET, HOPEFULLY BY THE END OF MARCH 2014
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* Alzheimer's Disease may be caused by Herpes Simplex Virus Type 1.   
* Alzheimer's Disease may be caused by Herpes Simplex Virus Type 1.   
* Amyloid Beta 42 Aβ42 may be the brain's immune response to HSV1.
* Amyloid Beta 42 Aβ42 may be part of the the brain's immune response to HSV1
* APOE4/4s seem unable to process insoluble Aβ42 to soluble Aβ40.
* Aβ42 collects as insoluble plaques and tangles, the post-mortem physical evidence of A.D.
* Aβ42 collects as solid plaques, the post-mortem physical evidence of A.D.
* More than 10 trials attempting to eliminate Aβ with monoclonal antibodies failed, some causing fatal brain infections.
* More than 20 trials attempting to eliminate Aβ failed, some causing fatal brain infections.
* Lifelong treatment with Valacyclovir may suppress HSV1 and reduce Aβ42 production
* Lifelong treatment with Valacyclovir may suppress HSV1 and reduce Aβ42 production
* Eliminating existing Aβ42 plaques will be very difficult without compromising immunity
* Eliminating existing Aβ42 plaques will be very difficult without compromising immunity
* I shall design a measurement and treatment protocol, and start testing myself.
* I shall design a measurement and treatment protocol, and start testing myself.
* Though I hope to collect data that will help younger people, this may not help me much, and it may kill me.
* Though I hope to collect data that will help younger people, this may not help me much, and it may kill me.
* '''DO NOT TRY THIS YOURSELF'''
* '''DO NOT TRY THIS YOURSELF'''
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The following wiki page is the background and and rationale for a personal experiment.  Unless something stops me from adding to this page, I would prefer you to make your comments on the discussion page, and I will change this page myself to accomodate them.   
The following wiki page is the background and and rationale for a personal experiment.  Unless something stops me from adding to this page, I would prefer you to make your comments on the [[ https://www.apoe4.info/MWiki/index.php?title=Talk:HSV1hypothesis | discussion]] page, and I will change this page myself to accomodate them.   


Perhaps 50% of what follows is baloney - but I don't yet know which.  I hope to improve it over time, but if something happens to me, I want to share my explorations and suppositions now, so others can avoid my mistakes.  I will add more citations in time.
Perhaps half of what follows is baloney - but I don't yet know which half.  I hope to improve it over time, but if something happens to me, I want to share my explorations and suppositions now, so others can avoid my mistakes.  I will add more citations in time.
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== The Evolution of the Human Brain ==


Like all brains, mammal brains grow a fixed number of neurons which last through life.  Like all brains, most of mammal neurons have fixed wiring and functions and mostly can't repair damage.  Vision, hearing, taste, smell, movement, etc. are directly connected to structures differing little from reptiles, fish, and other simpler animals.
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Mammals have a unique structure, the cortex, which seems to have evolved from the olfactory bulbs of mouse-like ancestors.  These warm-blooded small animals may have lived underground and oriented themselves by smell - remembering many "smell trails" and learning to abandon old food sources and find new ones required more flexible memory than reacting to fixed cues and habituating to a small range of stimuli.  Therapsid dinosaurs, of whom birds are the surviving remnants, shared some of this flexibility, but evolved in a different direction.
== The Manchester HSV1 Model - Herpes Simplex and Amyloid Beta ==


Primates, and especially our near-kin chimps and bonobos, have enormous cortexes compared to all other primates, and human cortexes are three times larger than chimp cortexes.  Size is not the only measure - human cortexes have more layers of connectivity and more crossbrain connectivity than other primates, and far more than non-primate mammals.  
Herpes Simplex Virus Type 1 is associated with Alzheimers, according to Ruth Itzhaki and Matt Wozniak and other researchers at the University of Manchester and elsewhere.  Neuropathologist Melvin Ball and other Canadian researchers observed that latent HSV1 was present in Alzheimer's neuroautopsies in 1982, and the Manchester team found HSV1 DNA by PCR in 1991.  Other researcher have also noticed the link.
What follows is my interpretation of these and many other papers.


Cortex neurons grow "long" axons (outbound signal paths), dendrites (inbound signal paths), and create and destroy synapses between them.  The synapses are nanometer-scale structure whose connectivity changes with contact area and spacing, with kinase molecules cutting protein scaffolding to rapidly (seconds?) change their shapes and the strength of the synaptic signals they pass.  Signalling is chemical, not electrical; that makes the brain much slower than wires in a computer, and it also makes experimental electrical interconnect very difficult.
Cholesterol is an essential structural material for animals.  Half the dry weight of the human brain is cholesterol.  Cholesterol sulfate is the starting material for the manufacture of vitamin D.  Cholesterol patches blood vessel inflammation - no inflammation, no dangerous plaques.  High LDL cholesterol correlates with cardiovascular disease, but that is a "surrogate outcome", not a disease. There may be many reasons for high cholesterol, the APOE4 genotype being one, an inflammatory diet being another.


Many brain researchers accept Eric Kandel's epigenetic DNA model of memory, which describes how habituation (selection between behaviors) occurs in very simple, easy-to-study animals like Aplysia sea snails.  In principle, an Aplysia can lose a neuron and regrow another that does the same thing, because the repertoire of possible behaviors is determined by DNA only.
LDL is a particle about 20 nanometers in diameter, containing about 40 thousand cholesterol molecules, triglycerides, and phospholipids.  The outer protein package is covered with apolipoprotein ligands, molecules that bind to LDL receptors on cells.  This triggers endocytosis, pulling in a bit of cell wall surrounding the particle and forming a coated vesicle inside the cell.  Other processes disassemble the LDL particle inside the cell, distibuting the LDL and other molecules for cell maintenance.


But Kandel's model is a poor fit for humans.  Mammals learn and must create their repertoire de novo by creating new structures, so when the structures go away, they take their memories with them.  Fortunately, the memories themselves are encoded in redundant networks of neurons, and brains extrapolate (confabulate?) around missing neurons, modifying but not completely losing memory.
Specifically, the ligand apolipoprotein E triggers matching LDL receptors to make this happen.  The apoE molecule has patterns of shape and charge that match corresponding shapes and charges on the LDLR molecule.  If the shapes do not match, binding is less successful.


The amygdala and the hippocampus (near the center of the brain) signal the cortex to remember the patterns it is currently running, in association with other patterns of memory.  Our brains remember sequences and rhythms, patterns and associations, not facts per se.  Human cogitation is an epiphenomena on rich and interconnected neural patterns, and the system continues to survive in spite of serious damage.  The sense of identity also survives and adapts, but that identity may be objectively quite different over time.  An Alzheimer's patient with advanced memory loss still thinks of themselves as a person - even after they can't remember their name.
The 299 amino acid apoE protein is encoded on chromosome 19 around position 45,410,000.  The 839 amino acid LDLR receptor is also on chromosome 19 around position 11,220,000.  The two positions are 34 million base pairs apart, which means there is about 30% chance that they will be swapped with DNA from the other chromosome 19 during meiosis and gamete production.  Over many generations, the LDL ligands and the LDL receptors correlate only weakly.


Structure is critically important to human brains, not just the general instructions stored in our DNA.  We can't regrow neurons - we die with a fraction of the neurons we developed with.  Even if new neurons could be added in place of missing ones, they cannot connect the way the old neurons did, that information is lost.
The protein coat of HSV1 mimics LDL ligands - that is how it binds and gains entry to the cell.  LDL receptors are in a "red queen race" with HSV1, the receptors evolving for incompatability with HSV1, HSV1 evolving to catch up.  Given the weak correlation between the apoE genetic sequence and the LDLR receptor sequence, the apoE protein must evolve to catch up, too, lagging the receptor.


Most of our brains are ''not'' neurons, but a large collection of chemical factory cells - glia and astrocytes.
We apoe4/4s are the genetic laggards.  Perhaps in the past, most receptors were compatable with apoe4, most individuals were 4/4, and LDL chemistry was good and HSV1 infection rates were low.  Then HSV1 evolved for compatability, the receptor subsequently evolved for incompatability (low LDL absorption is better than quick death from viral infection), and eventually the apoE3 mutation occured and ligand matched receptor for an increasing number of people.  That is where we are today.


To bacteria, humans are huge sacks of nutrients, and without aggressive immune systems, we would soon become microbe chow.  We have many forms of immune systems, macrophages (white blood cells) and antibodies in the blood, superoxides and other bacterial poisons, and no doubt other systems we don't understand yet. These systems classify every protein as friend or foe, with a very narrow definition of "friend". 
E4/4 LDL binds poorly to our cells.  So our bloodstream accumulates LDL more than most - it does not mean that 4/4s have "too much", it means 4/4s are using too little. The cells, starving for cholesterol, make more receptors.  The liver cells that manufacture cholesterol via the mevalonate/squaline pathway make more receptors too.  The liver does not sense enough LDL in the bloodstream, so it makes more cholesterol and more LDL particles.


Complicated, variable human neurons and synapses are too variable to always appear as "friend", too fragile and dense to survive the passage of macrophages, and too synaptically sensitive to tolerate the presence of antibodies.  The brain is walled off from the rest of the body with multiple membranes that compose the blood-brain barrier.  This keeps out many pathogens, and also excludes an immune system that could damage and add noise to the brain.
ApoE3 binds preferentially to HSV1 to LDLR receptors.  HSV1 binds preferentially to apoE4.  So more HSV1 enters E4/4 cells sooner than it does for others, and E4/4s get less cholesterol to repair inflammation and cell damage.


But the brain is still tasty to pathogens, so it must have its own defenses and immune system.  Since the brain lives inside a bone box, and is as fragile as pudding, these defenses are difficult to observe and poorly understood.  One (of many) plausible brain defense systems involves amyloid beta proteins, and will be discussed in the next section.
The brain is separated from the body's blood-borne immune system by the blood-brain barrier.  Without antibodies and macrophages from the blood, it must protect itself.  While mainstream researchers cannot figure out why the brain makes beta amyloid, some claim that it has antiviral properties, binding to intercellular HSV1.  


Humans are social creatures; we evolved to live and work and create children in groups.  So individual immune systems protect more than an individual, but prevent the spread of infection to the entire group.  If a human incubates a disease in some small portion of their body, it is better to destroy that portion than to risk death for the whole body.  If necessary, it is better to destroy a whole individual than a closely related kin group which could easily pick up the infection that individual is incubating.  So there is a strong bias for a hypersensitive, berserker immune system, and few plausible reasons to restrain that immune system in an older adult whose children are old enough to survive on their own.
Intercellular beta amyloid deposits formed from soluble amyloid are the signature of Alzheimer disease, and most researchers assume that it is the causitive agent.  So, pharmaceutical companies have produced half a dozen different varieties of monoclonal antibodies that target beta amyloid.  These MABs work fine in apoE4 knock-in mice, eliminating beta amyloid as expected.  In humans, MABs eliminate beta amyloid as well, but many of the experimental subjects developed non-bacterial encephalitis and trial after trial was terminated.  This reinforces the idea that beta amyloid has antiviral properties, and is produced by astrocyte glia to protect the brain from infection.


Memory is one plausible reason - an older human may have skills, relationships, and environmental knowledge that can help a whole clan survive.  Until this knowledge is passed on to many younger members of the clan, those memories can be indispensable.  At some age, incubation overrides indispensability, and we can expect the immune system to be tuned to that.  We can also expect the immune system to be tuned to the evolutionary past, so ours may be optimized for five thousand years ago, not the circumstances of 21st century civilization, with more crowding and interaction, and an evolving externally managed immune system.
According to a few papers, apoE also binds to intercellular beta amyloid, and endocytosis brings it into the cell for destruction by lysosomes.  Other papers claim the soluble beta amyloid 40 form is washed in the intracerebral fluid to the lymph nodes, while insoluble beta amyloid 42 form collects to form plaques.  Somehow, according to these researchers, E4/4s make more insoluble 42 instead of 40. The intracerebral fluid flows around the outside of blood vessels, pumped by the pulsation of those vessels, and moves detritus out of the brain.  Hypertensive blood vessels pulsate less, which can contribute to the accumulation of plaque.


The bottom line:
Blood pressure pulsates more during exercise. More exercise, more vigorous exercise, more pressure gradient and more stirring in the intracerbral fluid, perhaps cleaning out excess beta amyloid and reducing deposition and crosslinking.  While this seems at odds with the "amyloid irrelevant, worry about HSV" hypothesis, amyloid is a "janus molecule" - if it is potent enough to damage HSV, it is potent enough to damage neurons.  Best that it does its antiviral work and leave the brain as soon as possible.
  * Our brains have their own immune systems
 
* Immune systems are aggressive and protect the clan at all costs (including the individual)
Get your exercise!
* Nanometer structure is critical to individual survival
* New connections may be made, but damaged connections do not grow back


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== Herpes Simplex and Amyloid Beta ==
== E4/4s and cholesterol ==
 
My cholesterol runs about 190 mg/dl.  I have a strict low carb low sugar high greens vegan diet with moderate exercise.  LDL used to be 210 with a more cholesterogenic diet.  I've had nuclear stress imaging, and a carotid intima media ultrasound scan, showing no plaque and the circulatory system of someone 20 years younger.  A brief experiment with pravastatin lowered my cholesterol, but caused headaches, muscle pain, and the beginnings of arthritis.  Ending the statins ended the symptoms.
 
Some apoE4/4's have lower LDL than others.  It would be interesting to compare [http://snpedia.com/index.php/LDLR SNP sequences for LDL receptors.]


MORE LATER
Cholesterol is produced by the mevalonate/squaline pathway in the liver.  It is as essential to animal life as water (and as dangerous, in the wrong places in the wrong quantities).  Cholesterol an essential part of cell walls, especially the axons in the brain, and is used by the body to repair damage, patching the inside of damaged blood vessels, for example.  It is easy to conflate the patches with the damage itself;  perhaps it is better to have scarred, leaky blood vessels than to have them narrowed by patches plugging the holes, but it is better still not to have scarred blood vessels.  '''Don't eat garbage food''' and '''don't eat (or drink) garbage food''' and your LDL cholesterol may be high but your cardiovascular health can be great.
 
Statins poison the mevalonate pathway, jamming the first step in sterol synthesis (HMG-CoA reductase) that produces cholesterol - as well as vitamin D, hormones, and all the other sterols our bodies produce.  Statins were discovered by biochemist Akira Endo, who learned that some fungi protected themselves from animal predators by damaging their ability to make cholesterol (and a similar range of other sterols).  That led to lovastatin (Mevacor), and a very large class of me-too drugs, evading old patents and creating new ones.  Pharmaceutical companies have become adept at rigging clinical trials to produce spectacular results, seemingly much better than existing statins, generating high demand for their patented pills, until time and experience and adverse effects shows that the new pills are no better (and sometimes worse) than the old pills.  Of the multitude of available statins, lovastatin is among the cheapest, pravastatin (Pravacol) may be the least toxic, and rosuvastatin (Crestor) is the most heavily marketed and most expensive.  For the last, look at the sorry history of the Jupiter trials in the medical journals.
 
I am not a doctor.  The current standard of care is to prescribe statins if blood LDL is higher than 145, or if there is family history of cardiovascular disease.  It is up to you to decide whether evolution resulted in bodies that perversely expend great effort to synthesize sterols and beta amyloid and other "bad" molecules - or whether nature makes these molecules in response to a need.  It is our job as intelligent human beings to optimize our response to those needs.  It is unlikely that we evolved with a need for unrestrained consumption of pizza and soda pop.
 
So ... improve diet (mostly moderation and carb reduction) and exercise (park the car and walk) until the LDL drops.  If LDL doesn't drop below 145, get some primary measurements, like CIMT and an occasional nuclear echo.  Just remember that your brain is your most important organ, and there aren't many primary measurements you can make of that.


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== Diet, Exercise, Infection Suppression and Amyloid Flow ==
== Self-Experimentation With Valacyclovir ==


MORE LATER
The Manchester ''in vitro'' work suggests that valacyclovir (VCV) suppresses HSV1 in the brain and body.  VCV metabolizes into acyclovir, and the acyclovir is activated by the presence of HSV1 into a protease that specifically attacks HSV1 proteins - a clever molecule!  Valtrex (Glaxo Smith Kline's brand name VCV) is tolerated in doses up to 4g/day with few reported side effects, and is usually prescribed at 1g/day to suppress genital herpes (also caused by HSV1).  However, 1g/day Valtrex costs $5500 per year, while generic valacylovir costs $500/year.  I assume that the generics are less potent than the brand name Valtrex, so I asked my doctor to prescribe 1g twice per day of generic (in this case Northstar from China) valacyclovir, which I take at breakfast and before bed, costing a bit over $1000/year.  Note, these are big horse pills - you may ask your doctor for a prescription for a horse, too, to help you swallow them. 
 
Possible outcomes: (1) HSV1 suppressed, no further viral brain damage (though I am old enough to have some already). (2) No effect, I get AD in 2 to 20 years. (3) Somehow, the valacyclovir damages me.  All drugs, especially generics, carry this risk.  (4) I choke to death on one of these monster pills.  1/2 gram tablets are available, and might be easier to swallow, but they cost $1300 per year for the same dose.  For $300 per year, I'll learn to whinny!


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== The Failure of Anti-Amyloid Therapy ==
== Long Term Survival ==
 
For better long term survival, I need to learn how to do two more difficult things:  (1), increase my cellular uptake of LDL, and (2) clear out the amyloid plaques without lowering soluble beta amyloid.
 
My body, and especially my brain, needs cholesterol to maintain cell walls.  This is critical in the brain, and also in brain capillaries.  E4s also have a predilection for cerebral amyloid angiopathy, CAA, greatly increasing our chances of lobar intracerebral hemorrhage (ICH) and stroke.  This is probably what killed my father and grandfather, both at age 61 (which I will be 3 months after I write this), and why AD doesn't show up in my family.  I probably have better chances - a recent contrast MRI of my brain ($$$$!) showed no sign of CAA - yet.


MORE LATER
There may be nutritional means or drugs to increase uptake, but I've seen no direct evidence of that.  There's a local company that does computational drug design.  Perhaps I can talk them into designing a molecule that binds to apoE4 on one end, and normal LDL receptors at the other.  That would greatly improve absorption of LDL.


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== The Manchester HSV1 Model ==


MORE LATER
'''Important''' - both infarction (blood vessel blockage) and ICH present in ambulance and ER the same way - they are differentiated by imaging in the hospital.  Infarction is 10 times as common, and is treated with anticoagulants (heparin, warfarin, etc.) to dissolve clots. However, ICH is more deadly, and anticoagulants will kill a person with ICH.  ICH is far more common for E4's.  I have an '''IMPORTANT MEDICAL INFORMATION''' card attached to my refrigerator, with instructions to '''NOT administer anticoagulants''' (in the ER, or in the ambulance) unless imaging confirms an infarction.  That may cause more brain damage if I have an infarction, but is more likely to save my life. 


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== Self-Experimentation With Valacyclovir ==


MORE LATER
Clearing out amyloid plaques, that will be tough, because we want to attack a material hard as plastic without damaging the individual molecules it is made from.  This may be necessary for old folks to live a long time.  If young folks can prevent HSV1 infection and amyloid precipitation into plaques, then clearing them out won't be necessary for decades.  '''Note''' vigorous exercise pumps the blood faster, so it pumps intracerebral fluid faster, too.  So, get your exercise and move that amyloid to your lymph nodes!
 
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== Long Term Survival ==


MORE LATER
== References ==
 
Ball, Melvyn J. "Limbic predilection in Alzheimer dementia: is reactivated herpesvirus involved?" The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 9.3 (1982): 303-306.
 
Jamieson, Gordon A., et al. "Latent herpes simplex virus type 1 in normal and Alzheimer's disease brains." Journal of medical virology 33.4 (1991): 224-227.
 
Itzhaki, Ruth F., and Matthew A. Wozniak. "Could antivirals be used to treat Alzheimer's disease?" Future microbiology 7.3 (2012): 307-309.
[http://www.futuremedicine.com/doi/pdf/10.2217/fmb.12.10]
 
Itzhaki, Ruth F., and Matthew A. Wozniak. "Herpes simplex virus type 1 in Alzheimer's disease: the enemy within." Journal of Alzheimer's Disease 13.4 (2008): 393-405.
[http://www.coconutketones.com/pdfs/jad_enemy_within_2008%5B1%5D.pdf]
 
* quote: The virus was also absent from the brains of most young people tested, suggesting that the virus reaches the brain in older age as the immune system declines.
* quote: Intriguingly – and consistently, we also found that APOE-ε4 is a risk for cold sores.
 
Wozniak, Matthew A., et al. "Antivirals reduce the formation of key Alzheimer's disease molecules in cell cultures acutely infected with herpes simplex virus type 1." PLoS One 6.10 (2011). 
[http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0025152&representation=PDF]
 
Itzhaki, Ruth F., and Matthew A. Wozniak. "Herpes simplex virus type 1, apolipoprotein E, and cholesterol: a dangerous liaison in Alzheimer’s disease and other disorders." Progress in lipid research 45.1 (2006): 73-90.

Revision as of 10:02, 16 October 2019

Testing the HSV1 Hypothesis

Dangerous Speculation and Experimentation

by CrashTestDummy

  • Alzheimer's Disease may be caused by Herpes Simplex Virus Type 1.
  • Amyloid Beta 42 Aβ42 may be part of the the brain's immune response to HSV1
  • Aβ42 collects as insoluble plaques and tangles, the post-mortem physical evidence of A.D.
  • More than 10 trials attempting to eliminate Aβ with monoclonal antibodies failed, some causing fatal brain infections.
  • Lifelong treatment with Valacyclovir may suppress HSV1 and reduce Aβ42 production
  • Eliminating existing Aβ42 plaques will be very difficult without compromising immunity
  • I shall design a measurement and treatment protocol, and start testing myself.
  • Though I hope to collect data that will help younger people, this may not help me much, and it may kill me.
  • DO NOT TRY THIS YOURSELF

The following wiki page is the background and and rationale for a personal experiment. Unless something stops me from adding to this page, I would prefer you to make your comments on the [[ https://www.apoe4.info/MWiki/index.php?title=Talk:HSV1hypothesis | discussion]] page, and I will change this page myself to accomodate them.

Perhaps half of what follows is baloney - but I don't yet know which half. I hope to improve it over time, but if something happens to me, I want to share my explorations and suppositions now, so others can avoid my mistakes. I will add more citations in time.

The Manchester HSV1 Model - Herpes Simplex and Amyloid Beta

Herpes Simplex Virus Type 1 is associated with Alzheimers, according to Ruth Itzhaki and Matt Wozniak and other researchers at the University of Manchester and elsewhere. Neuropathologist Melvin Ball and other Canadian researchers observed that latent HSV1 was present in Alzheimer's neuroautopsies in 1982, and the Manchester team found HSV1 DNA by PCR in 1991. Other researcher have also noticed the link. What follows is my interpretation of these and many other papers.

Cholesterol is an essential structural material for animals. Half the dry weight of the human brain is cholesterol. Cholesterol sulfate is the starting material for the manufacture of vitamin D. Cholesterol patches blood vessel inflammation - no inflammation, no dangerous plaques. High LDL cholesterol correlates with cardiovascular disease, but that is a "surrogate outcome", not a disease. There may be many reasons for high cholesterol, the APOE4 genotype being one, an inflammatory diet being another.

LDL is a particle about 20 nanometers in diameter, containing about 40 thousand cholesterol molecules, triglycerides, and phospholipids. The outer protein package is covered with apolipoprotein ligands, molecules that bind to LDL receptors on cells. This triggers endocytosis, pulling in a bit of cell wall surrounding the particle and forming a coated vesicle inside the cell. Other processes disassemble the LDL particle inside the cell, distibuting the LDL and other molecules for cell maintenance.

Specifically, the ligand apolipoprotein E triggers matching LDL receptors to make this happen. The apoE molecule has patterns of shape and charge that match corresponding shapes and charges on the LDLR molecule. If the shapes do not match, binding is less successful.

The 299 amino acid apoE protein is encoded on chromosome 19 around position 45,410,000. The 839 amino acid LDLR receptor is also on chromosome 19 around position 11,220,000. The two positions are 34 million base pairs apart, which means there is about 30% chance that they will be swapped with DNA from the other chromosome 19 during meiosis and gamete production. Over many generations, the LDL ligands and the LDL receptors correlate only weakly.

The protein coat of HSV1 mimics LDL ligands - that is how it binds and gains entry to the cell. LDL receptors are in a "red queen race" with HSV1, the receptors evolving for incompatability with HSV1, HSV1 evolving to catch up. Given the weak correlation between the apoE genetic sequence and the LDLR receptor sequence, the apoE protein must evolve to catch up, too, lagging the receptor.

We apoe4/4s are the genetic laggards. Perhaps in the past, most receptors were compatable with apoe4, most individuals were 4/4, and LDL chemistry was good and HSV1 infection rates were low. Then HSV1 evolved for compatability, the receptor subsequently evolved for incompatability (low LDL absorption is better than quick death from viral infection), and eventually the apoE3 mutation occured and ligand matched receptor for an increasing number of people. That is where we are today.

E4/4 LDL binds poorly to our cells. So our bloodstream accumulates LDL more than most - it does not mean that 4/4s have "too much", it means 4/4s are using too little. The cells, starving for cholesterol, make more receptors. The liver cells that manufacture cholesterol via the mevalonate/squaline pathway make more receptors too. The liver does not sense enough LDL in the bloodstream, so it makes more cholesterol and more LDL particles.

ApoE3 binds preferentially to HSV1 to LDLR receptors. HSV1 binds preferentially to apoE4. So more HSV1 enters E4/4 cells sooner than it does for others, and E4/4s get less cholesterol to repair inflammation and cell damage.

The brain is separated from the body's blood-borne immune system by the blood-brain barrier. Without antibodies and macrophages from the blood, it must protect itself. While mainstream researchers cannot figure out why the brain makes beta amyloid, some claim that it has antiviral properties, binding to intercellular HSV1.

Intercellular beta amyloid deposits formed from soluble amyloid are the signature of Alzheimer disease, and most researchers assume that it is the causitive agent. So, pharmaceutical companies have produced half a dozen different varieties of monoclonal antibodies that target beta amyloid. These MABs work fine in apoE4 knock-in mice, eliminating beta amyloid as expected. In humans, MABs eliminate beta amyloid as well, but many of the experimental subjects developed non-bacterial encephalitis and trial after trial was terminated. This reinforces the idea that beta amyloid has antiviral properties, and is produced by astrocyte glia to protect the brain from infection.

According to a few papers, apoE also binds to intercellular beta amyloid, and endocytosis brings it into the cell for destruction by lysosomes. Other papers claim the soluble beta amyloid 40 form is washed in the intracerebral fluid to the lymph nodes, while insoluble beta amyloid 42 form collects to form plaques. Somehow, according to these researchers, E4/4s make more insoluble 42 instead of 40. The intracerebral fluid flows around the outside of blood vessels, pumped by the pulsation of those vessels, and moves detritus out of the brain. Hypertensive blood vessels pulsate less, which can contribute to the accumulation of plaque.

Blood pressure pulsates more during exercise. More exercise, more vigorous exercise, more pressure gradient and more stirring in the intracerbral fluid, perhaps cleaning out excess beta amyloid and reducing deposition and crosslinking. While this seems at odds with the "amyloid irrelevant, worry about HSV" hypothesis, amyloid is a "janus molecule" - if it is potent enough to damage HSV, it is potent enough to damage neurons. Best that it does its antiviral work and leave the brain as soon as possible.

Get your exercise!

E4/4s and cholesterol

My cholesterol runs about 190 mg/dl. I have a strict low carb low sugar high greens vegan diet with moderate exercise. LDL used to be 210 with a more cholesterogenic diet. I've had nuclear stress imaging, and a carotid intima media ultrasound scan, showing no plaque and the circulatory system of someone 20 years younger. A brief experiment with pravastatin lowered my cholesterol, but caused headaches, muscle pain, and the beginnings of arthritis. Ending the statins ended the symptoms.

Some apoE4/4's have lower LDL than others. It would be interesting to compare SNP sequences for LDL receptors.

Cholesterol is produced by the mevalonate/squaline pathway in the liver. It is as essential to animal life as water (and as dangerous, in the wrong places in the wrong quantities). Cholesterol an essential part of cell walls, especially the axons in the brain, and is used by the body to repair damage, patching the inside of damaged blood vessels, for example. It is easy to conflate the patches with the damage itself; perhaps it is better to have scarred, leaky blood vessels than to have them narrowed by patches plugging the holes, but it is better still not to have scarred blood vessels. Don't eat garbage food and don't eat (or drink) garbage food and your LDL cholesterol may be high but your cardiovascular health can be great.

Statins poison the mevalonate pathway, jamming the first step in sterol synthesis (HMG-CoA reductase) that produces cholesterol - as well as vitamin D, hormones, and all the other sterols our bodies produce. Statins were discovered by biochemist Akira Endo, who learned that some fungi protected themselves from animal predators by damaging their ability to make cholesterol (and a similar range of other sterols). That led to lovastatin (Mevacor), and a very large class of me-too drugs, evading old patents and creating new ones. Pharmaceutical companies have become adept at rigging clinical trials to produce spectacular results, seemingly much better than existing statins, generating high demand for their patented pills, until time and experience and adverse effects shows that the new pills are no better (and sometimes worse) than the old pills. Of the multitude of available statins, lovastatin is among the cheapest, pravastatin (Pravacol) may be the least toxic, and rosuvastatin (Crestor) is the most heavily marketed and most expensive. For the last, look at the sorry history of the Jupiter trials in the medical journals.

I am not a doctor. The current standard of care is to prescribe statins if blood LDL is higher than 145, or if there is family history of cardiovascular disease. It is up to you to decide whether evolution resulted in bodies that perversely expend great effort to synthesize sterols and beta amyloid and other "bad" molecules - or whether nature makes these molecules in response to a need. It is our job as intelligent human beings to optimize our response to those needs. It is unlikely that we evolved with a need for unrestrained consumption of pizza and soda pop.

So ... improve diet (mostly moderation and carb reduction) and exercise (park the car and walk) until the LDL drops. If LDL doesn't drop below 145, get some primary measurements, like CIMT and an occasional nuclear echo. Just remember that your brain is your most important organ, and there aren't many primary measurements you can make of that.

Self-Experimentation With Valacyclovir

The Manchester in vitro work suggests that valacyclovir (VCV) suppresses HSV1 in the brain and body. VCV metabolizes into acyclovir, and the acyclovir is activated by the presence of HSV1 into a protease that specifically attacks HSV1 proteins - a clever molecule! Valtrex (Glaxo Smith Kline's brand name VCV) is tolerated in doses up to 4g/day with few reported side effects, and is usually prescribed at 1g/day to suppress genital herpes (also caused by HSV1). However, 1g/day Valtrex costs $5500 per year, while generic valacylovir costs $500/year. I assume that the generics are less potent than the brand name Valtrex, so I asked my doctor to prescribe 1g twice per day of generic (in this case Northstar from China) valacyclovir, which I take at breakfast and before bed, costing a bit over $1000/year. Note, these are big horse pills - you may ask your doctor for a prescription for a horse, too, to help you swallow them.

Possible outcomes: (1) HSV1 suppressed, no further viral brain damage (though I am old enough to have some already). (2) No effect, I get AD in 2 to 20 years. (3) Somehow, the valacyclovir damages me. All drugs, especially generics, carry this risk. (4) I choke to death on one of these monster pills. 1/2 gram tablets are available, and might be easier to swallow, but they cost $1300 per year for the same dose. For $300 per year, I'll learn to whinny!

Long Term Survival

For better long term survival, I need to learn how to do two more difficult things: (1), increase my cellular uptake of LDL, and (2) clear out the amyloid plaques without lowering soluble beta amyloid.

My body, and especially my brain, needs cholesterol to maintain cell walls. This is critical in the brain, and also in brain capillaries. E4s also have a predilection for cerebral amyloid angiopathy, CAA, greatly increasing our chances of lobar intracerebral hemorrhage (ICH) and stroke. This is probably what killed my father and grandfather, both at age 61 (which I will be 3 months after I write this), and why AD doesn't show up in my family. I probably have better chances - a recent contrast MRI of my brain ($$$$!) showed no sign of CAA - yet.

There may be nutritional means or drugs to increase uptake, but I've seen no direct evidence of that. There's a local company that does computational drug design. Perhaps I can talk them into designing a molecule that binds to apoE4 on one end, and normal LDL receptors at the other. That would greatly improve absorption of LDL.

Important - both infarction (blood vessel blockage) and ICH present in ambulance and ER the same way - they are differentiated by imaging in the hospital. Infarction is 10 times as common, and is treated with anticoagulants (heparin, warfarin, etc.) to dissolve clots. However, ICH is more deadly, and anticoagulants will kill a person with ICH. ICH is far more common for E4's. I have an IMPORTANT MEDICAL INFORMATION card attached to my refrigerator, with instructions to NOT administer anticoagulants (in the ER, or in the ambulance) unless imaging confirms an infarction. That may cause more brain damage if I have an infarction, but is more likely to save my life.

Clearing out amyloid plaques, that will be tough, because we want to attack a material hard as plastic without damaging the individual molecules it is made from. This may be necessary for old folks to live a long time. If young folks can prevent HSV1 infection and amyloid precipitation into plaques, then clearing them out won't be necessary for decades. Note vigorous exercise pumps the blood faster, so it pumps intracerebral fluid faster, too. So, get your exercise and move that amyloid to your lymph nodes!

References

Ball, Melvyn J. "Limbic predilection in Alzheimer dementia: is reactivated herpesvirus involved?" The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 9.3 (1982): 303-306.

Jamieson, Gordon A., et al. "Latent herpes simplex virus type 1 in normal and Alzheimer's disease brains." Journal of medical virology 33.4 (1991): 224-227.

Itzhaki, Ruth F., and Matthew A. Wozniak. "Could antivirals be used to treat Alzheimer's disease?" Future microbiology 7.3 (2012): 307-309. [1]

Itzhaki, Ruth F., and Matthew A. Wozniak. "Herpes simplex virus type 1 in Alzheimer's disease: the enemy within." Journal of Alzheimer's Disease 13.4 (2008): 393-405. [2]

  • quote: The virus was also absent from the brains of most young people tested, suggesting that the virus reaches the brain in older age as the immune system declines.
  • quote: Intriguingly – and consistently, we also found that APOE-ε4 is a risk for cold sores.

Wozniak, Matthew A., et al. "Antivirals reduce the formation of key Alzheimer's disease molecules in cell cultures acutely infected with herpes simplex virus type 1." PLoS One 6.10 (2011). [3]

Itzhaki, Ruth F., and Matthew A. Wozniak. "Herpes simplex virus type 1, apolipoprotein E, and cholesterol: a dangerous liaison in Alzheimer’s disease and other disorders." Progress in lipid research 45.1 (2006): 73-90.

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