Mitochondrial Dysfunction in E4 carriers

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Julie G
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Mitochondrial Dysfunction in E4 carriers

Postby Julie G » Sun Feb 01, 2015 12:57 pm

I’ve been exploring mitochondrial dysfunction as it relates to…well, everything. Mitochondria are often referred to as the powerhouses of the cells. They generate the energy that our cells need to do their jobs. There’s plenty of evidence to indicate that E4 carriers (in a dose dependent fashion) seem to run underpowered compared to other genotypes. It’s hard to reconcile “that" with the fact that this is the ancestral allele. (I have some ideas.) But, from everything I’ve learned, this dysfunction appears to be the earliest manifestation of the ApoE4 allele at least in Western civilization... Dr. Huang from Gladstone concludes:
Thus, apoE4 may cause mitochondrial dysfunction at very early stages in life.


ApoE4 and its fragments impair mitochondrial function
http://labs.gladstone.ucsf.edu/huang/pa ... e-research

Mitochondrial dysfunction has been reported in AD, which is modulated by apoE genotype, with a greater effect in apoE4 than in apoE3 carriers [121-124,125]. In both AD patients and age-matched nondemented subjects, apoE4 is associated with decreased cerebral glucose metabolism [126-135], an effect that occurs decades before cognitive impairment become apparent [126,127,136] and, probably, also before significant Aβ deposition. Thus, apoE4 may cause mitochondrial dysfunction at very early stages in life. Mitochondrial dysfunction is clearly coupled with production of reactive oxygen species and increased oxidative damage, which in turn further impair mitochondrial activity. Temporary or sustained loss of mitochondrial function impairs cellular defenses and repair mechanisms, decreasing the ability of neurons to mount an appropriate stress response and causing cellular injury.


Mitochondrial Disease is, of course, a separate entity from what E4 carriers experience; but I decided to take a look and see if I saw any overlap.

What is mitochodrial disease?
http://www.umdf.org/site/c.8qKOJ0MvF7LU ... isease.htm

Symptoms of mitochondrial disease:
http://www.umdf.org/site/pp.aspx?c=8qKO ... &b=7934631

Perhaps I'm unique, but this 4/4 has experienced 17 of the 38 symptoms :? This feels significant to me. Mitochondrial dysfunction in Alzheimer's is well studied, but there is increasing evidence that mitochondrial damage/dysfunction occurs both in normal aging and in atherosclerosis. And, no surprise, E4 carriers are more dramatically affected.

Here's an interesting study in which APOE null mice (commonly used in atherosclerotic research, somewhat synonymous with E4 humans) demonstrated early widespread mitochondrial damage in vessel walls. The mitochondrial deficiency was found was to promote atherogenesis and was not a consequence of tissue damage.
Mitochondrial DNA Damage can Promote Atherosclerosis Independently of Reactive Oxygen Species and Correlates with Higher Risk Plaques in Humans
http://heart.bmj.com/content/100/Suppl_3/A128.2

Addressing mitochondrial dysfunction MAY be one of our most important strategies for preventing both AD and CAD.

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Re: Mitochondrial Dysfunction in E4 carriers

Postby LA18 » Sun Feb 01, 2015 9:00 pm

I also have a lot of the symptoms associated with mitochondrial dysfunction. This article is nice because it lists the supplements used to address this (many are part of the regimen suggested by Dr. Perlmutter and others) as well as drugs with mitochondrial toxicity. After I read this I started taking COQ10. Of all of the supplements I’ve tried, I would say that it has had the biggest impact on the way that I feel on a day-to-day basis.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561461/

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Re: Mitochondrial Dysfunction in E4 carriers

Postby Sandraz » Mon Feb 02, 2015 8:31 am

Hi Julie and Lance,
I have been reading some on mitochondrial disfunction too, wondering if my fatigue is due in part to that. Fortunately I do not see any of the other symptoms listed that I have. So Julie, I am hoping that the 17 symptoms you have seen are in the past? With everything you are doing so incredibly well, hoping you are all better? And you take CoQ10 like Lance? I have read that is one of the best supplements to address mitochondrial issues.

Hey Lance, which brand do you take and how quickly did you see your symptoms improve? And if you feel like sharing, what symptoms did you have?

I can't decide whether to add CoQ10 in now or wait for Breseden study...I think CoQ10 is on his protocol..
Thanks !
Sandra Z
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Re: Mitochondrial Dysfunction in E4 carriers

Postby ABrain4Me » Mon Feb 02, 2015 8:59 am

Genova Diagnostics has a test called Nutreval (which my functional medicine physicians likes to use), which will indicate the health of your mitochondria and which supplements you need, and how much to mitigate. I had it done 2 years ago, and the amount of information that came back was enormous, and I have to slowly work on each of the issues uncovered. I came out in high need of CoQ10, and a few B vitamins.

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Re: Mitochondrial Dysfunction in E4 carriers

Postby JulieAnnie » Mon Feb 02, 2015 9:47 am

If you look beyond the symptom list under treatments it says to avoid fasting even stating that it's dangerous. It goes on to recommend eating before going to bed :roll:

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Re: Mitochondrial Dysfunction in E4 carriers

Postby GenePoole0304 » Mon Feb 02, 2015 10:59 am


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Re: Mitochondrial Dysfunction in E4 carriers

Postby Julie G » Mon Feb 02, 2015 11:30 am

Great links, Gene & LAC1965- thanks.

Yeah, I certainly noticed that warning against fasting, JulieAnnie. Keep in mind, that information was for those with actual Mitochondrial Disease as opposed to E4 carriers, who show some mitochondrial dysfunction. FWIW, when I was eating carbs as my primary source of fuel, I never could have fasted. As recommended, I had to eat every few hours or I would experience severe hypoglycemia- not fun- as YOU know :shock: Several times my glucose meter read: "LOW" -no numbers. I almost lost consciousness twice; paramedics were involved once. Scary.

Now that I'm slightly ketogenic and using many of the supplements recommended, I CAN fast and feel more stable and energetic than I have at any other period in my life. I used to function around 60% of "normal." I often HAD to have an afternoon nap. Now, in comparison, I'm the Energizer Bunny :D. And, yes, Sandra, all of those 17 symptoms are either gone or vastly improved. For me, addressing the mitochondrial dysfunction has moved me away from being quite unwell towards optimal health.

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Re: Mitochondrial Dysfunction in E4 carriers

Postby LA18 » Mon Feb 02, 2015 12:03 pm

Sandraz,

Hi. This is Liz, who posted about the COQ10. I think my username is similar to Lance's.

My symptoms are cognitive impairment (addressed somewhat effectively with a ketogenic diet), exercise intolerance, intermittent fatigue, autonomic dysfunction (unstable temperature and blood pressure and postural tachycardia), gastric/digestive issues, and atypical diabetes with frequent hypoglycemia. In particular, the COQ10 has helped my blood sugar (it seems to drastically increase my sensitivity to insulin) and I seem to be able to tolerate more physical strain without getting shaky. Also, I’m less tired all the time than I was before, but I don’t know if that’s due to the COQ10, changes in diet, or a more consistent exercise regimen.

I take 200 – 300 mg of the COQ10 per day (200 two days, and then 300 on the third). This appears to be my threshold, where I get benefits, but it doesn’t make me agitated, give my hypoglycemia or increase my blood pressure, as does a higher dose. Before I started taking it, I had a Genova nutritional assessment (I think it was the one that ABrain4Me mentions) that indicated I needed to supplement, but I am taking more than the dosage they suggested. I have also had a Genova organic acids profile that cited a need for COQ10 (this was when I was supplementing but at a lower dose than what I’m currently taking).

As far as brands go, I had to try many. I have mast cell activation syndrome and am extremely sensitive to dietary histamine. My understanding is that COQ10 is fermented, and some brands really sent me off the deep end. The brand I settled on is Healthy Origins (https://www.pureformulas.com/coq10-100- ... igins.html).

I should also mention that I can’t take reduced form of COQ10 (ubiquinol ) or I get hypoglycemia. At one point, before I realized this, I tried a solubilized ubiquinol because it’s supposed to be more effective. After about three days my blood sugar took a nose dive, so I guess it is readily absorbed. The advantage of this type is that it’s easier on the stomach, but it was too much for me to use long term. This one isn’t pharmaceutical grade. It’s by Swanson.

When my stomach gets really touchy I sometimes substitute my Healthy Origins COQ10 with a powdered version by Solgar, since it seems to be easier to digest. I don’t think this form has been as effective for me as the heathy origins, though. Also, I have to make sure I buy the version that is soy free, which I usually get in 60 mg capsules.

I wonder what brand Dr. Bredesen uses, and at what dose. I didn’t get into the study, but I’m hoping to do the testing through my doctor here once that information is available.

Juliegee, I had the same issue with fasting when I was regularly eating carbs. I couldn’t do it and function, and I had hypoglycemia frequently. It was a nightmare, and my cognition was getting progressively worse. I’ve been doing a low carb diet for many years, but I wasn’t measuring my ketone level, and I wasn’t always consistent in my carb load. I’m really focusing on that now. The lower I can go, the better/more clearly I am able to think, but I have to be careful because if I eat too few carbs I get tachycardia. This happens every time I dip down under about 40 grams per day. I was wondering if you, or anyone else who eats low carb, has had this type of experience.

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Re: Mitochondrial Dysfunction in E4 carriers

Postby TheBrain » Mon Feb 02, 2015 1:17 pm

Over my lifetime, I've had 12 of the symptoms listed under the Symptoms of Mitochondrial Disease that Julie pointed us to. Now I have 7 (with 4 of them related to my digestion). (Though I have wondered at times if I also have dysautonomia...)

In August 2013, I had the Genova Diagnostics organic acids test (Organix® Comprehensive Profile – Urine). Information about the test is available here:

https://www.gdx.net/product/organix-com ... test-urine

I had requested to have the test done twice, and my Integrative Medicine doctor (Dr. B) finally agreed to order it. When Dr. B saw my results, he said: "Your mitochondria are struggling." I had high metabolites in my urine for fatty acid metabolism and carbohydrate metabolism, as well as high metabolites for energy production markers.

The related metabolic associations were to my fatty acid oxidation, glucose oxidation, citric acid cycle, ATP production, and HMG-CoA reducatase inhibition.

I also had tetrahydrofolate insufficiency (probably related to my MTHFR gene variant, C677T) and serotonin turnover stimulation (probably related to my gut dysfunction).

The results suggested intervention options in the form of supplements (with specific dosages based on my results), and my doctor went along with them. I started taking a B complex, L-cartinine tartrate, alpha lipoic acid, and CoQ10 (ubiquinol form) for the mitochondria and folate issues. I also started taking L-tryptophan for the insomnia (related to the serotonin issue).

OMG. Except for the L-tryptophan for the insomnia, the results were amazing, for a time. My malaise vanished, and my energy greatly improved. Unfortunately, all of my health problems weren't resolved, and the benefits have lessened over time. I have no idea why, except maybe I have built up a tolerance to these supplements and need higher doses?

I'm curious to see if the Bredesen study will do any testing for mitochondrial issues. One of the goals of the study is to "optimize mitochondrial function."
ApoE 4/4 - When I was in 7th grade, my fellow students in history class called me "The Brain" because I had such a memory for detail. I excelled at memorization and aced tests. This childhood memory helps me cope!

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Re: Mitochondrial Dysfunction in E4 carriers

Postby Russ » Mon Feb 02, 2015 3:38 pm

JulieAnnie wrote:If you look beyond the symptom list under treatments it says to avoid fasting even stating that it's dangerous. It goes on to recommend eating before going to bed :roll:


Just noting that hard to reconcile the call to avoid fasting with the paper I posted a while back in this thread showing that caloric restriction and even starvation *strengthened* mitochondira....?
https://www.apoe4.info/forums/viewtopic.php?f=6&t=1006&p=10281&hilit=mitochondria#p10281

Reading their call to avoid fasting and everything else around it, looks to me like repetition of conventional wisdom rather than any scientifically grounded and supported logic?
Russ
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