An introduction to ApoE4, biochemistry, and possible prevention strategies

A primer for newbies and old pros alike.
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An introduction to ApoE4, biochemistry, and possible prevention strategies

Postby Stavia » 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 (2017: now almost 57) 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 labelling 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) and also aged and dementia care. 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:

hastings.jpg



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

One of our members has kindly produced this primer in audio format. I have not reviewed it for accuracy, but here it is.
https://www.dropbox.com/s/d5s0epw83ttay ... 2.m4a?dl=0
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Re: An introduction to ApoE4, biochemistry, and possible prevention strategies

Postby Stavia » Mon Jun 15, 2015 1:41 pm

So what is this ApoE4 all about?

It’s very scary to open up 23andMe results or run your raw data through Promethease or similar and see red words flashing at you “high risk”. When I did this naively a year ago (2017 update: it's now over 3 years and I promise the pain fades) I went to pieces and cried for a week. Thank heavens I found this group very soon and everyone rallied and helped me over those awful first weeks. The first thing is to stay calm and think carefully.

GENETICS IS NOT DESTINY. Not everybody with ApoE4 gets Alzheimer’s Disease (I will abbreviate this as AD from now on). Not everyone with ApoE4 gets heart disease. (Doctors call this cardiovascular disease or CVD – this means heart attacks and strokes. Vascular means our arteries, cardio means our hearts).

The reason why not everyone gets these is twofold.
1. We are extremely complicated and scientists have only identified a few of the many, many genes in our body that work together to make us ourselves. Also, everyone is different, which makes it harder to work out what exactly is going on.
2. Our genes switch on and off depending on their environment. This is called epigenetics Epi is Greek for “outside, around”.
a. This means that everything in the body surrounding the DNA affects how it acts. THIS IS UNDER YOUR CONTROL. This is one of the main purposes of our forum – to help each other make the best choices in lifestyle and diet so that our ApoE4 variant affects us less.
b. Scientists have identified a range of factors that we think can help us prevent ApoE4 from causing AD or CVD in us. I will explain them a bit later.
c. Please take a minute to think this very carefully – you have the power to change your future, by the choices you make every day. I am not going to pretend it will be easy, but I promise you that you will feel much, much healthier for the changes you will make.
d. And the changes that are recommended will decrease your risk of cancer, diabetes, heart disease and dementia by 80%. (This is widely accepted, that basic lifestyle changes are effective in disease prevention. Taking a supplement and not making any other changes is not going to significantly work as prevention. A place to start if you want to know more about diet and lifestyle in all chronic diease, is the work of the widely respected public health specialist Dr David Katz. There is now heaps more evidence, as of 2017. We will be discussing specifically the role of these factors in AD in our primer and on our forum.
2017 update: Another good place to dip into various researchers' and scientists' view is Youtube - e.g. Ancestral Health Society videos on presentations over the years at their conferences. There are also many bloggers who explore the nuances, you will find us discussing their opinions on our forums.

Ok – what is ApoE4 and why is it a problem?
ApoE is a protein that helps carry cholesterol around the body. (I will explain what a protein is in part 3.) ApoE comes in mainly three forms – e2, e3 and e4 as discussed in part 1. It has at least a hundred complicated functions in the body. Our ApoE4 doesn’t work as well as the others and causes problems in many places. Scientists actually don’t agree yet on exactly why it is a problem, there is the “amyloid” hypothesis, the “tau” hypothesis, the “prion” hypothesis, the “mitochondrial” hypothesis. These are discussed in detail on our forum. 2017: It also appears that ApoE4 has effects on genes inside the nucleus of our cells - switching some on and some off. You can learn more here and here.

Below is a diagram of how incredibly complicated the effects of ApoE4 are on many parts of the body.
Figure3.jpg


Glossary for Primer
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Re: An introduction to ApoE4, biochemistry, and possible prevention strategies

Postby Stavia » Mon Jun 15, 2015 1:45 pm

What is a protein?

A protein is a kind of molecule found in living things. Atoms are the building blocks of everything in our bodies. Kinds of atoms are for example carbon, nitrogen, hydrogen, oxygen, selenium, magnesium etc. Have a look at the periodic table to get an idea of the different kinds of atoms. The atoms can be arranged in groups of various combinations. A group of atoms is called a molecule. Depending on the kind of arrangement the different kinds of molecules have different names. A protein molecule usually has a shape like a string of beads. The beads are molecules called amino acids. So a protein molecule is a big molecule made of smaller molecules called amino acids. The amino acids connect together in a special shape, which is specific for each particular protein. They are made up of nitrogen, oxygen, carbon, hydrogen in a kinda zigzag-straight arrangement seen here.

So...atoms group together to form molecules. One kind of molecule is called amino acid. Amino acids group to form proteins. Every kind of protein has a different sequence of amino acids which gives the protein its specific characteristics. The sequence of amino acids making each protein is determined by our genes - the genes hold the codes for the sequence of amino acids making up proteins.

What is important to know is that the protein string of beads isn’t straight. It is kinked. And here “form determines function”. Its squiggly shape determines how it works. And ApoE4 is a different shape to ApoE2 and ApoE3. Those with different forms of the ApoE gene have a couple of different animo acids at critical places in the ApoE protein molecule, causing the molecule to kink at different places. This has profound implications.

Here is a diagram of the shape of the molecules. You can see that our E4 variant is kinda squooshed together and the E3 variant is more open. Dr Robert Mahley, one of the discoverers of this protein, is working with his team on a corrector for the E4 which will push it open to look like the E3 shape. Many other researchers are working on different methods to overcome the problem. But there is nothing imminently available for us. (still not a silver bullet as of 2017)

untitled.png


Extra for experts: Below is the list of SNPs that code for the 3 major variants of the APOE protein. You can use this table to work out your APOE status from your raw data on 23andme if you wish.

Genes are the code for the body to build proteins. The DNA in out bodies is made up of a sequence of nucleotides, each group of three of these codes for one amino acid. There are only 4 nucleotides in DNA - adenine, guanine, cytosine and thymine. They are abbreviated A, G, C and T. The DNA is double stranded - like a ladder - and the strands are complementary - A always bonds with T and C always bonds with G. They are read in triplets: for instance GCA is alanine, GGC is glycine etc.

An "SNP" (short for single nucleotide polymorphism) is a single change in one nucleotide, resulting in a different amino acid being incorporated into the protein being built by that gene's code. Some snp's have no effect, some have profound effects. The APOE molecule's shape ie APOE2, APOE3 or APOE4, depends on two single places in the gene being different which results in two different amino acid at two places in the protein. These two single changes result in a different shape of the protein and hence a different function.

The changes are given names preceded by the letters "rs". They can be searched on 23andme. Every change is given an unique rs-number. Snpedia has a list of every single identified snp with each's unique numbers.
This picture is taken from Genomes Unzipped

Capture.PNG


Here is SNPedia's more complex table

Capture.PNG


More extra for experts: how do proteins carry out their functions? They do this by binding to little molecules called receptors on the cell surfaces. Remember each protein has an unique shape. There are receptors corresponding to each protein (each receptor may have several proteins that can bind to it) - and the protein fits in like a lock and key. Once fitted in, the receptor can now do its job. The numbers of receptors can increase (up regulation) or decrease (down regulation) in response to other influences.

Drugs work by binding to receptors and either causing an effect or blocking the action of the receptor. For instance caffeine binds to the adenosine receptor and blocks it from working. Adenosine accumulates during the day and makes us sleepy. On caffeine, your body senses that the receptors aren't activating, so it makes more (upregulates them). If you stop the caffeine suddenly you are left with many more adenosine receptors to bind to the normal amount of adenosine in the body and wham! you are exhausted and go through withdrawal until your body can down regulate the receptors back to normal levels.


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Re: An introduction to ApoE4, biochemistry, and possible prevention strategies

Postby Stavia » Mon Jun 15, 2015 1:46 pm

List of basic strategies

So you should now understand enough to look at what you can do today to reduce your chances of developing AD or CVD, by utilising epigenetics, ie creating an environment where the effects of your ApoE variant are lessened. I will explain more scientific terms later – concepts such as what is a carbohydrate, a fat, what a cell actually is, what are mitochondria, what is actually going on in our brains and hearts, and what the blood tests actually mean.

But now we need to start on simple steps.

I will be discussing possible positive strategies such as:

1. Lowering insulin resistance Many researchers and doctors, and many on our forum including myself, think this is the very most important thing you can do to hopefully prevent AD. In addition, it is critical for prevention of CVD. This latter statement is not controversial at all.
2. Exercise
3. Sleep
4. Stress management
5. Eating a healthy diet with heaps of micronutrients. These include vitamins, minerals and the amazing molecules made by plants - called phytochemicals. There are also nutrients in animal-based food. See this article. We will discuss what a "healthy" diet means to different people.
6. Cognitive enhancement
7. Social enhancement
8. Taking some important supplements if you are not able to get what you need from diet or sunlight. We will also discuss the range of possible supplements you can consider.

Many of these things together will do what I and many other doctors believe is the second most important thing you need to achieve after reducing insulin resistance. That inflammation in the body is not good is not controversial. What is controversial is if reducing it will definitely reduce the chances of developing AD. Although it is 9th on this list (because that is the way I can explain more clearly), it is as important as insulin resistance in my opinion.

This is something that is not just one thing, but a combination of factors. We will discuss this a bit later.
9. Reducing inflammation in your body. See this article.

And then things you should avoid
10. Avoid smoking
11. Avoid having high blood pressure
12. Avoid hitting your head hard enough to sustain a concussion

I will discuss these one at a time.

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Re: An introduction to ApoE4, biochemistry, and possible prevention strategies

Postby Stavia » Mon Jun 15, 2015 1:48 pm

1. Lowering insulin resistance.
2. Exercise
3. Sleep
4. Stress management
5. Eating a healthy diet with heaps of micronutrients.
6. Cognitive enhancement
7. Social enhancement
8. Selected supplements
9. Reducing inflammation in your body.
10. Avoid Smoking
11. Avoid having high blood pressure
12. Avoid hitting your head hard enough to sustain a concussion


What is insulin resistance? (Abbreviated as IR)
A bit of background: I have simplified this explanation a lot just to give you a bit of context and a place to begin. I recommend that you get to grips with the details and nuances later as this is likely to be one of the most critical aspects of prevention of AD.

Carbohydrate: Another kind of molecule that is made by living things. This is a different arrangement to the protein shape we have already discussed, and it behaves differently in the body because it has a different shape. Remember, the shape of molecules is very important and determines their effects in the body. Here the atoms are still mainly carbon, hydrogen, oxygen.

Digression: The main so-called building blocks of life are carbon hydrogen, oxygen and nitrogen. We call life on earth carbon-based. This has happened because carbon is a very versatile atom and can bond with 4 other atoms in a very stable arrangement. Carbon can form nice long chains or pretty rings. The next element in the periodic table that can do this is silicon, and science fiction writers have contemplated silicon-based life perhaps occurring on another planet.

We eat carbohydrates in our food. These molecules can be long chains or short chains. The smallest ones are called glucose, fructose and galactose. The scientific term for all of them is monosaccharide. We need to learn some words – sucrose is what we know as table sugar. We often colloquially call these sugars or simple sugars– scientifically not quite right, but we understand what we mean. The molecules of sucrose are made of one molecule of glucose linked to one molecule of fructose. Naturally occurring sources of sucrose include honey, cane sugar, beet sugar. (Lactose, found in milk, is made of galactose and glucose. Maltose is glucose plus glucose). These short carbohydrates are often called simple carbohydrates. The body breaks them down in the gut very fast and the resulting monosaccharide (usually glucose and fructose) gets absorbed into the blood very fast .

Longer chains of carbohydrate molecules are found in other foods. Complex carbohydrates is often what the longer chains are called. They take longer for the body to digest but they also ultimately are digested mainly to glucose molecules which also gets absorbed into the blood. Examples are grains which have a lot of carbohydrates per weight , veggies which have a low amount of carbohydrates per weight.

Glucose is a major source of energy for our bodies.

How does the glucose formed from digestion of simple and complex carbohydrates make energy? The glucose goes into the inside of the cells in our body with the help of a molecule called insulin.

Our bodies are made of billions of tiny units called cells. Inside the cells are tiny little "batteries” called mitochondria which use the energy from the glucose and turn it into a different form that the cells can use. This molecule that the cells can use is called ATP. An extremely simplified way to understand is that the glucose goes into the mitochondria and energy comes out.

Extra information as a digression: The process by which the ATP is ultimately made from glucose is called the Krebs, citric acid, or TCA cycle.

I just want to mention briefly that fats can also fuel the mitiochondria to produce ATP. This is called beta-oxidation. This becomes important later when we discuss mitochondria and ketones as fuel.

If we eat more glucose than our bodies need for fuel, it has to be stored. Some of it can be stored in long chains called glycogen in the liver and the muscles. Only a finite amount can be stored like this, not a lot. The rest is converted into fat and stored as fat. A similar thing happens with the fructose half of sucrose (table sugar), but what isn’t needed from fructose for energy immediately is changed into fats more than the glucose is. We have no limit of how much fat we can store from eating excess glucose and fructose. We can pack it on forever.

Our bodies know how much glucose there is in each meal, even the glucose chains in the complex carbohydrates. If we eat more carbohydrates than is prudent in a meal, they are broken down into more glucose, it goes into our blood, and the pancreas senses this and produces more insulin to cope with the bigger glucose load. The body can also sense the carbohydrates as they hit our small bowel, explained here. This would be all good but unfortunately as we get fatter or inactive our cells don’t respond to the insulin released by the pancreas very well. Thus, the body has to make even more insulin than it would in a thinner person to deal with the glucose produced from the food. This means that the glucose takes longer to be dealt with and is higher in the blood that it should be for longer than it should be, and the insulin in the blood is higher than it should be. This is called insulin resistance. We abbreviate it IR. Eventually the body just can't cope and this becomes full-blown type 2 diabetes where the blood sugar levels are persistently too high. The last stage is that the pancreas wears out - secondary pancreatic failure - and just cannot produce any more insulin, and injections of insulin are needed.

IR has many adverse effects – some related to the high glucose levels in the blood, some related to the high insulin levels in the blood, some related directly to the fat in the cells. Lots of bad things come from this in many organs, including the brain and heart.

So if the insulin resistant person eats what we have explained as simple carbohydrates, they are broken down very fast to glucose. The insulin resistant person can’t pack away the glucose into the cells fast enough and the glucose level in the blood goes much too high. Also if the insulin resistant person eats too many complex carbohydrates, even though the glucose is released slower, the body still can’t cope with the total amount and the glucose in the blood goes too high. You will see on the forums that many of us measure our blood glucose levels before and after eating. This is so we can see if we are eating too many carbohydrates which push our blood glucose levels too high. We use a glucose meter and prick our fingers to test.

If IR gets very severe, it becomes full blown diabetes. There is what we call a spectrum – it goes smoothly from normal to IR to diabetes. IR is just a place on the road to diabetes. But it can be reversed. I promise. This is not controversial at all. It is under your control. The next section will discuss what we can do about this.

Here is an excellent youtube presentation by psychiatrist Dr Georgia Ede on IR and the brain,
Here she is at our 2017 meet-up in San Diego

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Re: An introduction to ApoE4, biochemistry, and possible prevention strategies

Postby Stavia » Mon Jun 15, 2015 1:50 pm

What do I do about IR? Executive summary – stay lean, lose your belly fat, eat no processed sugar and limit your starchy carbohydrates. Exercise.
I and many other doctors believe that this is the single most important thing you can alter to reduce your chances of many diseases.

2017 Update: Here is Dr Georgia Ede's explanation of how this works. Her website is a wonderful resource.

Here is a scientific article explaining in detail what effects IR and diabetes (the stage after IR) have on AD.

Here is an article showing that IR is linearly associated with cognitive decline

1. Keep a healthy weight.
a. BMI is a crude tool, but it is a guide. Unless you are very muscular you should have a BMI <25. If you are small framed or of Indian or other Asian ethnicity 23 is a better goal. But you can have a BMI of 23 or 22 and still have IR - the best measurement is the following:
b. You should have no belly fat. At all. Nothing. Belly fat causes IR and shows that a person has IR. The reasons why belly fat is related to IR are complex. Here is a link to learn a little more. By belly fat I don't mean fat just under the skin - this is called subcutaneous fat and is not as dangerous as the fat inside the belly - as the latter creeps into the organs such as liver, pancreas and heart and causes nasty things. We attended a wonderful lecture on this by Dr Worm from Germany at LowCarbSan Diego 2017
c. Waist circumference is a better measure of IR than BMI. Below are charts – but everyone is individual. A tape measure is very cheap. Or use a mirror. You don’t necessarily need expensive blood tests.
d. If you have belly fat don’t despair! We can help you drop it. It will take time but it is doable. I have lost 40 pounds since I joined the forum doing what most of us do. (and 50 in total). And feel so much better. I have kept it off for over 3 years now by following a long-term sustainable path. My weight does fluctuate by 5 pounds depending on my stress levels though!

2. Avoid “sugar” aka simple carbohydrate containing foods.
a. These are often hidden in the food label. Don’t trust anything in a box or packet and learn to read a food label.
b. Other sneaky words used for hidden sugar are: Sucrose, Maltose, Dextrose, Fructose, Glucose, Galactose, Lactose, High fructose corn syrup, Glucose solids, honey (just because a bee made it doesn’t make it any better for IR), agave, molasses, Cane juice, Dehydrated cane juice, Cane juice solids, Cane juice crystals, Dextrin, Maltodextrin, Dextran, Barley malt, Beet sugar, Corn syrup, Corn syrup solids, Caramel, Buttered syrup, Carob syrup, Brown sugar, Date sugar, Malt syrup, Diatase, Diatastic malt, Fruit juice, Fruit juice concentrate, Dehydrated fruit juice, Fruit juice crystals, Golden syrup, Turbinado, Sorghum syrup, Refiner's syrup, Ethyl maltol, Maple syrup, Yellow sugar.
c. Remember we use the word "sugar" loosely to mean a few things: table sugar aka sucrose, small carbohydrate molecules or disaccharides (for instance maltose which is 2 molecules of glucose joined together is just as bad as sucrose) , and also we use it as a synonym for blood glucose levels when we use fingerpick measurements. The last one is often abbreviated as BSL or blood sugar level.

3. Limit starchy carbohydrates.
a. Starch is a word used for a long carbohydrate molecule that is basically a long chain of glucose. This is what a potato is made of for instance, it is a concentrated storage form for energy to the baby plant will use when it starts growing. Also wheat, rice, maize and cassava. Your body will chop up the chain into glucose molecules in no time at all. Brown rice is no different ultimately in the body, neither are whole grains. They are just broken down a little slower, sometimes not that much slower. They are still made up of glucose chains.
b. This means I and many mainstream doctors recommend limiting breads, rice, pasta, grains, also limiting starchy veggies like potato, sweet potato and focussing on non-starchy veggies like leafy greens, broccoli, cauliflower, zucchini, eggplant, carrot, tomato, yellow bell pepper and mushrooms etc (use your imagination – I have tried to pick one of each colour) – all the veggies across the rainbow of healthy yummy colours. The latter are made up of carbohydrates too, but there is far less amount in for instance greens than a potato and it is digested slower by the body because it is trapped in fibre that the body has to break down first before it can get at the glucose, giving it time to digest it without the glucose in the blood going too high.
c. Start by looking at how much of the starchy carbohydrates you are eating and try to slowly reduce these and replace them with the non-starchy veggies. The other reason for eating lots of veggies is to have heaps of nutrients – more on this later.
d. What about fruit? Fruit contains simple sugars – but much less than for instance a potato, because of the fibre it is absorbed slowly, and has much less impact on blood glucose levels. Berries are thought to be the best kind of fruit for IR people and for us ApoE4s because they are digested very slowly, have heaps of fibre, and also contain heaps of good chemicals. Eat the skin of your fruit eg of an apple. Don’t eat too many fruits a day and not all at once – maybe two portions a day for a woman and three for a man to start with. Fruit juice is a no no – the fibre is all gone and the carbohydrates get absorbed very fast. It is as bad as sugar. Manufacturers use “contains fruit juice” to con you into buying their product. It is pure glucose and fructose.
e. What about fuel for exercise? Absolutely if you cannot exercise without starchy carbs, then please make sure you don't eat more of them pre-exercise than you will burn off. This is where I recommend checking that your blood glucose levels don't go too high and that you are not overestimating the amount of carbohydrates that you will need as fuel for a workout. I for instance can do a hour long intense boxing class on an apple and a glass of milk. 2017 Update: Now I do it fasting. in 2015 I had to eat before exercise as I was not yet keto-adapted. Perhaps in our discussions we can explore how much each of you needs for exercise. Many of us on the forum exercise fasting, they can do this because they are using ketones as fuel rather than glucose (this is why I mentioned the way mitochondria can produce fuel in the form of ATP both from glucose and from fats). This is an area you can explore later if you wish.

4. Exercise.
a. This makes the cells more sensitive to the insulin, so that body has to make less of it to get the glucose into the cells. It is crucial both for IR and for other reasons we will discuss later.
b. We recommend starting slowly at 5 to 10 mins at a time if you are unfit and ultimately aim for 30 to 45 mins, most days of the week. Please do not start too fast and injure yourself. This has to be sustainable. This amount of exercise should not need any extra food as fuel.
c. You should aim for being puffed out in your exercise; you should still be able to talk though. Depending on your age, you might want to aim for a heart rate of 120 to 160/min or whatever is comfortable while still working moderately hard. Here is a start as a rough guide - but this is very individualized. If you have significant medical conditions please discuss with your doctor first.
e. Anything you enjoy is great – options are walking fast, running, cycling, swimming, group classes, boxing, dance – whatever you wish. The important thing is to develop a sustained programme of at least moderate intensity exercise.
f. Yoga, tai chi or pilates are good for other reasons (muscle strength, co-ordination, balance, stress management), but are not enough IMO for reducing IR.
g. I and most doctors do recommend a mixture of aerobic exercise and weight /strength training because we want you to maintain or build muscle as well. Muscle is very important for at least a couple of reasons - for reducing IR, and muscle loss is thought to be a risk factor for AD.
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Re: An introduction to ApoE4, biochemistry, and possible prevention strategies

Postby Stavia » Mon Jun 15, 2015 1:51 pm

Here is a list of some blood tests that you might see us discussing on the forum.

Blood tests that measure IR include
1. HbA1c . I recommend keeping this under 5.5% and preferably closer to 5%. For those not in the USA, the levels convert to under 37 mmol/mol and preferably closer to 32mmol/mol. Some of us manage to keep our HbA1c at 5% or lower (31mmol/mol). IMO It may not be necessary to be as low as this. So that you understand how high it can go, in diabetes we see levels of greater than 6.7% (50 mmol/mol). Poorly controlled diabetics may have levels of 8% (64mmol/mol) or 9% (75mmol/mol). The highest I have ever seen was around 15% (140mmol/mol)!
2. Fasting insulin. I recommend aiming for under 7mU/L, and as a final goal as close to 5mU/l or under as you can get. Some of us manage to get it down to 3mU/L. This may not be necessary IMO to be as low as this.
3. Blood glucose both fasting and an hour and two hours after meals. I recommend that if you are testing, or your doctor orders this test, that your fasting glucose is under 99 mg/dl (5.5 mmol/l) to start, and as you get better at managing your diet and reduce IR, aim for 90mg/dl or less (5mmol/l). After eating I recommend that the glucose should not be higher than 130-ish mg/dl (7.2mmol/l) if you can manage. As you get to grips with this aspect, you might want to aim lower. It is not necessary IMO in the beginning to test your blood glucose regularly. Some of us test when we are tweaking our diets and testing different macronutrient percentages. This means we test what different amounts of fat/carbohydrate/protein percentages in our diet do to our glucose and lipids. At a later stage you might want to explore this area.
4. Another indicator of insulin resistance is abnormalities in the liver functions. The level of a liver enzyme GGT (also called gamma GT) will be raised. Excess fat is packed in the liver, and this is called fatty liver. The medical word for this is non-alcoholic steatohepatitis, often abbreviated NASH. This means that liver is not suffering from effects of alcohol, but is suffering from too much fat (“steato”) and is inflamed “-itis”. When you see the suffix “-itis” this means inflamed. I will explain what inflammation means in a specific section. It is complex but very important.
5. Lastly we look at raised triglycerides in the lipid panel (made from excess carbohydrates). I recommend that triglycerides (TGs is the abbreviation) are under 70mg/dl ( 0.8mmol/L)

Now you are ready to delve into the forum topics discussing IR and what we call “glycaemic/glycemic control”. “Gly” means glucose and “aemic” refers to a condition of the blood. This means the level of glucose in the blood and how well it is controlled. The USA spelling is glycemic. British based countries spell it glycaemic.

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Re: An introduction to ApoE4, biochemistry, and possible prevention strategies

Postby Stavia » Mon Jun 15, 2015 8:46 pm

1. Lowering insulin resistance.
2. Exercise
3. Sleep
4. Stress management
5. Eating a healthy diet with heaps of micronutrients.
6. Cognitive enhancement
7. Social enhancement
8. Selected supplements
9. Reducing inflammation in your body.
10. Avoid Smoking
11. Avoid having high blood pressure
12. Avoid hitting your head hard enough to sustain a concussion



Exercise

Most mainstream doctors and scientists believe that physical exercise is beneficial for prevention of many chronic diseases. There is a lot of evidence linking inactivity with higher levels of AD, and regular exercise with lower levels of AD. In 2017 - this is still considered to be very important.

Here is an article from the NY Times discussing that it may be even more beneficial for those with ApoE4.

Here is a link to the abstract (a summary of a scientific paper, always under the title, before the body of the paper) of a more complex paper concluding that the evidence is in favour of exercise. Everyone can access PubMed (a collection of all scientific papers, usually just the abstract, able to be accessed by anyone)

Access to the full text of many scientific journals is limited to researches and university staff and students.

And here is a thread where we discuss a paper:

And here is a thread with Mac's excellent summary of a range of papers, his summary is on page 4 of the thread

Another discussion paper.

In my next post I will explain how to assess evidence and what is available on Google. I have given you three levels of information. The first is a reporter’s view of a scientific paper. The second is an abstract which is an executive summary. The last is the actual full text of the journal article. In my next post I will also explain the way scientific papers are written and published.

What exactly does exercise do to benefit our brains?

This is again very complex and scientists don’t understand fully everything that is happening during exercise.
However, we know the following:

1. Brain-derived neurotrophic factor (BDNF) is an extremely important molecule made by our brains, and critical in learning and memory. We make more of it in response to moderate to high intensity exercise. Effects of BDNF include support of brain cells connecting to each other in a network (more “synapses” or connections), support of brain plasticity (how the brain cells adapt their connections and functions as they react to changing circumstances), growth of new blood vessels providing more blood to the brain (called angiogenesis), support of neurogenesis (we can grow a limited number of new brain cells from our stem cells in our brains) and enhancement of neuronal survival (our neurones live longer). BDNF particularly is needed in the hippocampus – the seat of our memory in our brains.
2. Other growth factors are increased with exercise – GDNF (glial cell line-derived factor) and NGF (nerve growth factor). Basically growth factors are good – we need them
3. Oxidative stress is reduced by exercise. This is a complex issue – basically oxidation is bad, and our bodies need the famous “anti-oxidants” to balance oxidation. Exercise acts as an anti-oxidant, and it is a powerful one.
4. Exercise itself may also have a role in clearance of Aβ. This is a substance that accumulates in the brain in AD. You may have heard of it called “amyloid”.
5. Exercise increases blood flow to the brain, and encourages formation of new blood vessels to grow inside the brain, thus promoting good delivery of oxygen. It does this through the body making a molecule called VEGF (vascular endothelial growth factor).
6. Exercise might also be anti-inflammatory for the brain, through increasing the activity of an important molecule called SIRT1. We will discuss this later under the “inflammation” topic.
7. Exercise also reduces the incidence of diabetes, hypertension, obesity and atherosclerosis, all of which are risk factors for dementia.

How much exercise? well, the truth is that nobody knows. We (scientists and doctors) know that mild exercise does not increase the BDNF production so is unlikely to be effective. We think that it should be at least moderate intensity. We know that at least 30 minutes at a time is needed for BDNF production. There are varying recommendations. IMO I feel that exercise has so many benefits that it should be taken most days, in a decent dose. Two hours is IMO probably not necessary, one hour is amazing, but 30 to 45 minutes is a good goal to aim for as a beginner - but please start slowly if you are a beginner, maybe 10 to 15 minutes at a time. I recommend taking exercise most days of the week if possible, 3 days as a minimum. Once you get into the routine, you can aim at an hour most days, which IMO is optimal.

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This is probably a good place to explain some of the structures in the brain, as I have introduced the concept of BDNF as a molecule that works in the brain cells and I wish to show you some details.
The thinking parts of our brains are made up of millions of cells called neurones. Here is a picture.
neuron.png

The neurons “talk to” each other by connecting their axons to dendrites of an adjacent neuron. The axon is the long bit, the dendrite is the bushy short bit. They connect not physically, but by molecules moving from the axon to the dendrite across the gap called synaptic cleft. The molecules are made in little bubbles called vesicles, then they are secreted by the axon and move across the gap to lock into special places called receptors on the dendrite. This connection is called a synapse. The more connections aka synapses we have, the better our brains perform cognitively.
Here is a picture:
synatic cleft.1.png

This is how many molecules work in our bodies – by locking onto specific receptors. This is why I said that shape determines function – each special molecule has a special shape and its receptor has that perfect shape for it to fit into and activate its effect. Many drugs work by having the same shape as a natural molecule thus can fit into a natural receptor and initiate an action or outcome.

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Re: An introduction to ApoE4, biochemistry, and possible prevention strategies

Postby Stavia » Mon Jun 15, 2015 9:45 pm

Now I feel it is time to introduce some scientific concepts around evidence.
First: RCT aka randomised controlled trial:

If you throw a dice 3 times, you might end up with all sixes each time. This doesn't mean that if you throw it 100 times, sixes will come up every time. It was "chance" that gave you the first three throws. If a scientific trial has too small numbers, the results might be pure chance. Thus we should not trust trials with very few numbers. Some trials have only 4 e4's in them. One person might try something and say they felt better. Not good enough IMO. I personally like a trial to have at least 200 people in each "arm". An arm is a group - one will have the intervention, one group will not - this latter is called the control group.

Then there is "bias". We all have bias. If the doctors checking the intervention group really really want it to work, they might imagine the people are better than they actually are. Thus the best trial is where the researchers don't know which person has had the intervention. Then if the people know they are taking the active drug for instance, they might imagine they feel better. So the very best trials are what we call "double-blinded" where neither the researchers nor the patients know who is taking what. This is a bit difficult if the intervention is exercise!

Then finally the two groups have to be similar in every respect we can manage. You don't want the researchers choosing who gets the intervention because maybe they like that person, or they are a friend, or like the same baseball team, or are pretty. The people need to be "randomised" to the groups.

So the very best we can do its a Randomised, controlled, double-blinded trial. If double-blinded is too difficult then randomised, controlled trial is also very good. (Abbreviated RCT)
https://en.wikipedia.org/wiki/Randomized_controlled_trial

2017: Another warning about bias. If a researcher starts a trial with a pre-determined favoured outcome, it is more likely that the results will show his/her hypothesis is correct. This may not be actual lying, it might be interpreting the data in a way that favours their preferred outcome. Of course sometimes it might be actual lying as well. When you read or watch an analysis of data, please first see if the presenter has declared any conflicts of interest. If not, google them. You might be surprised. Be warned: not everyone who is vocal on social media is unbiased.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917255/
You may observe arguments between differing camps - on social media, sometimes on our forum. The evidence is NOT black and white in many areas. When you investigate this, please take into account the presenter's declared or undeclared bias. This is seen in hotly debated topics such as low fat versus high fat, and vaccines etc


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Re: An introduction to ApoE4, biochemistry, and possible prevention strategies

Postby Stavia » Mon Jun 15, 2015 10:03 pm

Then we need to talk about "observational studies".
This means that we look at say people living in Japan and see that they have a low incidence of diseases such as breast cancer. Lower than women in the Western world. So we think - why? And we try and figure out - is it the diet? Is it the soy they are eating?
And we try and compare to other places in the world. Here is an example of an observational study.

http://jnci.oxfordjournals.org/content/95/12/906.full

These studies have their limitations. The scientists try and allow for every other variable they can think of. They use very smart maths called "multivariate analysis" and they try and give an answer. But it is not as good as taking 400 Japanese baby girls, feeding half of them soy based foods and half of them everything exactly the same except the soy, and seeing 60years later who gets breast cancer. (which would be an RCT). Which is impossible given our long life span. So we unfortunately have to rely a lot on observational studies. Many of our lifestyle interventions we have available to us in AD prevention are observational studies.

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