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

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(Brand name of lovastatin is Mevacor (not Lipitor).)
(updated 2019 - Taiwan Trial, AMP, note other herpesviruses)
 
(One intermediate revision by the same user not shown)
Line 12: Line 12:
 
* 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.'''
 +
** If you do and have bad results, let us know! 
 +
** If you live to 120 without AD, also let us know.
 +
 
 +
* note: Most of the papers I've read focus on HSV1, but there are many herpes viruses.  I don't know whether those also correlate with AD, or whether Valacyclovir suppresses the others as well.  Help!  Send data!
 +
 
 +
 
 
----
 
----
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.   
+
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 accommodate 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.
 
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 ==
 
== 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.
+
Herpes Simplex Virus Type 1 is associated with Alzheimer's, 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 neuro-autopsies 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.
 
What follows is my interpretation of these and many other papers.
  
Line 33: Line 39:
 
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 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.
+
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 incompatibility 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.
+
We apoe4/4s are the genetic laggards.  Perhaps in the past, most receptors were compatible with apoe4, most individuals were 4/4, and LDL chemistry was good and HSV1 infection rates were low.  Then HSV1 evolved for compatibility, the receptor subsequently evolved for incompatibility (low LDL absorption is better than quick death from viral infection), and eventually the apoE3 mutation occurred 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.
 
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.
+
ApoE3 binds preferentially to LDLR receptors compared to HSV1.  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.  
 
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.
+
Intercellular beta amyloid deposits formed from soluble amyloid are the signature of Alzheimer disease, and most researchers assume that it is the causative 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.
 
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.
+
Blood pressure pulsates more during exercise.  More exercise, more vigorous exercise, more pressure gradient and more stirring in the intracerebral 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!
 
Get your exercise!
 +
 +
(joke: what has two heads, is positively charged, and sings?  Janus Ion)
 +
 +
 +
----
 +
== Amyloid-β Peptide as AMP ==
 +
 +
Aβ42 is highly conserved by evolution; "humans share Aβ42 sequences with coelacanths, a 400 million-year-old fish taxon" according to [https://stm.sciencemag.org/content/8/340/340ra72/tab-pdf DKV Kumar et al, 2016 ].  Aβ42 it has an important purpose, destroying it without understanding that purpose is bad science and bad medicine.
 +
 +
 +
----
 +
== Recent Taiwan Study Suggests HSV-AD Correlation ==
 +
 +
Data mining without blinded, controlled trials can be misleading, but this [https://link.springer.com/article/10.1007/s13311-018-0611-x nationwide population-based retrospective cohort study in Taiwan] suggests a strong correlation between anti-herpetic medications and reduced risk of dementia. 
 +
 +
From the abstract: "Thus, patients with HSV infections may have a 2.56-fold increased risk of developing dementia"
 +
 +
Who wants to volunteer for a double blind trial, perhaps ending up in the control group?
 +
  
 
----
 
----
Line 65: Line 90:
  
 
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.
 
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.
 +
  
 
----
 
----
Line 72: Line 98:
  
 
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!
 
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!
 +
  
 
----
 
----
Line 81: Line 108:
  
 
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.
 
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.
 +
  
 
----
 
----
Line 90: Line 118:
 
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!
 
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 ==
 
== References ==
  
Line 111: Line 139:
  
 
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.
 
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.
 +
 +
Nian-Sheng Tzeng et. al. 2018.  "Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections—a Nationwide, Population-Based Cohort Study in Taiwan" Neurotherapeutics April 2018, Volume 15, Issue 2, pp 417–429 [https://link.springer.com/article/10.1007/s13311-018-0611-x Free PDF]
 +
 +
DKV Kumar et al.  "Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease",  Science Translational Medicine 25 May 2016: Vol. 8, Issue 340, pp. 340ra72
 +
DOI:0.1126/scitranslmed.aaf1059 [https://stm.sciencemag.org/content/8/340/340ra72/tab-pdf | Free PDF ]

Latest revision as of 00:33, 2 December 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.
    • If you do and have bad results, let us know!
    • If you live to 120 without AD, also let us know.
  • note: Most of the papers I've read focus on HSV1, but there are many herpes viruses. I don't know whether those also correlate with AD, or whether Valacyclovir suppresses the others as well. Help! Send data!



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 accommodate 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 Alzheimer's, 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 neuro-autopsies 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 incompatibility 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 compatible with apoe4, most individuals were 4/4, and LDL chemistry was good and HSV1 infection rates were low. Then HSV1 evolved for compatibility, the receptor subsequently evolved for incompatibility (low LDL absorption is better than quick death from viral infection), and eventually the apoE3 mutation occurred 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 LDLR receptors compared to HSV1. 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 causative 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 intracerebral 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!

(joke: what has two heads, is positively charged, and sings? Janus Ion)



Amyloid-β Peptide as AMP

Aβ42 is highly conserved by evolution; "humans share Aβ42 sequences with coelacanths, a 400 million-year-old fish taxon" according to DKV Kumar et al, 2016 . Aβ42 it has an important purpose, destroying it without understanding that purpose is bad science and bad medicine.



Recent Taiwan Study Suggests HSV-AD Correlation

Data mining without blinded, controlled trials can be misleading, but this nationwide population-based retrospective cohort study in Taiwan suggests a strong correlation between anti-herpetic medications and reduced risk of dementia.

From the abstract: "Thus, patients with HSV infections may have a 2.56-fold increased risk of developing dementia"

Who wants to volunteer for a double blind trial, perhaps ending up in the control group?



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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