Julie G wrote: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.
Julie G wrote: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.