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

[Harrison]

One would want to increase lipidation of ApoE4, decrease apoE4 levels (preferentially non-lipidated apoE4), or alter apoE4 so that it could be more lipidated, or less toxic (Wang et al, 2018). I don't think these approaches need to be mutually exclusive either.

The holy grail! I like this, Harrison. If you've figured out a "home brew", let us know.

Unfortunately no home brew for this. It's possible the statins may lower apoE levels (https://www.ncbi.nlm.nih.gov/pubmed/16960448), but they also likely would lower apoE lipidation. ApoE is taken up by the LDL Receptor, and a little bit of work suggests resveratrol may increase LDL receptor number (https://www.ncbi.nlm.nih.gov/pubmed/22153697). I don't think anyone has figured out how to increase apoE lipidation via ABCA1 without toxicity, although this new finding is interesting: http://www.jlr.org/content/early/2018/03/21/jlr.M081851.

For me, it keeps coming down to peripheral apoE levels because that's something we can actually measure. Do we know anything definitive about the correlation between peripheral and cerebral apoE? I keep coming back to Rasmussen's and Goodenowe's work. Higher levels of plasma APOE are correlated with better cognition. Goodenowe has found that High HDL/low TG is a good proxy. It's telling (to me at least) that this combo is also associated with cardio and neuroprotection. I'd be hesitant to actively work on lowering HDL.

It's been long known that the brain makes it's own apoE based in liver transplantation studies. There are essentially 3 different pools of apoE: peripheral apoE, cerebrospinal fluid apoE, and apoE in brain tissue. There is little cross-talk between plasma and CSF https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338868/, cross-talk between CSF and brain tissue, but no direct relationship between plasma and brain tissue. What I think might be happening here is that there are variants of the apoE promotor that decrease apoE levels everywhere, which is what Rasmussen was studying. While it is good to have lower levels of non-lipidated apoE4, you do want lipidated apoE4 that functions properly and preserves cognition and brain function. There may not be a direct relationship between plasma apoE and cognition, but rather lower levels of apoE in plasma and brain are a independent downstream effects of ApoE promotor SNPs. Plasma apoE might be useful as a proxy for knowing if you have lower than typical apoE (or if you are increasing it), but doesn't tell you what the actual situation is in the brain.

[LG1]

Brian, exactly! I hope Dr. Huang is putting most of his energy into this lane as he has multiple projects going on at once.

[ApropoE4]

LG1, for the record, I totally see why Fiver put these two topics together. They both share the quality of seeming like potential outright cures for most dementias, once one realizes how much of LOAD and other dementias (to say nothing of heart disease, and so on) is the result of APOE-ε4–related pathology. And hence the question: Why no urgent push? Why aren't people screaming from the rooftops about this? With enough funding... like, wow, we could save tens of millions of people within a decade or so, I'd venture to say. (But the difference between the two techniques is that I think the funding push should be towards structure correctors, since that's a more realistic treatment option in the short- to medium-term.)

Brian

The problem is as soon as you present a pot of gold, there are going to be dozens of competitors, all of them presenting decent cases - one has a cancer drug with a known risk profile that seems to potentially be helpful for AD, so it's "cheap" and fast to test. Another has a structure corrector which is unproven but seems feasible to bring to trial long before any CRISPR based therapies... this one is presenting a peptide that he's promoting both as a diabetes drug and as an APOE4 drug... that one is promoting diet and pointlessly expensive snake oil...

It's hard to tell in advance which approach will pan out, and it's possible that even if a structure corrector is the way to go for the next decade, e-scape bio may not be the company to reach that goal (although imho it is still the most likely to do so), so you can scream off every rooftop but it won't help make things come along any faster...

[Orangeblossom]

I wonder if there's anything they can do with the promoter genes, can they switch them on and off or do something to increase APOE levels if that is helpful.

[Brian4]

so you can scream off every rooftop but it won't help make things come along any faster...

ApropoE4, agree about all the bottlenecks, roadblocks, and complexities to moving things forward that you note, but that doesn't seem to constitute at all an argument against shouting from the rooftops: there are people and institutions with deep pockets who are entirely unaware of the work with small molecule correctors. Make them aware, and more funding and research is likely to result. That some of the research might be conducted by people or companies not ideally suited to bringing a drug to market, and that there is competition, is simply an unavoidable downside of the imperfect reality of the research world in which we live, whatever the research might be. But floor it in your very out of tune, old Dodge, and the car still goes faster.

I think we need to floor it with this research. Things can indeed be accelerated.

[Fiver]

I do think apoe4 "fixes" should get some focused attention. As much as AB antibodies, for example. Maybe we could help with that. It would also be helpful for cardiovascular disease, Parkinson's etc.