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Epigenetics - can we really turn APOE4 off?

Posted: Sat Aug 24, 2019 9:22 am
by Emerald
I have a question - I definitely understand the concept of epigenetics and how certain genes can be turned on or off based on emotional, environmental, etc. factors. That said, is APOE4 really one of those genes? Aren't the two copies of APOE we have (whether they're 2, 3, and/or 4) technically always going to be active? I fully understand that we can make choices that influence how APOE works (and significantly decrease the likelihood of Alzheimer's and other issues this way), and APOE interacts with various other genes that can be turned on or off. However, we can't really turn APOE off, can we?

I studied health and diseases, so I apologize if I'm getting too technical. I suspect "turn APOE4 off" is really just a simple way of referring to our ability to make positive choices and lessen its impact (which is totally fine with me!), but wanted to confirm. Thank you!

Re: Epigenetics - can we really turn APOE4 off?

Posted: Sat Aug 24, 2019 9:51 am
by Fiver
Hi Emerald. It's an interesting question isn't it? As far as I know targeting apoe4 with such precision requires a precision approach, some sort of RNA silencing, gene therapy, or CRISPR technology. Epigenetic approaches to controlling DNA methylation, histone acetylation, or small non-coding RNAs are possible. Some plant products in our diets are good histone deactylase inhibitors, for example sulforaphane from broccolli (esp sprouts). And there are even more powerful versions of these inhibitors used in medicine - against cancer, and many other disorders. Interestingly, they do cross the BBB. However, they influence whole groups of genes - opening and closing genetic programs like computer program windows. It could be good, if it leads to a healthy growing brain. I'm aware of studies showing the drug-induced changes in epigenetics can stimulate the "clean up" procesess of brain cells (in cell culture) - that seems promising. But it doesn't target apoe4 specifically, as you probably already know.

One challenge - despite much reading and asking around there does not seem to be any argeement as to whether apoe4s would want less or more apoe4 being produced. That's frustrating, because it's such a simple question and probably very important. Until those details are worked out it might actually be a better approach to shift whole epigenetic programs, tweeking apoe4 and hundreds of other genes to get some benefit. Unless, of course, one can *replace* apoe4 with apoe3, which would seem to solve the problem entirely - if it can be done.

Marc R posted a recent paper summary about this, which I haven't read yet. You might want to find that post.

Re: Epigenetics - can we really turn APOE4 off?

Posted: Sat Aug 24, 2019 10:27 am
by floramaria
Fiver wrote:One challenge - despite much reading and asking around there does not seem to be any argeement as to whether apoe4s would what less or more apoe4 being produced. That's frustrating, because it's such a simple question and probably very important

Hi Fiver, Since you seem quite knowledgeable in this area I am very interested in your thoughts . There seems to be something missing in the first sentence I quoted . I’m curious about what you intended to write.

Re: Epigenetics - can we really turn APOE4 off?

Posted: Sat Aug 24, 2019 11:31 am
by circular
floramaria wrote:
Fiver wrote:One challenge - despite much reading and asking around there does not seem to be any argeement as to whether apoe4s would what less or more apoe4 being produced. That's frustrating, because it's such a simple question and probably very important

Hi Fiver, Since you seem quite knowledgeable in this area I am very interested in your thoughts . There seems to be something missing in the first sentence I quoted . I’m curious about what you intended to write.

I believe 'would what' = 'would want'.

Re: Epigenetics - can we really turn APOE4 off?

Posted: Sat Aug 24, 2019 1:25 pm
by Fiver
Oops. Circular is right. My typing skills were never great. :)

Re: Epigenetics - can we really turn APOE4 off?

Posted: Sat Aug 24, 2019 3:33 pm
by floramaria
circular wrote:I believe 'would what' = 'would want'.

OHHHHHH... Now I get it! Makes sense. Thanks.

Re: Epigenetics - can we really turn APOE4 off?

Posted: Tue Aug 27, 2019 5:23 pm
by mike
Fiver wrote:One challenge - despite much reading and asking around there does not seem to be any argeement as to whether apoe4s would want less or more apoe4 being produced. That's frustrating, because it's such a simple question and probably very important.

I haven't read anywhere that E4 is actually harmful (unless it becomes a prion?), just that it is less effective at either binding to receptor or fatty acid, can't remember which... Maybe if one is 3/4, the 4 could get in the way of the 3? But seems unlikely.

Re: Epigenetics - can we really turn APOE4 off?

Posted: Tue Aug 27, 2019 5:54 pm
by Fiver
Hi Mike. Hope you're well.

I've read solid reviews and articles in good journals, which disagree on it entirely. I think you have good points. apoe4 does bind poorly to the LDLr (low density lipoprotein receptors) on cells because of it's "pinched" shape. SO LDL stays in the blood, and LDL levels might be higher on a blood test, while cells aren;t getting the resources they need. And overall, if I recall correctly, apoe4 levels are lower overall compared to apoe3. So more might be better. But there is also evidence that apoe4 is toxic by itself, in part by binding with AB to form plaques. It also binds to DNA, acting as a transcription factor to start up some "bad" genetic programs.

I tried to understand it and found papers where researchers up-regulated, down-regulated, or silenced apoe4. The individual studies make total sense. The changes were dramatic. But they contradict often one another. I've just never been able to find an agreement on it. The last review I read seemed to be really good - then just kind of concluded at the end that it was a lack of function problem in the most unconvincing way. If I had to guess I'd say I'm a little bit more convinced that apoe4 is bad and more of it is worse, i.e. that it is harmful. But that's just me.

I suppose it could be both, right? It lacks proper functions AND has negative functions. So then the answer is not to raise or lower levels, but to replace it with apoe3 or 2.

That will be a good day when that is an option!

Re: Epigenetics - can we really turn APOE4 off?

Posted: Wed Aug 28, 2019 5:48 pm
by mike
Except E4 seems to improve ketone metabolism in the brain. And remember that at one time E4 is all that there was. I find it hard to accept that it would be harmful in itself, at least in early man...prior to man moving from mostly meat and fat to having a good portion of carbs, and especially sugar and concentrated fructose. Once that happens the brain is burning mostly glucose and oxidative stress is higher, which I'm thinking leads to the problems we see. Also, if one is eating little carbs, then the body must produce any needed glucose from fat and/or protein, which is a controlled process and allows the blood glucose levels to stay even. Instead, as we eat carbs, it is converted quickly to glucose, causing blood levels to rise rapidly and therefore causing it to rise in the brain as well. This can't be good for our brains. Our bodies are all about keeping things in balance.

Re: Epigenetics - can we really turn APOE4 off?

Posted: Thu Aug 29, 2019 6:40 am
by Fiver
Hi Mike, interesting. I hadn't been thinking that apoe4 improves ketone metabolism. I can see how it might, indirectly, especially is sugar metabolism is compromised. I'll read up on that! Thanks.

I'll admit that over time I've kind of lost interest in the evolutionary story of apoe4, human diets, etc. I used to find it interesting but now I just don't know what to do with it. Evolution is messy, especially with regard to negative consequences of genes that emerge later in life, in years beyond reproduction or what was then the expected lifespan. I think I've just grown impatient. Even if apoe4 conveyed some advantage long ago I don't want that "advantage" now. I'd be first in line to trade my apoe4 for some apoe3/2. I hope that's not a reckless point of view It's just how I feel.

I see epigenetics as perhaps a way to reduce the negative impacts of apoe4 in the meantime. For example, altering histone acetylation using well-known medicines and plant products seems to boost the "garbage recycling" system - and do other things that seem a bit promising. I hope researchers do more in this area.

But it sure would be nice to know if we would want more or less apoe4. It is really amazing to me that we don't know the answer to that question.