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 » Mon Jun 22, 2015 9:12 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

Sustained high blood pressure damages the little arteries carrying blood to the brain. When one or more become blocked, the blood flow to the brain supplied by those arteries is compromised. Neurone damage or neurone death will result. High blood pressure in midlife (more than 140/90) increases the risk of AD significantly. http://www.dailymail.co.uk/health/article-2716164/High-blood-pressure-midlife-raises-risk-dementia-20-years-Taking-drugs-hypertension-help-lessen-impact.html

Medication usually prescribed does not appear to increase the risk of AD. In fact, some medications appear to reduce the risk.
https://www.apoe4.info/forums/viewtopic.php?f=2&t=1433

Here is a study of hypertension and apoe4. http://www.utdallas.edu/news/2013/3/19-22631_Hypertension-Could-Bring-Increased-Risk-for-Alzhei_article-wide.html

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

Postby Stavia » Mon Jun 22, 2015 9:13 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

For those of us who have had significant concussions, read my story first before you panic. I am fine after a serious head injury (2 actually). Since I wrote this post, I am even sharper, I think because I have been following all the above the strategies for a significant period of time. I lost more weight than I hoped in my post above (I am 12kg less than when I wrote it, I have lost a total of 25kg) and am feeling great.


A new study says that perhaps head injury is not a risk for late onset Alzheimers

First of all, this is not about a little bump, or repeated little bumps. This pertains to a significant injury. The official definition is "Traumatic brain injury (TBI) is a nondegenerative, noncongenital insult to the brain from an external mechanical force, possibly leading to permanent or temporary impairment of cognitive, physical, and psychosocial functions, with an associated diminished or altered state of consciousness"
If loss of consciousness is less than 30 minutes this is termed mild TBI. Moderate TBI has loss of consciousness more then 30mins and severe TBI has loss of consciousness 24 hours or more. Moderate and severe TBIs are associated with increased risk of AD and repeated mild TBIs also associated with increased risk of AD. A single mild TBI has not been shown to increase the risk of AD.

It is your personal choice if you chose to take part in sports that have a risk of head injury. I would urge you to wear a helmet and take special care. If you have had a head injury previously, please consider being extra vigilant about not hitting your head again (I do not ski anymore) and applying all the prevention strategies we have discussed.

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

Postby Stavia » Wed Jun 24, 2015 2:54 am

Lastly, some basic biomarkers. This is the word we use to denote the things about our body and its function we can measure and track. Here is a summary of the areas we have already discussed. There is very little new information here.

1. Physical measurements
a. waist circumference
b. BMI
c. Blood pressure

2. Functional measurements - this would include areas such as sleep, cognitive testing, exercise tolerance.

3. Blood tests
a. HbA1c, fasting insulin, fasting glucose, 1 and 2 hour after eating (post prandial) blood glucose
b. Lipids - both basic (TC HDL LDL TG's) and advanced (LDL-p or apolipoprotein b)
c. Vitamin B12
d. Vitamin D3
e. TSH, T3, T4 (thyroid function)
f. Liver functions
g. Homocysteine
h. CRP (inflammation) (to define values under 1, a high sensitivity assay is used - denoted hsCRP)
i. Full blood count (FBC) also called complete blood count (CBC) in the USA, measures the red cells, white cells and platelets in the blood.
j. Ferritin (measure of iron stores but also goes up in chronic inflammation)
k. Renal function is usually given as creatinine and electrolytes. In the USA it is still incorrectly called BUN (blood urea nitrogen) as years ago urea was measured instead of creatinine. Sometimes incorrectly it is still called u&e's by British/Europe docs because we also used to measure urea years ago. From the creatinine a measure of renal function can be estimated, called eGFR. It is inaccurate at extremes of body habitus. It overestimates renal function in small people and underestimates renal function in large muscular people. A more accurate measure is the GaultCockroft equation which requires more information.


4. Imaging such as coronary calcium scanning is an option you might wish to consider. https://consumer.healthday.com/vitamins-and-nutrition-information-27/high-cholesterol-health-news-359/calcium-scan-can-predict-premature-death-risk-study-says-701059.html

These are what I consider some basic markers. As you understand more, you might wish to delve into more detailed blood analysis, for instance you might want to check your magnesium, zinc, copper levels. You might wish to investigate your hormone status. You might want to access more complex test such as fatty acid analysis or cholesterol balance or adiponectin or TNF1-alpha...... There is much information about these details in our main forum. But please start with the basics before getting tangled up in small details.
We call getting lost in small side details and losing sight of the big picture getting trapped in the rabbit hole amongst ourselves. Stay in the light where you can see all the things ;)

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

Postby Stavia » Mon Jun 29, 2015 10:53 pm

Conclusion

Thank you for joining in this discussion of the basics underpinning why many of us do what we do every day. Many of us believe that genetics is not destiny.
Let's play our hand of cards cleverly and with hard work and commitment.
Together.

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

Postby Stavia » Mon Aug 22, 2016 12:13 pm

Extra material added August 2016

Our group has recently attended the Ancestral Health Symposium in Boulder.
https://www.apoe4.info/forums/viewtopic.php?f=22&t=2515
Susan, our vice president, and I thought that one of the presentations would be useful for new and old members alike: strategies to help implement behaviour change. Aaron Blaidsell delivered an excellent talk on why we are hardwired to seek out food that we know is bad for us, and what we can do to reduce these cravings.

Here is his video
https://www.youtube.com/watch?v=js8MELGn3XM

and this is my summary of the bare bones of his discussion. In italics are my layman's explanation of some of the terms he uses.

AARON BLAISDELL
Diet and cognition: data, theory and some solutions from the playbook of psychology: Detrimental effects of low fat diet and rats' cognition placed in the greater context of psychological theory and phenomena. Psychological solutions for diet related health problems

Aaron has studied the effects of diet on rat cognition and mood. There are striking reductions in motivation, impulse control, vigilance, working memory, hippocampal memory, integrity of hippocampal blood brain barrier and spatial learning with a highly refined diet as opposed to a whole foods diet.

In humans pathways to this have been identified and include increased inflammation through cytokine activation which then dysregulates neurotransmitters and neuromodulators. Inflammatory mediated depression resembles sickness behavior with withdrawal and energy conservation as opposed to anhedonia.

Refined foods are also shown to increase anxiety most likely through micronutrient deficiency eg Zinc Magnesium Lithium and Chromium.

Why do we eat refined foods?
1.Supernormal Stimuli : a bird will nest on a giant egg in preference to the normal size. Supernormal stimuli will override normal stimuli - refined foods are hyperpalatable. and elicit consummatory responses larger than are elicited by whole foods. thus leading to overcomsumption and dysregulation of appetite this means that very sweet or very chemically engineered foods are more powerful in activiating brain response than normal tasting foods
2. Pavlovian Response: we learn to like foods based on Pavlovian preferences. Refined foods are calorie dense thus drive association stronger than whole foods. this means like when Pavlov did the bell thing with the dog before food and the dog started salivating with the bell before the food appeared, we learn very quickly to respond even to the thought of refined food and feel desire for it. why do you think Subway "bakes" the bread in house? for the smell.
3. Habit Learning: as we learn a skill we turn it into a habit and it becomes automatic eg driving. Refined foods accelerate and strengthen habit learning. There are more neurones in the basal ganglia of obese persons in areas that code for value and saliency of food food creates habit and the habit part of our brains grow. ugh. scary stuff
4. Delay Discounting: we discount rewards that are too far in the future or when the immediate reward is too enticing ie we want it NOW and can't think about the future
5. Learned Helplessness: this is the curse of yoyo dieting - repeated unsuccessful attempts to lose weight results in feelings of helplessness we gain, we lose, we gain, we lose, we feel helpless, we give up. sigh.
6. Overshadowing: We all know the Pavlovian dog response to the bell. However if there are multiple cues the loudest overshadows the quieter - refined foods overshadow whole foods due to their stronger stimulus the sight or taste of a processed or very sweet food will drown out the taste of a whole food. food companies know this. they engineer their foods for maximum addiction
7. Counterconditioning of bad tastes: chemicals taste awful but their pairing with sugar they start to taste good go off diet coke for 6 months then try it. omg it tastes awful. but over the years of addiction the sweet taste overrode the nasty chemicals
8. Sensory Adaptation and Habituation: Overstimulation causes down regulation of receptors (e.g. down regulation of tongue sweet receptors with repeated ingestion of sugar rich foods) and habituation (one gets used to feeling unwell with a diet of refined foods) this means that if we eat heaps of sweet things our taste buds get dulled. we also get used to generally feeling bleh.

What can we do?
1.Extinction of food cue responses: presenting a food without eating will eventually break the prior association of that cue with food - looking and smelling without eating. eventually a new habit will form and we will now naturally not eat the bad food if we see it
2. Break food cravings : Seth Roberts discovered that eating calories without flavour or taste decreases body fat set point - this can be achieved by drinking EVOO for calories or eating with a clothes peg on the nose. This works through Pavlovian reconditioning fancy words but basically eating without tasting seems to break some ties of food->fat
3. Reward devaluation: devaluing refined foods can help us mentally avoid seeking them out - mentally devalue junk food and develop an aversion for it tell yourself it is junk and will cause you to be unwell
4. Equivalence class formation: we all classify objects into categories - we can reclassify junk food as toxic non-food tell yourself it is poison and will kill you and its not actually a food. This really works. I developed a life threating allergy to a preservative in food called sulfites about 8 years ago. Dunkin Donuts literally are not food for me they are certain death. Its great!
5. Cultivate new eating habits: make a habit of avoiding refined foods and eating whole foods good habits eventually stick
6. Mindful eating: suggestions are choosing only whole foods, drinking only water, coffee, tea, moderate alcohol, eat only at the meal table not while distracted, keep snacks in pantry not in plain view, keep fruits and nuts as snacks, eat slowly and taste your food, if a craving develops, go for a walk this is great advice
7. Social support! This is what we do here! ask for help on the forum, complain, share strategies, whatever - this is what a community does well
8. Redefine yourself as someone who does not eat junk food welcome the new you!

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

Postby Stavia » Sat Feb 04, 2017 10:58 am

Extra material added February 2017

viewtopic.php?t=2918

Here our Theresa discusses advanced topics such as TNF-alpha, IgF-1 and mTOR.
These are complex molecules involved in inflammation, cellular growth (not always good, sometimes growth means muscle increase, sometimes it means cancer) and cellular aging.
Many of our strategies are aimed at optimising these biomarkers.
I thought I would introduce them so that new members can understand that they are critical in optimal health.

TNF-alpha is short for tumour necrosis factor. It is involved in inflammation.

IgF-1 is short for insulin-like growth factor. It is involved in muscle growth but if too high may promote cancer growth.

mTOR is short for mechanistic target of rapamycin. It used to be called mammalian target of rapamycin. It is involved in cellular aging and research shows it is associated with AD pathology.


Dr Dale Bredesen emphasizes exercise in his protocol to reduce, even reverse, hippocampal atrophy in the brain; to increase BDNF (Brain Derived Neurotrophic Factor); and to work hand in hand with diet and fasting to create ketones to fuel the brain.

Now I’m just an ApoE4/4 layperson (no medical or scientific background) trying to make sense of EVERYTHING to live a healthful life in both mind and body. I’ve often wondered what is the best exercise “formula.” I’ve specifically pondered the role, if any, of strength training. I’ve heard that body builders have a high IGF-1 which is contrary to longevity. What I was unsure about was if the high IGF-1 was the result of gym time, or if body builders induce a high IGF-1 through diet to develop muscle growth. Adding to my confusion was Dr Steven Gundry’s comment during his Ancestral Health Symposium presentation (August 2016) in addressing the lab results of a particular patient by saying, “that the last thing ApoE4s should be doing is Cross Fit.”

Dr Gundry prides himself in aiding the longevity of his patients, particularly his ApoE4s. When we consulted with him, he made a point of telling us of two 4/4s, one 85, the other 86, and three 3/4s at 90, 91 and 93, all of whom are thriving, active, and “bright eyed and bushy tailed.” Toward the goal of longevity, one of the things Dr Gundry emphasizes is a low IGF-1 (insulin like growth factor). He’s told us IGF-1 is a marker for how well a person is aging, saying that super old people who are aging well in their late 90s/early 100s usually run an Insulin Like Growth Factor around 70. He also stresses keeping mTOR turned off. There is no way to measure mTOR directly, but IGF-1 seems to be a good proxy.

I now feel the culprit is the diet that the body builders follow to induce muscle growth that results in high IGF-1. Dr Gundry had previously told us IGF-1 is raised through sugars and animal protein. It can be also lowered to a certain extent with calorie restriction and intermittent fasting, but Dr Gundry mostly emphasizes lowering animal protein to bring IGF-1 down.

In my first consult with Dr Gundry, May ’15, my IGF-1 was 129, and I was following a vegan diet (no animal protein) at the time! After incorporating intermittent fasting and following his diet which reduced my carbs/sugars, added good fats, and is nearly vegan with some, albeit low and only certain kinds of animal protein, my IGF-1 went down to 75 in Jun ’16. But then I started a strength training program and my IGF-1 went “up” to 79 in Jan ’17. What I didn’t know was this the result of adding strength training? the “holiday cheats?” or merely a reflection of everyday “noise?”

Dr Gundry had also previously told us that the all the literature is very, very clear, that the amino acids in animal protein absolutely turn on mTOR and you want to keep it turned off. There’s a direct association of mTOR to cancer. According to Wikipedia, “Over-activation of mTOR signaling significantly contributes to the initiation and development of tumors and mTOR activity was found to be deregulated in many types of cancer including breast, prostate, lung, melanoma, bladder, brain, and renal carcinomas.”

Of additional interest to us ApoE4s, Wikipedia also says, “mTOR signaling intersects with Alzheimer’s disease (AD) pathology in several aspects, suggesting its potential role as a contributor to disease progression.”

So during our recent consult, concerned about my recently adopted strength training program, I asked Dr Gundry about his comment that the last thing ApoE4s should be doing is cross-fit. He confirmed the indictment is on cross-fit, not on strength exercise in general. He told us that as ApoE4s, we have to be mindful that we have the potential to develop small vessel disease because our cholesterol is more “active” and small blood vessels occur in the brain, and in the heart, and elsewhere. He doesn’t view cross-fit as a strength training program, he views it as trying to damage your heart as much as you can. He told us almost every patient of his who is a big time cross-fitter has positive Cardiac Troponin-I elevation which is a test that is hundred times more sensitive than the test used in an emergency room looking for heart attacks. When his cross-fit patients back off, their Cardiac Triponons go back to normal. Not just cross-fit, he says he also sees this in marathoners and in a patient of his who is an avid hiker.

I’d been going to a coach-supervised class (meaning I couldn’t wimp out) following progressively harder strength work-out routines for four months prior to my last lab test, yet my Cardiac Troponin-I was the lowest it’s ever been at a very good level of <.4. The range is listed from 0.0 to 2.7. So exercise is good, just not too much/too hard, especially for ApoE4s. I now attribute my bump in IGF-1 to my holiday “cheats.” (Rats! Those blood tests won't let you get away with anything!)

Although it is aimed at cancer, this article, “Muscles Fight Cancer – The Science behind Outmuscling Cancer” has helped me put some of the pieces together. I now understand some of the science behind why strength training is good for us ApoE4s. It specifically discusses how muscles fight cancer and addresses the relationship between exercise and IGF-1/mTOR. As suggested above by Wikipedia, mTOR also contributes to AD progression, so I felt it relevant to present here.

To highlight from the article:

Resistance training increases IGFBP-3, which binds to insulin-like growth factor (IGF), decreasing its ability to promote cancer (growth factors are normal within the human body, but too many can lead to excessive cellular growth, including cancer growth)

The body holds a balance between TNF (tumor necrosis factor) and IL-6. Fat tissue secretes the pro-inflammatory cytokine TNF-alpha. Muscles secrete IL-6 which fights inflammation. The article says “inflammation is the fertilizer of cancer cells.”

Having heard Dr Bredesen speak many times, my non-scientific mind says inflammation is also an AD “fertilizer.”

AMPK (AMP-activated protein kinase) is an enzyme extensively expressed in our muscles, liver and brain. (my emphasis) It serves as an energy sensor and regulator. AMPK signals to our body and cells that it is not a time for building, but rather for breaking down. AMPK is the antithesis of cancer.

Muscle-derived IL-6 helps regulate AMPK (while muscle contraction directly activates AMPK), which stimulates the breakdown of fat and cholesterol, stimulates our mitochondria,and potentially fights cancer.

I’ve also heard Dr Bredesen emphasize optimizing mitochondrial function. Mitochondria are the small subunits within cells that manage the energy supply for that cell— if they stop working well, this leads to early death of brain cells, causing shrinking of the brain, so stimulating mitochondria sounds like a good thing to me.

AMPK blocks mTOR. mTOR is the same pathway that is blocked with targeted cancer drugs.

The article also introduces the Warburg hypothesis. Warburg showed that regardless of the presence of oxygen, cancer cells prefer to use glucose for energy. In normal cells, preference is given to the mitochondria for energy production. Newer data shows that AMPK blocks the Warburg Effect by blocking the ability of cancer cells to use sugar for energy.

AMPK is upregulated via several mechanisms (in no apparent order):
• Muscle contraction during exercise with the more intense exercise resulting in increased expression of AMPK
• Carbohydrate restriction (with or without fasting and even in the face of an increase in calories)
• Intermittent fasting

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

Postby Stavia » Sat Feb 25, 2017 10:58 am

Extra material added March 2017 and March 2018

Here is a detailed example of applying the strategies discussed in the thread.
It is Julie's protocol
Julie.protocol.pdf




Here is a thread with one of our members, Drae, explaining how she implemented her chosen strategies in an achievable manner.
viewtopic.php?t=4393
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Re: An introduction to ApoE4, biochemistry, and possible prevention strategies

Postby Stavia » Tue Oct 10, 2017 9:54 pm

October 2017 - we had a fabulous conference in San Diego in August this year, where we met with old friends and new. My report on the conference is here. viewtopic.php?f=15&t=3315

Other exciting news this year is the publication of two books

Dr Dale Bredesen's book
The End of Alzheimer's
and
Dr Steve Gundry's book
Plant Paradox

If you buy these, please consider doing so through our through our amazon smile link: here


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