Thanks everyone. It really helps to be able to talk through all these confusing studies.
I agree with this summary too: 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.
I suspect that the E-Scape Bio folks and the PH-001 compounds (and similar) must have not themselves been good drug candidates. And, I assume, they are looking for similar candidates to screen. I found a few papers from other labs suggesting that plant natural products like polyphenols might have a somewhat similar effect, but I was less than convinced.
Julie - I did actually read something yesterday about general circulation and CNS apoe levels "going in opposite directions"....so many papers, I will look for the quote again.
A few asked about my results. I don't have all the papers here. But here is a summary, for what it is worth.
I've had poor lipid numbers for at least ten years - the typical pattern B thing. LDL and TGs always ran borderline high, my HDL started out at 29 about ten years ago, I have a family history of CVD (some at young ages). My cardiologist had me try niacin (1g, then 2g) but numbers barley improved. HDL went "up" to 31 and the particle size pattern improved some. Not very exciting. I was already exercising a lot - running, lifting - mostly as stress relief. I was 6'0" 170-178 lbs during this time. I began having strange symptoms, on and off, that were neurological things - just worrying. I was tested for MS. Ultimately, I was told it was just stress....a very unsatisfying answer....but, sure, I had some stress.
Turns out my vitamin D level was 9!
So I added a vitamin D supplement. Fish oil (2x1g capsules / day). Tumeric 400mg. And I slowly began trying out a pre-ReCODE program in the past few years, as I tried to get my mom on the plan.
In January I had phased in a real ketoflex type diet with 1 hour overnight fasting. I lost ~13 pounds in maybe 4 weeks and it has stayed "lost". I focused on lowering carbs and, as a result, I was probably getting more saturated fats than is ideal. In January I got a large number of labs and consulted a FM doctor.
LDL, TGs, and other "negative" lipid numbers were all up, way up, even compared to my already existing pattern-B. HDL was "up" to the mid-30s.
Tests showed I had a wheat gluten allergy I wasn't aware of. Some indications of inflammation in vessel linings, a high PLA-2. And low levels of some steroid hormones that would have required some sort of replacement therapy. The working hypothesis was a "pregnenolone steal" sort of situation where a stress response was stealing away steroid skeletons for cortisol production, reducing levels of other steroids.
* later I would learn that niacin treatment raises PLA-2 biomarker, making it seem like there is more inflammation than there actually is.....hmmmmm.....
5000 IU of Vitamin D got my levels up to 40, still not where FM doctor (or Dr. Bredesen) would want it.
So I had to make some decisions. For various reasons I opted not to work with the FM doctor at this time. I made my open-minded research-savy cardiologist my go-to doctor and kind of took control.
I researched the statin question and, for me, decided it was necessary. Started with mid-level rouvastatin, then switched to the older, slightly less powerful atorvastatin specifically because it was more lipophillic and more likely to reach the brain. I know, easy to argue either side of this one. But I was convinced by some large studies showing benefits, and papers indicating that potential side effects like "brain fog" are unrelated to AD. I'm on 40mg atorvastatin - the high dose. I do get a little "fuzzy" sometimes, like for 1-4 hours after taking it. So I take it at night.
I added: B vitamins (I alternate between the methylated (Life Extension's "homocysteine resist") and regular formulations), ACAR and ALA, 470mg Aswagandha. Took some NR and quercitin for a while too.
For 5 months I cut out wheat (all breads for example) and kept carbs low. I learned to like, then really NOT like, avacados. I set a lower weight limit, and when I reached that weight I relaxed my diet. I found I can relax carbs from 30g max (January-February), to 60g max (spring), to having the occasional slice of pizza so my family doesn't think I'm totally no fun...and it seems ok.
Anyway, my June numbers after being on a "half reCODE" plan in 2016-17 and getting serious in January 2018....so 6-7 months on this newer plan:
total CHO: 104
HDL: 38 (highest it has ever been)
CRP: 0.21 (normal range (0-3) mg/L
vitamin D: 72
total T: doubled, now in mid normal range.
all other numbers: normal
Very pleased. It seems the ketoflex diet and the statin work well together. Vitamin D is good, inflammation seems down, and my total T is now normal (surprising since statins usually lower T about 5-10%). I think the statin obviously had a huge effect on the blood work, though I'd like to think the exercise and diet helped too.
Of course, absolutely none of this tell me what is going on inside my head.
Concerned, but hopeful. Introverted, but will talk about science.