News from our SFO Meet-up

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Stavia
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Re: News from our SFO Meet-up

Post by Stavia »

No no no.
Oxidative stress and other stresses in his hypothesis cause fragmentation of all apoe proteins. The fragments are toxic. E4 fragments most easily.
If you reduce all the stress them the fragmentation should be reduced to a level that the body can clear. But they are not working on a prevention approach but a molecule corrector
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Re: News from our SFO Meet-up

Post by LillyBritches »

Thank you, baby girl. That's JUST what I needed. :D (((Stavia))) <3
I'm just a oily slick in a windup world with a nervous tick.
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Re: News from our SFO Meet-up

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I wuv you Lilly darling
Huggles
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Re: News from our SFO Meet-up

Post by Stavia »

Ok so just to clarify, everyone is correct.
Mahley and Huangs hyopthesis is that all apoe molecules can fragment. 2 <3 <4. Its the fragments that are toxic and disrupt cytoskeleton and interfer with mitochondrial metabolism. So yes they believe its the apoe itself, more accurately its fragments. The body can clear the fragments but if too many are made from stressing the cell then we can't clear them fast enoughy. BUT there are many many modifiable factors and not everyone with e4 will fragment enough to get AD.
Thats why I plan to work on prevention strategies.
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Re: News from our SFO Meet-up

Post by Julie G »

I’m only half-way through sharing my notes from our meet-up; just slow in reporting. Life keeps getting in the way ;) I’m really excited to let you all know what we learned from Gladstone Institutes. I was w-a-y more impressed and hopeful than I expected to be...

Our first speaker was Dr. Leon Chen, the CEO of the new company (unnamed so far) that will take Drs. Mahley's & Huang's E4-focused efforts and work to turn them into a viable reality for our population. According to notes from Dr. Mahley, "Leon has now worked with us for a year to set the stage for this endeavor and has absolutely caught the vision, mastered the knowledge and recognized the importance of developing a treatment for apoE4." Dr. Chen has had impressive previous experience in developing a successful company. He is skilled in drug discovery and development. He has secured 100% of the funding for the project through the health focused venture capital fund management firm Orbimed http://www.orbimed.com. Orbimed only supports projects they think will succeed and will become ultimately profitable. Luckily for us, both the E4 structure corrector and the protease inhibitor made the grade.

There is still MUCH work to be done. They'll begin by translating their work from the mouse model to humans via trials. The Gladstone team was very hesitant to provide us with a time frame, but Dr. Mahley guessed that the structure corrector would be commercially available in 4 years, the protease inhibitor (to be used as an adjunct or secondary therapy if the structure corrector is insufficient) shortly after. These will be oral medications. No one knows yet if we would have to take them for a lifetime or for a shorter treatment period. For mice, there appears to be a window of opportunity. If they get the medications at 10 months and take them for several months; they are done for life. At that point, the E4 protein self-transforms into a corrected version. Very hopeful. My guess is that the later we get it (the more damage is done) the longer we’d have to take it.

(((Lilly))) I repeatedly heard the exact same thing that Karelena did; ApoE4 CAUSES Alzheimer's. I had it underlined because each time it was repeated it felt like an arrow to my psyche. This is their hypothesis, their rhetoric, their semantics. We already KNOW that E4 is not deterministic, but it IS the gene that confers the highest risk of developing Alzheimer’s. The Gladstone team called it "semi-deterministic."

Others have done a great job describing the science of the molecule corrector and the protease inhibitor. According to Mahley & Huang, what causes both E3s & E4s (but especially E4s) to begin creating fragments are the risk factors listed below. Our site is full of alternative ways to address these issues:
-Aging
-Oxidative Stress
-Trauma
-Amyloid deposition
-Low Oxygen

IMO, brilliant Karalena asks a great question? If we carry the ancestral allele, WHY is it so vulnerable? My guess dovetails with the side discussion held by Russ & Stavia. Perhaps we were not intended to survive beyond reproduction? Perhaps a primitive non-Westernized lifestyle was not rife with the environmental factors that cause the oxidative stress we now face: Frankenfood, toxic environment, sedentary lifestyle? Perhaps E3, which only came about 200,000 years ago, and E2, about 80,000 years ago, are the adaptations/mutations designed to deal with donuts, air pollution, and 9-5 sitting? That correlates with the notion that E4 carriers are not inherently unhealthy; but rather a mismatch with our modern environment. Hopeful and daunting...

I was equally excited about a new Alzheimer’s bio-marker assay that the Gladstone team has developed that actually measures fragments in the serum. Apparently it STRONGLY correlates with cognition; much more so than amyloid. As expected, homozygotes typically have the highest levels, heterozygotes come in second, with E3 carriers demonstrating the least. Through the generosity of the Banner Alzheimer’s Institute, Drs. Mahley & Huang were provided with decades worth of E4 and other high risk patients' blood samples already correlated with cognition via extensive neuropsych testing in an effort to prove that fragmentation correlates with worsened cognition. It did. Interestingly, depression patients have 10x more fragments than their non-depressed ApoE counterparts. Also, anyone exposed to any of the stressors above, regardless of ApoE genotype, also showed higher fragmentation. That’s somewhat hopeful for us, as it gives us a path forwards until this is ready.

Intrepid and innovative George & Merouleau were working overtime during the lectures, passing note & exchanging ideas. They asked Drs. Mahley & Huang if we could possibly use the new fragment bio-marker assay to test and tweak our regimens until the small molecule corrector and protease inhibitor are ready. They were open to the idea (no idea of cost!) and guessed it would be ready in approximately one year.

I would be remiss not to include my girly observations. When I popped into our lecture hall, I immediately recognized Dr. Mahley by his Gladstone photo, but when he asked “How’s Ski?” I knew we were in the right place :D Apparently he, and others in the group, had corresponded with him. Those interactions clearly meant a lot to him. Dr. Mahley was a brilliant speaker. We may have gotten a 1.5 hour lecture, but the geek in me could have listened forever. He is is walking APOE-ε4 dictionary. I’ve heard ApoE pronounced two ways; with both a hard & soft “A.” When the man who discovered it pronounces it with a soft sound, I need to change my pronunciation.

His lovely wife, Dr. Linda Mahley, joined us for the whole afternoon. During breaks, she regaled us with stories of the day Dr. Mahley discovered apolipoprotein back in 1972. He was all excited about a piece of paper from the lab with a new protein on it. She recalls that they took multiple pictures of it when “Bob” came home from work. Little did they both know, it would change their lives...and ours. Others have shared the humorous story of the mistakenly labeled E1, which turned out to be sugar-enriched E2. I vote that corrected E3s and E4s should be re-labelled E1s to fix that little boo-boo.

Dr. Huang was equally impressive. Dr. Mahley described him as the MOST brilliant scientist he’s ever had the pleasure to work with. Seeing the love, friendship, and respect between the two men meant a lot to me. It was almost like a proud father/son. Dr. Huang came to the US, already scientifically trained; but not speaking English. Dr. Linda Mahley, also a scientist, actually taught him. Of course, I found that endearing.

In another thread, Circ asked about dietary advice. We didn’t go there with this group. We were so time pressed to learn all that we did. They offered us butter cookies and soft drinks -all untouched- which may provide a clue that that isn’t their arena. Dr. Huang hurt me (drool) when he actually popped open a Diet Coke in the middle of his lecture. Overall, it was an amazing historical interaction. It meant a lot to us to spend time with these legends. It meant a lot to them to meet us and see how hard we were working to find (diet/lifestyle) strategies alongside of them.

This just might work, folks. IMO, our job now, is to stay well enough to be ready for it. Teezer, we decided we need a "Waiting to be... De-Fragged" Tee 8-)
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Re: News from our SFO Meet-up

Post by Teezer »

Juliegee wrote:Perhaps we were not intended to survive beyond reproduction? Perhaps a primitive non-Westernized lifestyle was not rife with the environmental factors that cause the oxidative stress we now face: Frankenfood, toxic environment, sedentary lifestyle? Perhaps E3, which only came about 20,000 years ago, and E2, about 8,000 years ago, are the adaptations/mutations designed to deal with donuts, air pollution, and 9-5 sitting? That correlates with the notion that E4 carriers are not inherently unhealthy; but rather a mismatch with our modern environment.
As far as evolution "intended," life forms only need to survive long enough to ensure the survival of the next generation. Anything more is a happy accident. And 20,000 years ago, the environment was even more toxic than it is today, with rampant infectious diseases and large animals that regarded us as food. Even as recent as 100 years ago, my father's life expectancy was 46 years at birth (he would have been 101 this August, but he passed at 84, with AD).
Teezer, we decided we need a "Waiting to be... De-Fragged" Tee 8-)
You might have to do a lot explaining with that one, as "Fragged" is what happens to you when someone rolls a live hand grenade into your tent while you're sleeping...
It's weird how I'm constantly surprised by the passage of time when it's literally the most predictable thing in the universe. -- xkcd
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Re: News from our SFO Meet-up

Post by pgf54 »

Julie brilliantly explained , thank you. I would think from my point of view by the time we get the corrector and inhibitor approved in Australia and then on the governments subsidized lists , as i am guessing initial costs will be high (too high for the like of me to purchase the product ) I will have forgotten what its all about to begin with. Therefore on a more serious note without being negative i can and will concentrate on our current preventative measures............which i am hoping will be enough...........................however it is a very exciting development and makes total sense............
ps Re the tee , i think a lot of people may mix up the word fragging with fracking and thats contentious over here........It would certainly provoke awareness :)
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Re: News from our SFO Meet-up

Post by ApropoE4 »

Juliegee wrote:He has secured 100% of the funding for the project through the health focused venture capital fund management firm Orbimed http://www.orbimed.com. Orbimed only supports projects they think will succeed and will become ultimately profitable. Luckily for us, both the E4 structure corrector and the protease inhibitor made the grade.
That is lucky - just imagine if they'd gone and secured financing from a company that only supports projects they think will fail :lol:

Thanks for all the notes. Interesting stuff!
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Re: News from our SFO Meet-up

Post by Silverlining »

Thanks for the notes people! It is all fascinating; Karelena, thanks for the HDL reminder...it has spurred me to address my husbands low HDL; he's a 3/3 with family CVD. Julie, I LOVE the girly side input, certainly provides a better visual and enables me to feel the "vibe" of these researchers. I feel grateful every day for my apoe4 friends.
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Re: News from our SFO Meet-up

Post by Russ »

For those seeking some depth on understanding the interplay of diet, human health and longevity in human evolution, this looks like an exceptionally strong paper...

http://www.unm.edu/~hkaplan/KaplanHillL ... lution.pdf
From the paper...
The first is a change in the distribution of foods with the emergence of African savannas in the Pleistocene, which increased the abundance of high-quality but protected plant foods (nuts and tubers, in particular) and animal foods. The second change is the pre-adaptation of bipedality, emerging in the Australopithecines as a locomotor adaptation. This adapta- tion frees the hands for tool use, which allows more efficient extraction and hunting and frees the hands for carrying large packages of food suit- able for sharing.128,129 It also results in efficient terrestrial locomotion and higher daily mobility that would in- crease the daily encounter rate with rare but energetically rich resources. These changes led to an increased em- phasis on large, high-quality, but difficult-to-acquire foods. Our hypothesis is that this feeding niche had multiple effects: It increased the pre- mium on learning and intelligence, delaying growth and maturation; increased nutritional status and de- creased mortality rates through food sharing (predicted by the provisioning of young sick or injured individuals); and released selection against larger group size, which lowers predation mortality.
...and their Conclusion...
The human adaptation is broad and flexible in one sense, but narrow and specialized in another sense. It is broad in the sense that, as hunter- gatherers, humans have existed suc- cessfully in virtually all of the world’s major habitats. This has entailed eat- ing a very wide variety of foods, both plant and animal, both within and among environments. It also has en- tailed a great deal of flexibility in the contributions of individuals of differ- ent ages and sex. The relative contri- butions of men and women to food production appear to vary from group to group. Even the contributions of children and teens to food production vary predictably with the abundance of easy-to-acquire foods.

Our adaptation is narrow and spe- cialized in that it is based on a diet composed of large, nutrient-dense, difficult-to-acquire packages and a life history with a long, slow develop- ment, a large commitment to learning and intelligence, and an age profile of production shifted toward older indi- viduals. We do not expect to find any human population that subsists on leaves or other low-quality foods. In- deed, we expect humans to remain at the very top of the food hierarchy in every environment they live in (for ex- ample, humans often exterminate all other top predators in their habitat). Humans ingest foods that are already high in quality and do not require much digestive work or detoxification. And if a food contains toxins, they are generally removed prior to ingestion by processing techniques. This dietary commitment is reflected in the ex- tremely reduced size of the human hindgut.23 Humans use their great in- telligence to extract and hunt those foods. In order to achieve this diet, humans also engage in extensive food sharing both within and among age and sex classes of individuals. Finally, the effect of the commitment to food sharing is evident in the reproductive physiology of human women. Provi- sioning permits human women, in contrast to other female primates, to reduce rather than increase their rate of energy production during their re- productive years, when they have both infant and juvenile nutritional dependents and a greatly reduced spacing between births.

The model and the data we have presented suggest that the human life course is based on a complex set of interconnected, time-dependent pro- cesses and the co-evolution of physi- ology, psychology, and behavior. There appears to be a tight linkage among the ordering of major psycho- logical milestones (language learning, understanding and mastering the physical, biological, and social envi- ronment); the timing of brain growth; growth rates during childhood and adolescence; developmental changes in survivorship; behavioral, psycho- logical, and physiological changes with the transition to adulthood; pro- files of risk with age; and rates of se- nescence and aging. It is very likely that a species-typical life course evolved in response to the demands of a hunting and gathering lifestyle that was broad and flexible enough to al- low successful exploitation of the world’s environments, but specialized toward the acquisition of learned skills and knowledge to obtain very high rates of productivity later in life.
It sure seems sensible to me that within this environment, E4 was a strong advantage to maximizing the uptake and utilization of nutrients from episodically available food... especially the lipid components needed to build big brains.
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Eat whole, real, flavorful food - fresh and in season... and mix it up once in a while.
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