I wonder if Dr. Goodenowe would share his thoughts on the lipophilic stain question?
Lol, chrissyr. I'm one step ahead of you and already got his response:
The issue of cholesterol gets contentious because people confuse biomarkers of cholesterol with the function of cholesterol. Circulating cholesterol biomarkers (total, ldl, hdl) are crude biomarkers that we can use to infer the relative status of biological functions that are influenced by cholesterol levels. Cholesterol exerts its biological function in membranes, which is where 80% of your body’s cholesterol resides. This cholesterol cannot be detected by blood tests. However, it can be inferred from biological processes known to be heavily influenced by membrane cholesterol levels – like APP processing. The Crum paper indirectly shows that statin use does not affect membrane cholesterol levels in the brain (i.e. no change in amyloid). For example, high levels of HDL cholesterol is good because it infers that membrane levels will be lower. If you translate the Michikawa figure to the human brain, then e2 carriers would have high brain HDL-cholesterol (good) and e4 carriers would have low HDL-cholesterol (bad), however, this translates into the exact opposite effect in the membrane where the e2 membrane will have low cholesterol (good) and the e4 membrane will have high cholesterol (bad).
One of the possible pleiotropic effects of statins is as a ppar agonist. This would explain the data in the barter paper that shows that the increase in HDL is associated with a decrease in triglycerides (a ppar effect). The subtle nature of the effect means that the most likely ppar subtype is gamma (but it could be a bit of alpha too – I do not know the relative specificities of the different statins on the different ppar types at different doses). Ppar-gamma induction is neuroprotective and increases plasmalogens and may explain the association between statin use and reduced AD in some studies – may also explain negative muscle symptoms in some statin users. Discussing this further requires a lot of detail digging, and I am not totally up to speed on all the research in this area.
When we start talking about off-target drug effects, things get really complicated and it become very difficult to determine what is affecting what.
I hope that this is helpful.
Clear as mud, eh? Later today, I'll try to refer back to the Crum paper to assess the size of the dataset, etc. If anyone else can make any inferences, I'm all ears.