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

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

Postby Stavia » Sat Jun 20, 2015 5:11 pm

THIRD IMPORTANT KIND OF LIPID: TRIGLYCERIDES
It is best to use the word fat to denote fatty acids and triglycerides and to use the word lipids to denote all the different kinds of lipids including cholesterol, phospholipids, fatty acids, triglycerides etc. However we colloquially say fat when we mean all lipids.

We now understand what the building blocks called fatty acids look like, BUT they don't occur like this in food. They are found joined to a glycerol molecule.

The glycerol looks like this. Please note it has three little sticky out thingies that are available to hold hands with something

Glycerin_Skelett_svg.png



It loves to hold hands with three fatty acid chains. Thus we get the word triglyceride. Tri meaning three.
Now the word acid comes into play. Acid means the fatty acid molecule can give up a hydrogen atom, thus freeing a hand. It can then use this hand to hold onto one of the hands on the glycerol molecule.
Here is a picture of a triglyceride, you should be able to recognise the three fatty acids in this triglyceride. The carbons are not denoted by C's because it there can only be a C at each link in the chain. It is not necessary to write the C each time like in the ring. But it is important to denote if there is a single bond or a double bond at each place.
The red one is polyunsaturated. It has three double bonds. They are each denoted by a double line between the carbons.
Can you work out what the blue and green ones are?
(Answer is here: viewtopic.php?f=6&t=1305&start=10 )

220px-Triglyceride_Structural_Formulae_V_1.png


So what is the deal with triglycerides?
We eat triglycerides in our food. The triglycerides are made up of glycerol and three fatty acids each. We eat the triglycerides and they are chopped into the fatty acids and glycerol in our intestines so they can be absorbed. They are then reformed back into triglycerides in our blood. I will be calling triglycerides TG's from now on. The TG's are packaged together with cholesterol into particles by the liver, and the particles go through stages to eventually form LDL particles. They then go to the cells of the body for various purposes.

If there are more than we need, they are stored as fat. They are mainly stored inside the abdomen (Women store fat also under their skin and on their hips - less detrimental). This is belly fat. It is unfortunately not good for many reasons. It promotes IR, but it also secretes various hormones which cause inflammation in the body and make us hungry. Excess glucose is also converted to TGs for storage. So high TGs in the blood are a direct marker of IR. They are the excess glucose you can't burn being shuttled to your fat cells.
This is why we should not have an excess of calories. Excess TG's are stored as fat. Excess glucose is converted to TG's stored as fat. Excess protein is converted to glucose and then converted to TG's and stored as fat.

So let us assume that we are eating just enough fat for our needs. We then use it for various structural components - the skin of each cell, called the cell membrane, is made up of fats. Fats form the basis of many hormones. There are many other complex functions, but we can also use fats as fuel. This is called β-oxidation. It is pronounced "beta-oxidation". The β is the Greek symbol for the equivalent of "b" in our alphabet. This has implications for what I mentioned earlier - our mitochondria.
I will first briefly mention the last group of lipids and then get back to our mitochondria.

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

Postby Stavia » Sat Jun 20, 2015 5:12 pm

FOURTH IMPORTANT KIND OF LIPID: PHOSPHOLIPIDS

Here is a diagram of a cell.
cell-diagram-8.jpg


We have already mentioned that the outside cover is called the cell membrane. It is made up of lipids, specifically phospholipids. An important one is called phosphaditylcholine. Some of us supplement our choline, some of us try and get enough from diet.
edit 2018: new evidence that a kind of phospholipid called a plasmalogen is important in cell membrane structure and thus its function. See thread here viewtopic.php?f=16&t=4290

200px-Phospholipid_Chemicalmakeup.png


Cell_membrane_detailed_diagram_4_svg.png


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

Postby Stavia » Sat Jun 20, 2015 6:05 pm

Mitochondria

Have a look at the diagram in the post above. You will see little structures inside the cell. These are the little batteries that provide all the power for all living processes. The mitochondria are actually thought to be remnants of bacteria that crept inside primitive cells over a billion years ago. They have their very own DNA. We get our mitochondria directly from our mother's egg at the time of fertilisation, thus the mitochondrial DNA is a direct maternal line right back as far as it goes. The sperm does not contribute mitochondria.
I have always been fascinated by them since I was a child. They are IMO beyond cool. They have many other functions in the cell beside their critical role in energy production.

12-06a.jpg


The mitochondria produce energy in the form of a molecule called ATP. They do this in a complex pathway called the citric acid cycle or Krebs cycle. Basically a molecule called acetyl-CoA goes in and ATP comes out. All the parts of the cell use ATP for energy.

Citric_acid_cycle_with_aconitate_2_svg.png



Where does the acetyl-CoA come from? Usually it comes from pyruvate which is made directly from glucose. This is how glucose is the usual fuel for our bodies. But if this was the only fuel possible, we would not be able to tolerate fasting.
Fatty acids can be turned directly into Acetyl-CoA in the mitochondria and feed into the citric acid cycle. As we already discussed , this is called β-oxidation.
In addition, our livers can make molecules called "ketones" under certain conditions (fasting, exercise, high fat diet) and the ketones can directly be used by the mitochondria to produce Acetyl-CoA for the citric acid cycle.
So we are not completely glucose-dependent for energy, which is good news for us e4s, because unfortunately one of our issues is that our mitochondria do not produce ATP efficiently from glucose. Two of the top researchers in the field are Cunnane and Gibson. Here is a report from a conference in NYC that our Julie and our Martha attended, and our discussion of this event.
https://www.apoe4.info/forums/viewtopic.php?f=4&t=1244&hilit=cunnane&start=130

This is a very complex topic, but the bottom line is that our mitochondria don't work very well on glucose alone, and our brains have up to a 15% deficit in the energy we produce from glucose alone. This is shown in even in young apoe-e4 carriers as well as older people with AD. It is not controversial. If there is not enough energy being produced for on-going requirements, our brain cells are stressed (oxidative stress), produce nasty by-products (such as amyloid) and might even die (apoptosis). In addition we can't think as clearly as we should and might have brain fog. Evidence suggests that we might be able to bridge the deficit by supplying an alternative fuel source to our mitochondria. This means a little bit of ketones to produce some extra ATP to make our mitochondrial output back to what it should be if we weren't e4's. Cunnane's work suggest this might be achievable by lowish consistent levels of ketones - up to 0.5mmol/l.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478067/
This is not the same as what you might have read of as high fat ketogenic diet aimed at high levels of ketones and comprising heaps of saturated fat eg red meat and butter. This is a low level of ketones produced by not overeating calories, by fasting 12 to 18 hours a day, but eating higher fat but not necessarily saturated fat, by limiting starchy carbohydrates, by exercise, and by possible tiny amounts of supplements (Julie knows about this latter point more). So please don't interpret this to mean I am advocating bacon and eggs and butter for breakfast, fatty meat for lunch and dinner, and heaps of other saturated fats. By higher fat I usually mean fat derived primarily from EVOO, avocado, nuts, fatty fish and a bit of other sources. However, if you wish to use animal fat as your primary source of fat calories, please watch your biomarkers. It may or may not be safe in you, the evidence is conflicting at present. Please do not think that what is true for a non-E4 is necessarily true for you - there is at yet not enough evidence for effects of high saturated fat in E4s.
Finally I would like to stress that I believe you should first get your head around all the other prevention strategies before you begin to consider this facet. It is complex, if done wrongly can adversely affect your lipids, and should not be embarked on without thoroughly understanding the complex biochemical processes involved. We do have members who practise ketosis more "deeply" that what I have introduced, but they are highly experienced in its application and follow their biomarkers very carefully.
However you need to know it exists, and we discuss it on the forums. Often quite animatedly! You will see this on our forum, where there has been heated discussion and possibly conflict https://www.apoe4.info/forums/viewtopic.php?f=6&t=1344 - IMO it comes from a misunderstanding of what we specifically mean by ketosis. Unfortunately the word is used for both kinds of approaches - ours and "high-fat-ketogenic" and misunderstanding has occurred and will, I am sure, continue to occur.

Here is a thread where we discuss the complex issue of mitochondrial dysfunction in e4s
https://www.apoe4.info/forums/viewtopic.php?f=16&t=1122

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

Postby Stavia » Sat Jun 20, 2015 9:10 pm

Before I go back to prevention strategies, I wish to emphasise how ambiguous the word "fat" is, and we need to understand exactly what we are talking about when we use the word loosely. These following pictures are not equivalent. They are completely different.

Example one:
This is visceral fat. It is fat cells full of triglycerides (called adipocytes - adipo=fat, cytes=cells) inside the abdomen. They are a storage for excess calories. The triglycerides have come from eating too many calories, and most likely these calories have been excess carbohydrates, usually refined carbohydrates such as bread, pizza, chips, etc. Remember, excess carbs -> glucose-> TG's. This situation of belly fat has very little to do with eating fatty-looking food. Usually there is so much excess TG's in the body that they even fill up the liver. Then we get fatty liver or NASH. This is infiltration of triglycerides in the actual liver tissue.
2017: if you look at the diagram, you can see there is fat just under the skin as well as inside the belly. The former is called subcutaneous (sub=under, cutaneous=skin) and is not as dangerous as the fat inside the belly (called visceral - viscerae=organs) which causes inflammation in the body and insulin resistance.

visceral-fat-and-toxicity.jpg

imagesS0134IPI.jpg


Example two:
This is also called fat.
imagesPVBA4F86.jpg

This meat shows deposits of saturated fat. We now know that saturated fat is a kind of fatty acid. this is not the same kind of fat that is stored in the belly of the man above. It doesn't go directly unchanged from the meat to the fat cells in the belly. (This doesn't mean that this steak is good for apoe4's)

Example three
This is also fats. These foods contain monounsaturated fatty acids. This portion of food is extremely high in fat.
avocado%20and%20nuts.jpg


Example four:
This meal is also very high in fat and very high in calories. It should sustain you for at least 6 to 8 hours. Here there is salmon and veggies with lots of olive oil. The fat in the salmon is polyunsaturated omega 3 fats.
imagesET26BYC1.jpg


THESE THINGS ARE NOT THE SAME

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

Postby Stavia » Sat Jun 20, 2015 9:22 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


I will discuss these together, as I feel they are inter-related. Evidence for the benefits of these strategies comes both from multiple observational studies and interventional studies. The evidence is consistent across the literature and is solid both for mouse and human models. Participating in activities that are cognitively and socially stimulating is protective for AD. Being socially isolated and cognitively un-stimulated are risk factors for development of AD and other forms of dementia.

So I highly recommend you add daily cognitive activities to your prevention strategies, and regular social activities. Use your imagination! Anything that you need to stretch your brain to achieve is good! I believe it needs to be hard to be effective in growing new neuronal connections and promoting brain plasticity, which is the whole point. The more "cognitive reserve" we have, the better we fare in later life. https://en.wikipedia.org/wiki/Cognitive_reserve

Here is a great infographic: http://bigthink.com/ideafeed/this-nifty ... plasticity
Rewiring_the_Brain_Infographic.jpg



My personal strategies are that I have started playing the piano as an adult beginner. Badly lol but I love it. I go to a crossfit and can deadlift 150 pounds. I work at a very challenging job and try to learn something every day. I go to symphony and opera. I engage with my family and friends and co-workers regularly. I read science fiction and read around quantum physics for fun.


Use your imagination.
Live your life to the fullest!!

ars longa.png


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

Postby Stavia » Sat Jun 20, 2015 9:46 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


This is a tricky area. I am not the forum's supplement expert. Julie knows heaps more than I do about them. But I will walk you through the basic ones and then I suggest you explore others as your understanding of the area grows. Supplements are only IMO part of an overall approach to prevention. Popping a few capsules IMO will not undo the damage that an unhealthy lifestyle will do, and the evidence appears to support this. However IMO some targeted supplements appear to be beneficial, and in the case of Vitamin D3 for instance, very necessary for optimal health. At worse, I do not believe they will do any harm.
I recommend you do your own research. A useful non-biased website is http://examine.com/
Please do not take at face value the opinion of a website that is also selling supplements. Follow the money. They are there to make money, not to save the world.


Here is a full list of what Dale Bredesen recommends. It is daunting. I will attempt to pick out a few and explain a bit about them.
Chocolate and HRT have their own posts after this one.
Mend 1.pdf

Mend 2.pdf


1. Vitamin D3, also abbreviated D3 by us, or sometimes just D. This is an extremely important vitamin in the body, it is crucial for bone strength for instance and deficiency leads to osteoporosis. It is made by the skin when it is exposed to sunlight. It is very difficult to get enough from a normal diet alone, so those who do not get enough sun should supplement it. Target blood levels are not clearly defined yet. There has been much debate. Please be very careful when reading a target blood level - there are two different units used - one kind is 2 1/2X the other so you can be confused very easily.
The two units are nmol/L and ng/ml. "nmol" means "nanomoles" - this is a unit of counting. "ng" means "nanograms" - this is a unit of weight.
Usual recommended levels are over 50 nmol/L which corresponds to 20 ng/ml. However, higher levels may be necessary for optimal functioning. The evidence points this way. Here is one study about this, http://www.neurology.org/content/early/ ... 0755.short . We have discussed it a lot on the forum.
It is as yet unclear what the optimal level for prevention of AD might be. I would suggest that you aim for over 75nmol/l and consider levels of 125nmol/l as Dale Bredesen recommends. You might need anywhere between nothing (if you are lucky enough to be a beach bunny) and 5000IU to achieve this level, it is very individual.

2. Melatonin. This is used for optimisation of sleep, if sleep is an issue. The evidence is not conclusive if it is beneficial in the absence of insomnia. Doses are usually in the order of 0.5mg to 1mg at bedtime. Taking more is not considered to be harmful but may lead to morning grogginess. As discussed elsewhere, sleep is very important for cognitive health.

3. DHA and EPA. This follows on from my section on lipids, specifically omega3 polyunsaturated fatty acids. It is difficult to get what is considered enough for neuroprotection from diet alone. This is some indication in the literature (when we use this word "literature" we mean evidence-based scientific articles published in scientific, peer-reviewed journals. We do not mean blogs) that e4s may need more of these than non-e4 folks. Dr Richard Isaacson recommends 900 to 1000mg DHA a day. Dr Bredesen recommends 1000mg DHA a day. This can be obtained from a 3 ounce can of sardines, or 3 ounces of salmon. It can also be obtained from 3 capsules of Ovega for instance (I have to use this brand because I am allergic to sulphites in gelatine, most DHA/EPA capsules are gelatine). What I personally do is add up roughly how much DHA I have eaten in food (I know there will be EPA with it as well so I don't count that up as well) and bridge the gap with one or two or three or no Ovega capsules. I have done a blood test whilst in the USA and this method has led to excellent omega3 levels in my blood.

4. Supplements to reduce homocysteine - vitamins B12, folate and B6. This area has previously triggered enormous debate and the field has traditionally been polarised. You will quickly realise which camp your own doctor belongs to! Mainstream medicine has traditionally had the stance that homocysteine is an innocent bystander of other processes going on and taking it out of the picture by lowering it does not affect real outcomes. (Remember mainstream doctors also traditionally are slow to change their thinking and may lag years behind the evidence in their practice.) Then there are those who have always believed that it is detrimental in itself. In fact, now evidence is accumulating that lowering homocysteine has a positive effect on cognitive function. There have been two trials showing positive results with reducing homocysteine (FACIT trial of folic acid in the Netherlands & VITACOG trial of folic acid, B12 and B6 in people with Mild Cognitive Impairment in Oxford). The current experts in the field are Drs. Smith and Refsum. See links to recent talks below where they carefully outline the homocysteine connection to cognitive decline. (You need to register with Nestle Nutrition Institute for free access.)
Dr. Smith: https://www.nestlenutrition-institute.o ... sease.aspx
Dr. Refsum: https://www.nestlenutrition-institute.o ... Brain.aspx
Here is our discussion of the homocysteine issue.

In addition, low B12 levels have been associated with greater incidence of dementia. This is not controversial. It may be that "normal" reference ranges may be set too low for optimal cognitive health. Many of our members run their B12 levels at the upper limit of "normal" , not the lower. If one is addressing raised homocysteine, this happens automatically usually

If you wish to lower your homocysteine you will need the above three vitamins to do so. It is unclear how low it should be, Dr Bredesen wants it under 6, which is not easy to achieve in many people. Many of us are very happy to run at 7. (I started at 11 for instance, and am now 7 which I am happy with.)

Doses per Dr Bredesen's protocol - B12: 1mg methylcobalamin (1mg "milligram"=1000mcg "microgram"), folate: 0.8mg methyl-tetrahydrofolate, B6: 20mg pyridoxal-5-phosphate aka P5P. These are the active forms. Those people with what we call methylation defects do not efficiently convert the usual forms of cyanocobalamin and folic acid to the active forms the body needs.

Methylation defects are an extremely complex issue and our Susan knows far more than I do about it. I haven't studied them in detail because I am extremely lucky not to have any, not because I don't think they are important.
Here is a link to our darling Susan's excellent methylation article on our wiki.

Susan adds: If you are feeling unhealthy, have a history of reacting to supplements or know your methylation genetics contain variants from GeneticGenie or Strategene, my caution is to start supplementation slowly to avoid side effects. Start with a week on B12 at 500 mcg/day, to avoid something called "methyl trapping" which happens if your B12 levels are low (more on the wiki about this.) Then add folate at 400 mcg/day for a week. Last, add the B6. If your homocysteine does not go down enough, then increase to the amounts listed above. If it still doesn't go down, try adding 500-1000 mg/day of TMG, which is commonly used to effectively decrease levels in people with familial hyperhomocysteinemia.

5. Curcumin is the active component of turmeric, a herb. It appears to be anti-inflammatory and may reduce accumulation of amyloid. Please refer to http://examine.com/supplements/Curcumin/ for some crucial details - it is poorly absorbed and needs to be taken with black pepper (usually in the form of bioperine) or as special forms (Meriva or BCM-95) to be absorbed sufficiently. It is also absorbed better with some fat, so it is well suited to take with an omega3 supplement.

6. CDP-choline (also known as citicholine) or alpha-GPC (also known as Alpha-glycerophosphocholine) may be taken in doses of 500mg a day, though the optimal dose is not clear. Both these work very similarly, they are converted to phosphatidylcholine (remember, a structural component of cell membranes and very abundant in the brain) but also have many other complex effects. They are considered to be possible nootropic or cognitive enhancers.

7. Alpha-lipoic acid is also considered to be a possible nootropic. It is used in the generation of energy by the mitochondria. Doses are usually up to 600mg a day. Our Julie takes 200mg twice a day.

8. Acetyl-N-Carnitine is also called ALCAR. It is usually taken in doses of 500mg a day. It works by facilitating the mitochondria to generate energy from fatty acids.

9. N-acetylcysteine or NAC is usually taken in doses of 400mg once to twice a day. It works by increasing production of a molecule called glutathione by the neurones, which promotes signals moving from one neurone to another.

10. CoQ10/ubiquinol is also taken by many people. It is made by the body for the purposes of facilitating the generation of ATP in the mitochondria. You may wish to supplement this if you are on a statin as levels have been shown to be lower in those on a statin and this may be related to the muscle aches that some people get while taking statins. Please do your own research on this supplement and make your own decision.

There are other possible supplements on Dr Bredesen's list, I have not researched them thoroughly. There will be a full list in his book https://www.amazon.com/s?ie=UTF8&page=1&rh=n%3A283155%2Cp_27%3ADale%20E.%20Bredesen

I do urge you to do your own research and make up your own mind. I also urge you to be very careful that the brand of supplements you buy is reputable. Consider buying a subscription to Consumer Labs, which independently tests the various products. http://www.consumerlab.com/. I and this community are not touting any particular brand or type of supplement. I and this community carefully consider the evidence for each supplement and we all make our individual decisions. This is not a black and white area, there is uncertainty about the efficacy of many of these supplements, about what dose is optimal, and what blood levels to target

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

Postby Stavia » Mon Jun 22, 2015 6:22 pm

Oestrogen/estrogen aka HRT (hormone replacement therapy)
Now this is a biggie. I have given this topic its own section after supplements. It is also far from clear what we should do. We have a 24 page thread discussion pros and cons. This thread is still growing. viewtopic.php?f=16&t=119
I think it is our longest thread on the forum. This speaks to the uncertainty around this crucial topic.

Not taking HRT if you are in the peri-menopause (the time when the periods are becoming irregular and the oestrogen is dropping as evidenced by hot flushes/flashes, sleep disturbance and dry genital tissues etc) or in the period soon after the menopause is also an active decision and may have consequences, just as taking HRT may have consequences. Whatever you decide may have consequences. Please consider this area extremely carefully if you are in this demographic.

A few notes about the words we use - HRT is hormone replacement therapy. Its basis is some form of oestrogen (British spelling)/estrogen (USA spelling). I will be using the first form as it is the spelling I am most familiar with and I think it would be nice to welcoming to our European members and be a little less USA-centric.

Forms of oestrogen
1. This may be the same molecule that the body makes itself, which is 17β-oestradiol/estradiol. This is sometimes called "bio-identical" which may be a marketing-purpose branding when this term is used for creams or lozenges containing it, because there are formulations of 17β-oestradiol available on prescription as well in the form of tablets or patches. The molecule is identical in all formulations. The bio-identicals are the same molecules of 17β-oestradiol as the commercial preparations.
2. This may be an synthetic molecule which has similar effects on the body to the one above. The most famous would be "premarin" which is conjugated equine oestrogen. There are others such as oestradiol valerate. They have no added benefit over 17β-oestradiol apart from cost, as they are cheaper.
NB: oestrogen by itself has not been shown to increase the risk of breast cancer. This is seen in the famous WHI (Women's Health Study).
NB: oestrogen doses are individualised and may be adjusted according to symptom control, within reason. The symptoms used to decide if the dose is adequate are the hot flushes, sleep, dry genital tissues. Breast tenderness may occur of the dose is too high.
NB: vaginal oestrogen creams are not absorbed sufficiently into the blood to be classed as HRT. They have purely local effects when used twice weekly.
NB: oestrogen patches do not appear to increase the risk of clots in the legs which can travel to the heart. (venous thromboembolism) or stroke.

If a woman has a uterus still, if she only takes oestrogen by itself (this is called unopposed oestrogen) she will eventually get uterine lining cancer (endometrial cancer). If we add a progesterone type drug in some form, this does not happen at all ever. This is thus imperative if the woman still has her uterus and has not had a hysterectomy. It is called combined HRT.
If the woman has recently been having periods, we give the progesterone sequentially so that she has a bleed every month. This is necessary to stop irregular, nuisance, unpredictable bleeding that would happen if we didn't schedule a regular bleed. If it is more than a year since her last period, we give it continuously and there is usually no bleeding.

Forms of progesterone
1. This again may be the same molecule that the body makes. The equivalent is micronized progesterone, which is supplied in a capsule that is swallowed. It may also be applied in a patch which is available in some countries. Marketed as bio-identical, it is available as a cream. To protect the uterus, dose of 100mg capsule a day every day, or 200mg a day for 2 weeks every month are necessary. I have no experience with the progesterone patches as they are not available in my country, but I hear they deliver daily progesterone. The bio-identical creams are absorbed variably and are not considered sufficient to ensure consistent uterine protection.
2. This is also available as a synthetic progestins, such as medroxy-progesterone acetate. They have similar action to the micronised progesterone but possibly different side-effects. This is where the increased risk of breast cancer with combined HRT might be coming from. It is probably safer to be taking the micronized progesterone rather than this. However cost may be a barrier.
3. Uterus protection may be obtained by a Mirena, which is a progesterone containing IUD that releases the active molecules locally and shrink the uterus lining. An insignificant amount is usually absorbed into the blood.

So what is the deal with AD and HRT?
Women get AD more than men. It is plausible that oestrogen drop at menopause is detrimental to the optimal functioning of the neurones. It is plausible that replacing oestrogen may reduce the risk of AD by promoting optimal functioning of neurons in multiple complex ways. It may also be beneficial for optimal functioning of mitochondria. Thirdly, it may work through epigenetic influence ie influence the expression (means activation) of many other genes. Please see the thread above for details.
However there may be a window period after menopause within which HRT may be protective, and after this window period it may be too late to obtain cognitive advantage from HRT. This theory proposes that absence of oestrogen for a certain (as yet undefined) time might irreversibility change the brain in some way. It is uncertain how long this window period might be, if it does exist. If it does exist, it may be anywhere from 1 year to maximum 10 years.

I am sorry to be so vague. This area is extremely tricky. Please discuss with your doctor. Here is an scientific review article you might want to suggest to your doctor. http://www.nature.com/nrendo/journal/v1 ... 15.82.html

You might also wish to print off other articles from our HRT thread.
Here is a powerpoint by Dr Anne Hathaway in more detail (she is an expert in the field and works with Dr Dale Breseden viewtopic.php?f=16&t=2797&p=32953#p32953) https://netorgft2290643-my.sharepoint.c ... ction=view
We met with Dr Anne Hathaway in 2017 - here is my report on her presentation. We have a video: viewtopic.php?f=15&t=3315

Here is more Anne Hathaway support material viewtopic.php?t=2797

This following link is an excellent place to get non-biased information - the international menopause society. Please be very careful of biased opinions re this issue, it is extremely emotional and many people are biased one way or the other, dogmatically pro or con. Please be wary of dogmatism in this area. The evidence IMO does not support absolute certainty.
http://www.imsociety.org/
In addition, since the Women's Health Study (WHI) was published some years ago, there has been a massive pendulum swing of opinion from greatly pro (prior to the publication of the WHI) to greatly con (after the publication of the WHI) back to cautiously pro again in some groups more recently. There was panic when the first results were out, but now there have been many sub-group analyses (the researchers looked much more carefully at the data and separated out different ages of women, different kinds of HRT and many other factors) and it is much more complex than "HRTis bad". Please be careful when you read out of date articles on Google. Anything prior to 2013-ish will be outdated and possibly wrong.
http://www.npr.org/sections/health-shot ... initiative

October 2017: new paper, with great evidence for oestrogen, glucose metabolism, AD
http://journals.plos.org/plosone/articl ... ne.0185926

I will share my personal decision with you: I agonised over this, I was still having irregular periods last year when I was 53. A woman is considered menopausal once she has had no period for a year so I was not yet menopausal, I was considered peri-menopausal. I then started waking every hour at night after a lifetime of sleeping 8 to 9 hours with no waking at all. (sleep disturbance is a typical menopausal issue due to the brain clock not working well). I was exhausted. I knew I would have a fatal car accident if I couldn't sleep, or make a mistake at work that would be fatal for a patient, so I had no other option than sleeping pills which are IMO worse than HRT. I started oestrogen patches (50mcg) and micronized progesterone tablets (100mg) and have done very well, sleeping beautifully again within 2 weeks of starting it. It is the oestrogen which makes me sleep, not the progesterone because I have had two months off the progesterone when I had difficulty sourcing micronised progesterone in a non gelatine capsule that didn't make me wheeze (don't worry, I had a scan and all is safe, but kids - do not try this at home!). I intend to continue with this for 5 years and then reassess as I am sure new evidence will be out by then.
2016- I am still doing well on estradiol 50mcg patches, but now have a Mirena for endometrial protection as the oral progesterone makes me very sleepy.
2017- I am still doing well on estradiol 50mcg patches, and am trialing a small dose of oral progesterone at 25mg as new evidence is suggesting that the brain needs progesterone to function optimally as well.

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

Postby Stavia » Mon Jun 22, 2015 6:25 pm

Chocolate/Cacao

This deserves a post of its own, though strictly speaking it is a supplement. The cacao is thought to reduce the formation of β-amyloid in the brain tissue as well as having many other complex positive effects both on the brain and on other parts of the body. There have been no studies specific to apoe4.

Please be careful about which chocolate/cacao nibs you buy. Some are contaminated with cadmium and apoe4s are thought to be particularly sensitive the heavy metals. I urge you to consider accessing the consumerlab.com report re this.
In addition, the flavanol (active ingredient) of brands varies significantly, and to get a decent amount of flavanol without overdosing on saturated fat and calories is difficult with some brands.
Finally, the percentage you see on the wrapping of a chocolate bar is the total of cocoa liquor, cocoa powder and cocoa butter in the bar. Cocoa butter has zero flavanols.
I am unable to link the data as it is copyrighted.

However I can share that I have chosen to take "cocoavia" capsules for my flavanols. https://www.cocoavia.com/ This was recommended by Dr Richard Isaacson in his book, at a daily dose of 500 to 750mg flavanols per day. http://www.alzheimersdiet.com/
2017: I have stopped this as it is expensive and I don't think it adds extra value to what I am doing, just eat chocolate instead.
I do have dark chocolate as a treat. In the USA the Ghirardelli and Endagered Species brands are cadmium free and have a modestly higher flavanol concentration than for instance the Lindt and Green&Blacks at equivalent "percentages". This is because the latter most likely have a higher amount of cocoa butter making up their "85%" shown on their wrappers.

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

Postby Stavia » Mon Jun 22, 2015 9:09 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


This is the last complex issue I will be discussing. It is actually a common endpoint of many of the factors we have already discussed, so most of these strategies are well known to you already.


Firstly, we need to define what inflammation means. The traditional definition allegedly goes back 2000 yrs to Celsus, who used the words we still use medically today - rubor, calor, dolor, tumor in Latin - redness, heat, pain, swelling - to describe what he saw as the body's response to an injury or infection (the medical word for these two things is "insult"). Then Galen a little later added the 5th "sign". ("sign" is the doctor word we use to describe things we see or feel or hear or smell in the patient's body, "symptom" what the patient tells us). The 5th sign is loss of function - function laesa in Latin. All these things are seen in the process when the body defends itself against an insult and then repairs the damage. The immune system is the body's mechanism for this response.

These five things that we can see happening in the body in response to an insult are the consequences of two major kinds of defence and repair mechanisms swinging into action - the "cellular response" (this is the white cells in the blood and other cells that help them in their defence. They work directly and also by producing special chemicals, which can be of many types - you may have heard the words: antibodies, cytokines, chemokines, interleukins, leukotrienes, TNFα, prostaglandins) and the "humoral" response - this means antibodies made by various cells and released into the tissues to help defence and repair. The cells (and their chemicals) and the antibodies (in the case of germs = pathogens) are meant to kill the invader or toxic insult, and usually do this very well.

This process is usually beautifully orchestrated and for instance if you cut yourself and get a little bit of an infection, it all works smoothly and the tissue eventually repairs. This is called acute inflammation and it serves its purpose well, in neutralising the threat and effecting repair of the damaged tissue. After the threat is vanquished, the immune response stops.

But sometimes things go awry and chronic inflammation can supervene, where the cells and their chemicals continue to be active and cause on-going damage to normal, healthy body cells. Examples are:
1. A good example of this would be rheumatoid arthritis.
2. Another example that is very pertinent to us is the presence of visceral fat. The fat itself makes the inflammatory chemicals and this causes ongoing chronic inflammation in the body http://www.ncbi.nlm.nih.gov/pubmed/23107257
3. Another example is atherosclerosis - once the lipid particles get into the artery wall, they are perceived as a threat by the immune system and the inflammatory response is activated. This adds to be damage to the artery wall on an ongoing basis.
4. Oxidative stress and mitochondrial dysfunction can cause ongoing inflammation.
5. Another example is chronic gum infection or gingivitis. The swollen infected gums produce an ongoing inflammatory response by the body.
6. Smoking is our final example. It is nasty. Do not smoke. Ever.

So why would for instance smoking that causes lung inflammation affect our brains?
Now in Apoe4 our blood brain barrier (abbreviated BBB) which normally protects our brains from molecules in the blood circulating in the body, is leaky. https://www.urmc.rochester.edu/news/sto ... k-die.aspx
Edit January 2018: there is increasing evidence that those with Apoe4 have a more pronounced inflammatory reaction to external factors. This is very good if one is living in a third world situation, beset by parasites and bacteria. However in our first world lives, the factors causing inflammation are usually not infections but factors such as (in no particular order) heavy metals, industrial seed oils (omega 6 excess), obesity, visceral fat, poor glycaemic control, mould exposure, dental caries and gingivitis, smoking, leaky gut etc etc - and the effect of these is thought to be more pronounced in APoe4s due to our more reactive inflammatory tendency. You may see the terms NF-k1 (increases inflammation, ie bad) and SIRT1 (decreases inflammation ie good), when talking about the inflammatory pathways in our bodies.
https://lipidworld.biomedcentral.com/ar ... 016-0288-2


This means that if there many inflammatory chemicals floating around in the blood, they can get through the leaky blood brain barrier into the brain itself and cause damage to our brain cells on an ongoing basis. Our brains are evolved to survive a few days' inflammation as we would get with a cut finger and infection, or pneumonia, for instance. But our brains do not seem to do well with years of ongoing constant inflammation. Ongoing chronic inflammation is a risk for AD.
http://www.hindawi.com/journals/tswj/2012/756357/

So what can we do? Can we take medication like NSAIDs? (*see PS at end of this post) These medications are the colloquially termed anti-inflammatories. They include drugs such as diclofenac, naproxen. Unfortunately they have not been shown to prevent AD.
But we can do the following:
1. Eliminate visceral fat. Reduce insulin resistance.
2. Eliminate obvious gum infection
3. Watch your Omega3/6 ratio as we discussed earlier, and try and keep it at 1:3 or less. This is thought to reduce inflammatory molecule production
4. Avoid trans-fats
5. Prioritise sleep and eliminate sleep apnoea
6. Stress is thought to increase inflammation. Decrease stress
7. Reduce oxidative stress on the cells by eating heaps of healthy phytonutrients and targeted supplements
8. Consider targeted supplements such as Curcumin, Ashwagandha, Resveratrol etc and others as we discussed in the supplements post.
9. Consider 12hour or more daily fasts to reduce oxidative stress and improve mitochrondrial efficiency by generating small (or large if you wish) constant amounts of ketones.
10. Consider targeted mitochondrial-specific supplements.
11. Consider your gut health 2017: Here is an area that has evolved over the last few years and appears to be very important: gut health ie the role of the bacteria that live in our colon. Basically if our gut is not healthy, nasty molecules leak through into our blood and cause inflammation. This area is very complex and we do still not understand it fully yet. The bacteria may even migrate up into the small bowel, where they are not supposed to be, causing a condition called SIBO.
https://genomemedicine.biomedcentral.co ... 016-0303-2
Here is a presentation on the gut and brain connection
http://sage.buckinstitute.org/watch-dr- ... onnection/
Here are Dr Terry Wahls' strategies for improving gut health
https://www.facebook.com/TerryWahls/pos ... 2549404463 - a. Eat fermented foods with every meal b. Have a dog c. Play in the dirt d. Stop eating sugar e. Eat more organic dirtf. Eliminate fructose g. Eliminate artificial sweeteners h. Eat organic food to avoid antibiotics and pesticides in the food (which kill healthy gut bacteria) i. Eliminate flour based baked goods j. Eat more vegetables
12. Avoid mould infested houses, pollution, heavy metal and toxin exposure - they may cause chronic inflammation, also known as CIRS. Here is Dr Mary Anne Ross's presentation on this important topic viewtopic.php?f=15&t=3315


Do you see a pattern here? Apart from the dental hygiene, it's everything we have already discussed. It is the common end point of many of our strategies.

----------------------------------------------------------------------------------------------------------------------------------------------------------------
Rant warning
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*PS. this is my plea to PLEASE use generic names for medications. Every drug is a special chemical that has a unique name. It is specific to that chemical, and with a handful of exceptions, it is an internationally consistent word that is recognised in every single country. This chemical is then made by one company until the patent runs out - and then afterwards by several or many companies. Every different commercial company uses a different name as its "trade name" for that drug and tries to brand the drug so that their brand is prescribed more often and they get more money. Unfortunately most lay-people are suckered into this branding. They use the trade names most of the time.

For instance: amoxicillin started not working decades ago, as the bacteria became resistant. A drug company added a molecule called clavulanic acid to the amoxicillin to make a drug whose generic name is amoxi-clavulanate. That company decided to call their brand Augmentin. They have been so successful at branding, that now even decades after the patent expired, people still call amoxi-clavulanate, Augmentin. This is not good practice. Someone from a different country may not recognise the name, it may have never been sold under that brand in their country. And why would you want to continue to advertise a drug company?

Please please please learn the generic names of your medication you are on. If you are very ill and need attention fast, it will waste a couple of minutes while the doctor who needs to attend to you urgently looks up exactly what drug you are taking. I do not live in the USA and I have to look up what the trades names on the forum actually refer to. Members from Europe will be having to do the same.
Paxil for instance is not your medication. It is a brand. Paroxetine is your medication.
Lexapro is not your medication. It is a brand. Escitalopram is your medication.
Rosuvastatin is the statin we think is best in many circumstances. The patent to market it under the name Crestor expires in 2016.

PPS: three exceptions to the international nomenclature are epinephrine=adrenaline, furosemide=frusemide and acetaminophen=paracetamol. (USA vs rest of the world)

PPPS: generic is not a word for an inferior molecule. It is the word for the actual drug, without the allure of branding overlaid.
Thank you. Rant over.

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

Postby Stavia » Mon Jun 22, 2015 9:10 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


Don't smoke. It promotes atherosclerosis. This is blockage of all the arteries of the body with plaque. Atherosclerosis causes impaired blood flow to the brain, heart, kidneys etc. Impaired blood flow to the brain is a non-controversial significant risk factor for dementia because cells are damaged and can die if they don't get enough oxygen.

Plus smoking causes lung cancer. And heaps of other nasties.

Even one ciggie is a risk.

Don't smoke.
That is all.


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