E4: why no urgent push for structure correctors, gene editting?

[Fiver]

Hi everyone. I've been reading. A lot. And I think I've come to a conclusion of sorts. I'd be interested in opinions.

Over the years I've come to appreciate Dr. Bredesen's patching "many holes" approach, trying to optimize as many parts of the system as possible and tip the balance towards better outcomes. Given the state of the science, that approach might be all we have at this time.

But the more I read the more all "LOAD roads" come back to apoe4. In the vast majority of cases it seems to be the culprit that put all those holes in the roof. If you separate out familial alzheimer's and the "type 3" pathogen/toxin triggers cases, apoe4 seems to be a root cause for most of the remaining cases.

So I've been paying special attention to studies I find showing that good things seem to come from (a) reducing apoe4 levels, (b) "correcting" apoe4 structure to be "E3-like" using small molecules, and (c) what seems like the futuristic approach to gene edit apoe4 to apoe3 in humans one day.

I know these studies have been discussed. I'm just wondering....is there some debate that apoe4 isn't the root cause of most instances of LOAD? Is there some really intensive effort out there that I'm not aware of? Is it all hush-hush secret R&D at biotech firms? Is it hard to find volunteers? In short, why no public aggressive international push to somehow "correct" e4....one that seems proportional to the scale of the problem? What's slowing things down?

Thanks for thoughts. I'm learning along with everyone else.

[Julie G]

Really good question, Fiver. A few years ago a bunch of us met with Drs. Mahley and Huang at Gladstone. They’ve made the most progress with an E4 structure corrector. They gave us an amazing presentation and felt certain the structure corrector Pharma would be available soon. For some unknown reason, it’s lagging. Many of us have donated our blood for in vitro proof of concept, but we’ve heard nothing since... I wonder if the science isn’t translating from the mouse model. Who knows? If anyone has an update, please share.

[Orangeblossom]

Seems to be more about raising levels would help, though rather than lowering. I'm not so sure.

[Fiver]

Really good question, Fiver. A few years ago a bunch of us met with Drs. Mahley and Huang at Gladstone. They’ve made the most progress with an E4 structure corrector. They gave us an amazing presentation and felt certain the structure corrector Pharma would be available soon. For some unknown reason, it’s lagging. Many of us have donated our blood for in vitro proof of concept, but we’ve heard nothing since... I wonder if the science isn’t translating from the mouse model. Who knows? If anyone has an update, please share.

I had this same thought. I did see though that big parts of their studies were with human apoe4 in mice or human cell cultures from iPSs, which makes it seem more likely that the effects would transfer.

I understand if they go quiet for a while, focusing on the science and patenting new structures. But it seemed like they had such a complete idea of what the molecule needs to look like to work that finding one that was less toxic and more able to enter the brain would be possible. .....or maybe it's the usual slow progress and just silly to get hopes up.

It does seem like this should be getting more attention though.

[Fiver]

Seems to be more about raising levels would help, though rather than lowering. I'm not so sure.

Hi Orangeblosson. I had the same question. But I was convinced by several of the recent studies that lowering apoe levels was the way to go.....they saw great improvement in all sort of markers by lowering apoe4 (and even apoe3) levels by about 50%. This is consistent with studies suggesting that it is not a lack of apoe3 but rather the toxic effects of apoe4 that cause trouble.

The problem seems to be with "free" apoe4 or "poorly lipidated apoe4". Once the apoe4 creates the particles and fills up with lipids and cholesterol is it "safe", i.e. does not seem to get involved in amyloid aggregation, messing with secretases, or altering gene expression. That's presumably why ABC1 activity (which fills particles up with lipids when they emerge from cell at the cell membrane) is important - the "fuller the better".

well, anyway, that's what I took from my readings. But it sure is complicated! I could be wrong.

Plus - I've not come across any practical way to lower apoe levels. Except to avoid sleep deprivation and head trauma, since apoe and apoj flood the sleepy brain, and after injury.

[Orangeblossom]

Seems to be more about raising levels would help, though rather than lowering. I'm not so sure.

Hi Orangeblosson. I had the same question. But I was convinced by several of the recent studies that lowering apoe levels was the way to go.....they saw great improvement in all sort of markers by lowering apoe4 (and even apoe3) levels by about 50%. This is consistent with studies suggesting that it is not a lack of apoe3 but rather the toxic effects of apoe4 that cause trouble.

The problem seems to be with "free" apoe4 or "poorly lipidated apoe4". Once the apoe4 creates the particles and fills up with lipids and cholesterol is it "safe", i.e. does not seem to get involved in amyloid aggregation, messing with secretases, or altering gene expression. That's presumably why ABC1 activity (which fills particles up with lipids when they emerge from cell at the cell membrane) is important - the "fuller the better".

well, anyway, that's what I took from my readings. But it sure is complicated! I could be wrong.

Plus - I've not come across any practical way to lower apoe levels. Except to avoid sleep deprivation and head trauma, since apoe and apoj flood the sleepy brain, and after injury.

Hi Fiver. That's interesting about the lipidation. I was thinking of this discussion on the levels viewtopic.php?f=4&t=1155&p=55311&hilit=apoe+levels#p55311 wonder if it is possible to ensure it is lipidated properly. - is it related to the ABC1 as mentioned and anything else - anything we can change?

[Julie G]

Super interesting discussion! I hate that I'm so short on time...

The problem seems to be with "free" apoe4 or "poorly lipidated apoe4". Once the apoe4 creates the particles and fills up with lipids and cholesterol is it "safe", i.e. does not seem to get involved in amyloid aggregation, messing with secretases, or altering gene expression. That's presumably why ABC1 activity (which fills particles up with lipids when they emerge from cell at the cell membrane) is important - the "fuller the better".

Therin lies the conundrum: Is it better to try to lipidate our APOE or simply reduce it? It's very frustrating to still not know for certain which is the better path. Strategies associated with reducing APOE would include: less exercise & low fat diet, leading to low HDL... feels incompatible with what I understand to help E4 carriers.

Here's an interesting blog post that provides additional help on how to reduce APOE.

-hypoxia from airline travel
-EMF exposure
-heavy metal exposure, esp. mercury
-SFA
-Vitamin B6 deficiency
-Vitamin C deficiency
-Vitamine E deficiency

He also outlines strategies for increasing APOE. Is this blogger off the mark?

[Orangeblossom]

Well, in general vitamin deficiencies aren;t good, are they? I'm unsure about the blogger and how correct he is, but think we have seen studies recently saying having good levels of vitamin C or B its, for example are better? So that would not tie in would it.

I'm short on time too, sorry, but HDL is an interesting one. As we know higher levels are good for cognition- both in E4 and non carriers. I'm tempted to think it therefore increases the lipidation of the E4 and making it work better, but unsure if that is correct or not.

[Fiver]

Yep, not a lot of clear evidence. The recent papers showed reducing apoe4 reduced markers of pathology by about 50%. That seems encouraging. But, probably too early to tell.

There is no HDL made in the brain, as far as I know. There are HDL-like particles containing apoe, however, made primarily in astrocytes. Apoe and apoj production increase greatly following head trauma.

(Higher HDL in the rest of the body might protect against vascular dementia, etc.)

Free apoe is bad. Poorly lipidated apoe causes problems, but perhaps fewer. Fully lipidated apoe seems, to my readings, relatively safe.

I'm not aware of many options to tip the balance. Julie knew more.

In theory one could alter gene expression, translation, handling and transport of apoe proteins, bind them up, or cut them to pieces. Or make sure they were fully lipidated asap. Easy peezy, right?

[Fiver]

Super interesting discussion! I hate that I'm so short on time...

The problem seems to be with "free" apoe4 or "poorly lipidated apoe4". Once the apoe4 creates the particles and fills up with lipids and cholesterol is it "safe", i.e. does not seem to get involved in amyloid aggregation, messing with secretases, or altering gene expression. That's presumably why ABC1 activity (which fills particles up with lipids when they emerge from cell at the cell membrane) is important - the "fuller the better".

Therin lies the conundrum: Is it better to try to lipidate our APOE or simply reduce it? It's very frustrating to still not know for certain which is the better path. Strategies associated with reducing APOE would include: less exercise & low fat diet, leading to low HDL... feels incompatible with what I understand to help E4 carriers.

Here's an interesting blog post that provides additional help on how to reduce APOE.

Is this blogger off the mark?

Hi Julie, I've read this blog before and re-read it quickly now. What I see is the blog text conflates genotype (e2, e3, e4) and protein levels in a confusing way. To be fair, I was basing my thoughts in very recent studies the blogger didn;t have access to when the blog post was written. But it still is a very confusing way to organize the discussion and leaves us with the big question: if we could, should we raise or lower apoe4 levels?

Maybe the answer would be different for e3/e4s and e4/e4s.

From what I am reading it is pretty clear that free and poorly-lipidated e4 is toxic and reducing levels of apoe4 results in "good things" for human cells in culture, mice with human apoe4, etc.