PRIMER: An introduction to ApoE4, biochemistry, and possible prevention strategies
Posted: Mon Jun 15, 2015 1:40 pm
Greetings brother and sister e4's and our extended family!
Welcome to what I hope will be a good place to begin in getting to grips with the complexities of the APOE gene and its effects. This thread is aimed at those just starting their exploration of the complex issues facing us all. It will be locked, I will add to it from time to time. There is a huge amount of information that I need to synthesise for you, I have just started and hope to add at least one section per week. So please be patient while I make my way carefully through from beginning to end. (For questions, comments, please start a new thread in this section.)
This primer was written in 2015. In August 2016, and again August 2017, I edited it and new sections are in italics.
Allow me to introduce myself - I am Stavia, I am a 54 year old (2019: now almost 59) woman who only learned in 2014 that I was homozygous for the gene that codes for apoE4. This means that I have two copies of the gene that codes for the apoE4 variant of a really important protein in our bodies. We colloquially on our forum abbreviate this by saying I am e4e4, E4E4, or 4/4. You will see us using this language a lot.
(The terminology I will be using is not strictly correct, but it is currently colloquially accepted. The real scientific accurate way is to call the gene APOE and our variant APOE-ε4. The ε is the Greek letter epsilon which corresponds to the letter "e" in our alphabet. Scientists often use Greek letters to name things. So strictly I should say I am homozygous for APOE- ε4. The protein made by this gene that causes all the fuss is called apolipoprotein E. It is abbreviated apoE4.)
We all have two copies of every single one of the thousands of genes coded in the DNA in the nucleus of every cell of our body - one from our mommy and one from our daddy (when a mommy and a daddy love each other very much....but I digress, it's my quirky sense of humour!) The general word used to denote that there are two copies is allele. So each gene has two alleles.
The APOE gene has three commonly different possible versions/alleles. So you might have one copy of the e4 version, or two, or none. The second copy might be e2 (least common, less than 10%) or e3 (most common, about 60%). 15 to 20% of people carry at least one apoe4 allele, depending on the ethnicity:
So the options for your two APOE alleles can be:
e4/e4 - we sometimes abbreviate this as 4/4
e3/e4 - 3/4
e3/e3 - 3/3
e2/e4 - 2/4
e2/e3 - 2/3
e2/e2 - 2/2
If both alleles are identical, we use the word homozygous to denote this - "homo" being Greek for "the same". If the two alleles are different, we use the word heterozygous to denote this (Greek for different). Thus 4/4 is homozygous for ApoE4, 3/3 is homozygous for ApoE3 etc whereas 3/4 is heterozygous for apoE4.
There was originally no apoe1, it was a labeling error 40 years ago when it was first discovered. The ApoE4 variant is the oldest evolutionarily speaking. The ApoE3 variant is thought to have occurred through mutation around 220 000 years ago and has become the dominant version. The ApoE2 variant is thought to have appeared around 70 000 years ago.
2017 update: Other versions have been identified, they are very rare and now called apoe1, 5, 6, and 7 .... more mutations may be identified in the future. You can learn more here.
The ApoE-e4 variant is what our forum is mainly about. It is a risk factor for Alzheimer's disease (specifically "late onset" Alzheimer's disease, abbreviated "LOAD") and heart disease. I hope to lead you through the basic science in understanding this gene and its effects on so many parts of our bodies, but most of all I hope to give you hope that there is much we all can do to lower our risk of developing Alzheimer's, and to help sufferers when this has unfortunately already started. (Alzheimer's is usually abbreviated AD. You will see us use a lot of abbreviations in our chatting. If I have missed out explaining any, please ask me in a thread in this section of the forum. There is a glossary for this Primer that can be found here. (You can open it in a separate tab as a reference )
A little bit of background about myself: I am a doctor in a beautiful small country far away from the USA. I work in family medicine (USA word) general practice (British based country word). I have a passion for education, and a passion for life. Together I hope to help you understand as much as you need. Please don't feel shy to ask anything you want, I learn something from every single question, and so will our other members. Please ask any questions you wish by starting a new thread under this section. I will try and answer as speedily as I can manage. I work full-time so it might not be as fast as you might wish. I apologise in advance.
Here is a picture of a beautiful beach in my country:
A small heads up: Not all our members agree on some of the strategies I will discuss. Not all scientists agree on the strategies either. It is a complicated area. I will try and introduce the least controversial/most widely accepted strategies and at all times I will try a keep a middle ground as is my philosophy, summarized here.
Once you have got to grips with the basics and I hope have got the most important areas of lifestyle change under control, you can then decide which of the more complex areas you wish to explore and which might suit your individual circumstances best. There is no "one size fits all". Some of our members follow extra strategies such as caloric restriction, deep ketosis, hacking of lipids etc. There is great discussion on these and other areas on our forums. I will highlight where the areas of the most discussion lie. I hope that you will join us in exploring these areas. Discussion is excellent, it makes us think.
So let's start this together!
Since this thread is information rich, here are some links to quickly navigate to specific topics:
Glossary for Primer
So what is this ApoE4 all about?
What is a protein?
List of basic strategies
Strategy 1. Lowering insulin resistance
Blood tests that measure IR
Strategy 2. Exercise
Some scientific concepts around evidence: (1) RCT aka randomised controlled trial
Some scientific concepts around evidence: (2) observational studies
Some scientific concepts around evidence: (3) Mice studies
Some scientific concepts around evidence: (4) correlation is not causation
Strategy 3. Sleep
Strategy 4. Stress management
Strategy 5. Eating a healthy diet with heaps of micronutrients.
A macronutrient is fat or carbohydrate or protein
Fats aka lipids
Glycaemic Control trumps Lipids, Every Time
First important kind of Lipid: Sterols
Second important kind of Lipid: Fatty Acids
Third important kind of Lipid: Triglycerides
Fourth important kind of Lipid: Phospholipids
Mitochondria
The ambiguous word "fat"
Strategy 6. Cognitive enhancement
Strategy 7. Social enhancement
Strategy 8. Selected supplements
Oestrogen/estrogen aka HRT (hormone replacement therapy)
Chocolate/Cacao
Strategy 9. Reducing inflammation in your body.
Strategy 10. Avoid Smoking
Strategy 11. Avoid having high blood pressure
Strategy 12. Avoid hitting your head hard enough to sustain a concussion
Biomarkers
Conclusion
Ancestral Health Symposium - Diet and Cognition notes and video - Aaron Blaisdell
TNF-alpha, IgF-1 and mTOR
Example of applying the strategies – Julie’s Protocol
Welcome to what I hope will be a good place to begin in getting to grips with the complexities of the APOE gene and its effects. This thread is aimed at those just starting their exploration of the complex issues facing us all. It will be locked, I will add to it from time to time. There is a huge amount of information that I need to synthesise for you, I have just started and hope to add at least one section per week. So please be patient while I make my way carefully through from beginning to end. (For questions, comments, please start a new thread in this section.)
This primer was written in 2015. In August 2016, and again August 2017, I edited it and new sections are in italics.
Allow me to introduce myself - I am Stavia, I am a 54 year old (2019: now almost 59) woman who only learned in 2014 that I was homozygous for the gene that codes for apoE4. This means that I have two copies of the gene that codes for the apoE4 variant of a really important protein in our bodies. We colloquially on our forum abbreviate this by saying I am e4e4, E4E4, or 4/4. You will see us using this language a lot.
(The terminology I will be using is not strictly correct, but it is currently colloquially accepted. The real scientific accurate way is to call the gene APOE and our variant APOE-ε4. The ε is the Greek letter epsilon which corresponds to the letter "e" in our alphabet. Scientists often use Greek letters to name things. So strictly I should say I am homozygous for APOE- ε4. The protein made by this gene that causes all the fuss is called apolipoprotein E. It is abbreviated apoE4.)
We all have two copies of every single one of the thousands of genes coded in the DNA in the nucleus of every cell of our body - one from our mommy and one from our daddy (when a mommy and a daddy love each other very much....but I digress, it's my quirky sense of humour!) The general word used to denote that there are two copies is allele. So each gene has two alleles.
The APOE gene has three commonly different possible versions/alleles. So you might have one copy of the e4 version, or two, or none. The second copy might be e2 (least common, less than 10%) or e3 (most common, about 60%). 15 to 20% of people carry at least one apoe4 allele, depending on the ethnicity:
So the options for your two APOE alleles can be:
e4/e4 - we sometimes abbreviate this as 4/4
e3/e4 - 3/4
e3/e3 - 3/3
e2/e4 - 2/4
e2/e3 - 2/3
e2/e2 - 2/2
If both alleles are identical, we use the word homozygous to denote this - "homo" being Greek for "the same". If the two alleles are different, we use the word heterozygous to denote this (Greek for different). Thus 4/4 is homozygous for ApoE4, 3/3 is homozygous for ApoE3 etc whereas 3/4 is heterozygous for apoE4.
There was originally no apoe1, it was a labeling error 40 years ago when it was first discovered. The ApoE4 variant is the oldest evolutionarily speaking. The ApoE3 variant is thought to have occurred through mutation around 220 000 years ago and has become the dominant version. The ApoE2 variant is thought to have appeared around 70 000 years ago.
2017 update: Other versions have been identified, they are very rare and now called apoe1, 5, 6, and 7 .... more mutations may be identified in the future. You can learn more here.
The ApoE-e4 variant is what our forum is mainly about. It is a risk factor for Alzheimer's disease (specifically "late onset" Alzheimer's disease, abbreviated "LOAD") and heart disease. I hope to lead you through the basic science in understanding this gene and its effects on so many parts of our bodies, but most of all I hope to give you hope that there is much we all can do to lower our risk of developing Alzheimer's, and to help sufferers when this has unfortunately already started. (Alzheimer's is usually abbreviated AD. You will see us use a lot of abbreviations in our chatting. If I have missed out explaining any, please ask me in a thread in this section of the forum. There is a glossary for this Primer that can be found here. (You can open it in a separate tab as a reference )
A little bit of background about myself: I am a doctor in a beautiful small country far away from the USA. I work in family medicine (USA word) general practice (British based country word). I have a passion for education, and a passion for life. Together I hope to help you understand as much as you need. Please don't feel shy to ask anything you want, I learn something from every single question, and so will our other members. Please ask any questions you wish by starting a new thread under this section. I will try and answer as speedily as I can manage. I work full-time so it might not be as fast as you might wish. I apologise in advance.
Here is a picture of a beautiful beach in my country:
A small heads up: Not all our members agree on some of the strategies I will discuss. Not all scientists agree on the strategies either. It is a complicated area. I will try and introduce the least controversial/most widely accepted strategies and at all times I will try a keep a middle ground as is my philosophy, summarized here.
Once you have got to grips with the basics and I hope have got the most important areas of lifestyle change under control, you can then decide which of the more complex areas you wish to explore and which might suit your individual circumstances best. There is no "one size fits all". Some of our members follow extra strategies such as caloric restriction, deep ketosis, hacking of lipids etc. There is great discussion on these and other areas on our forums. I will highlight where the areas of the most discussion lie. I hope that you will join us in exploring these areas. Discussion is excellent, it makes us think.
So let's start this together!
Since this thread is information rich, here are some links to quickly navigate to specific topics:
Glossary for Primer
So what is this ApoE4 all about?
What is a protein?
List of basic strategies
Strategy 1. Lowering insulin resistance
Blood tests that measure IR
Strategy 2. Exercise
Some scientific concepts around evidence: (1) RCT aka randomised controlled trial
Some scientific concepts around evidence: (2) observational studies
Some scientific concepts around evidence: (3) Mice studies
Some scientific concepts around evidence: (4) correlation is not causation
Strategy 3. Sleep
Strategy 4. Stress management
Strategy 5. Eating a healthy diet with heaps of micronutrients.
A macronutrient is fat or carbohydrate or protein
Fats aka lipids
Glycaemic Control trumps Lipids, Every Time
First important kind of Lipid: Sterols
Second important kind of Lipid: Fatty Acids
Third important kind of Lipid: Triglycerides
Fourth important kind of Lipid: Phospholipids
Mitochondria
The ambiguous word "fat"
Strategy 6. Cognitive enhancement
Strategy 7. Social enhancement
Strategy 8. Selected supplements
Oestrogen/estrogen aka HRT (hormone replacement therapy)
Chocolate/Cacao
Strategy 9. Reducing inflammation in your body.
Strategy 10. Avoid Smoking
Strategy 11. Avoid having high blood pressure
Strategy 12. Avoid hitting your head hard enough to sustain a concussion
Biomarkers
Conclusion
Ancestral Health Symposium - Diet and Cognition notes and video - Aaron Blaisdell
TNF-alpha, IgF-1 and mTOR
Example of applying the strategies – Julie’s Protocol