Woo hoo! My comments/questions are then officially directed to Dr. Cain
Your generous sharing of this paper came at a good time for me. This is also something I'm struggling to wrap my head around. I've been reading as much as I can of the mainstream hypothesis vs.the Seneff hypothesis and I'm left with more questions than answers. Your paper improves my understanding, BUT I'm far from fully grasping everything- understatement
Part of my problem results from the scientific community's evolving understanding...
-Several papers have theorized/demonstrated that E4 carriers may have "leakier" BBBs.http://www.urmc.rochester.edu/news/stor ... fm?id=3512
ApoE4 makes it more likely that cyclophilin A will accumulate in large amounts in cells that help maintain the blood-brain barrier, a network of tightly bound cells that line the insides of blood vessels in the brain and carefully regulates what substances are allowed to enter and exit brain tissue.
ApoE4 creates a cascade of molecular signaling that weakens the barrier, causing blood vessels to become leaky. This makes it more likely that toxic substances will leak from the vessels into the brain, damaging cells like neurons and reducing blood flow dramatically by choking off blood vessels.
Could this also lead to more
crosstalk between the two cholesterol pools in E4 carriers, allowing us to benefit from increased peripheral cholesterol?
-Apparently cholesterol is necessary to maintain the integrity of the myelin sheath that comprises the BBB. Of the APOE genotypes, E4 carries cholesterol the most poorly leaving our myelin more susceptible to injury. Could that also help explain why some patients (including members here) taking medications or supplements with statin-like properties exhibit cognitive dysfunction? http://www.medscape.com/viewarticle/465883_3
A widely accepted theory involves myelin. Cholesterol is essential in the formation of myelin. The more lipophilic statins are able to cross the blood-brain barrier and decrease the amount of CNS cholesterol below the critical value necessary for the formation of myelin. Inadequate myelin production results in demyelination of nerve fibers in the CNS, resulting in memory loss. Once the offending statin is removed from the patient's system, myelin stores are replenished and mental status returns to normal. In our two patients, as well as another patient who received simvastatin, mental status returned to normal within 1 month of discontinuing the statin.
-While brain cholesterol and peripheral cholesterol remain separate pools, HDL is the exception. Small HDL can cross the BBB and perform a beneficial clearing function there. Several papers have theorized high HDL is especially beneficial for E4 carriers. http://www.ncbi.nlm.nih.gov/pubmed/23576895
Our findings suggest that an interaction between apoE and HDL is facilitated by APOE4, and is possibly linked with an enhancement of neuroplasticity and with resultant protective effects on cognitive function in later life. Preservation of higher plasma apoE and HDL from early life is proposed as a possible strategy for maintaining cognitive function in later life, especially for APOE4-positive individuals.
My understanding of the HDL maturation process is that all HDL begins small, then becomes larger & more functional (in the absence of mutations.) I'm left to assume that the maturation of the small HDL occurs within the brain for the HDL to be effective? I ask, as larger HDL particles have been found to be the most cardio-protective and, I'm assuming, neuro-protective. They must start out as small HDL (to be able to cross the BBB) before maturing in the brain and performing clearing functions.
-Lastly, we briefly "chatted" about the Federoff/Georgetown group discovery- that a deficiency in 10 lipid metabolites predicts AD. I theorized that replacing some of those metabolites might be a prevention strategy. Did you see a group in Sweden followed through with that concept and indeed boosted 5 of the 10 metabolites?A Nutritional Approach to Ameliorate Altered Phospholipid Metabolism in Alzheimer'sDisease.http://www.ncbi.nlm.nih.gov/pubmed/24898653
We show that a 24-week nutritional intervention in drug-naïve patients with very mild to mild AD significantly increased 5 of the 7 measured biomarker phosphatidylcholine species. By providing nutrients which normally rate-limit phospholipid synthesis, this nutritional intervention could be useful in asymptomatic subjects with a plasma lipid biomarker profile prognostic of AD.
Also, in this transcript http://www.usagainstalzheimersnetwork.o ... mers-talks
Dr. Federoff surmises that cholesterol lowering medications MAY account for the drop in lipid metabolites. Aside from asking participants to refrain from morning meds, they weren't controlled for in his experiment
Thanks again for sharing, Dr. Cain
. This is something I've been working on as well. I appreciate the mainstream scientific community's assertion that there is limited interaction between the two cholesterol pools, but there is enough evidence/ambiguity for me to suspect that we have more to learn on the subject. I'd appreciate any edification you can share.