So, the whole idea of liver produced apoe4 having a hard time binding to LRP1, hence leaving cyclophylin A free to cause damage to the bbb is purely theoretical and correlative. It is based on a mouse model and has yet to be reproduced in humans. There are so many lifestyle and dietary factors which can cause cyclophylin A to be upregulated and released into circulation, hence the correlation.
Rapamycin is one of those compounds that may be very useful for those who have issues with high blood sugar and cognitive damage, to help decrease the activation of mTORC1 and increase autophagy, but that is about all the benefit I can see in it. If the body is relatively metabolically healthy, I would not risk the negative effects of rapamycin on that body and focus rather on fatty acid intake, antioxidant intake, theracurmin and high dose, phospholipid DHA, phosphatydil choline and Alpha GPC, all of which are hard to overdose on and which heal the blood brain barrier and mitigate oxidative damage in the brain itself. Everyone has different clearance rates for compounds in the liver. Once weekly may still be too much or not enough.
And finally, wanted to point out - per Dr. Green - It's too late to start rapamycin once cognitive damage is obvious. I've posted multiple links below that might give you (and others) more insight. APOE Genotype-Dependent Pharmacogenetic Responses to Rapamycin for Preventing Alzheimer’s Disease
That doesn't make sense. If Rapamycin down regulates inflammatory pathway which is causing oxidative stress and hence apoe4 production in the brain and resulting ptau production and amyloid plaques, how would that not be beneficial to someone with cognitive decline which is being caused by the downstream effects of said inflammatory pathway, which is the whole point of taking Rapamycin, right? I mean, that's the whole point and action of any of the diet and lifestyle interventions in any protocol which is targeted to lower this type of inflammatory cognitive decline, type 3 Alzheimer's, I believe, is how Dale Bredesen identifies it. Anything that increases autophagy and mitochondrial efficiency in the body is going to help reverse cognitive decline, to a certain extent, if not entirely, or prevent it. In other words, Rapamycin is an inflammatory mitigator, which prevents inflammation in those without it and removes inflammation in those with it, making room for the body and brain to start healing.
Yes, I understand that there is research, like the papers you have attached, which seem to show little effect of Rapamycin post cognitive decline. But again, like I said earlier, the effect of any type of healing or reversal is based on how much damage has already been done. In the mouse model of Majumder et al, the extent of damage done to the brains of the mice not treated until after the fact may have crossed the line of not much return. There are many other apoe4 specific mouse studies which show that Rapamycin does indeed help to reverse cognitive decline after the fact, not just prevent. Here is one by Caccamo et al, 2010: https://pmc.ncbi.nlm.nih.gov/articles/PMC2857107/
I side with Dr. Green's theory on this one. The APOE4/CypA mechanism isn't proven in humans, but that doesn't make it irrelevant. Preventive medicine is often based on animal and observational evidence while human outcome data develop - and often RCTs will never happen when there's no financial incentive. I agree that fatty-acid composition matters enormously for brain and BBB health. But is there evidence that fatty-acid intake actually suppresses the APOE4–CypA–NFκB–MMP9 pathway? I haven't seen it. Rapamycin has been studied for a while now - and I'll take my recent normal ptau217 at almost 74 as evidence I'm doing something right. Been on rapa since 2021 @ 6mg with NO side effects. And others have come to recognize the potential role of rapamycin for AD prevention. https://pmc.ncbi.nlm.nih.gov/articles/PMC12220712/
So, the whole idea of liver produced apoe4 having a hard time binding to LRP1, hence leaving cyclophylin A free to cause damage to the bbb is purely theoretical and correlative. It is based on a mouse model and has yet to be reproduced in humans. There are so many lifestyle and dietary factors which can cause cyclophylin A to be upregulated and released into circulation, hence the correlation.
Rapamycin is one of those compounds that may be very useful for those who have issues with high blood sugar and cognitive damage, to help decrease the activation of mTORC1 and increase autophagy, but that is about all the benefit I can see in it. If the body is relatively metabolically healthy, I would not risk the negative effects of rapamycin on that body and focus rather on fatty acid intake, antioxidant intake, theracurmin and high dose, phospholipid DHA, phosphatydil choline and Alpha GPC, all of which are hard to overdose on and which heal the blood brain barrier and mitigate oxidative damage in the brain itself. Everyone has different clearance rates for compounds in the liver. Once weekly may still be too much or not enough.
And finally, wanted to point out - per Dr. Green - It's too late to start rapamycin once cognitive damage is obvious. I've posted multiple links below that might give you (and others) more insight. APOE Genotype-Dependent Pharmacogenetic Responses to Rapamycin for Preventing Alzheimer’s Disease
https://pmc.ncbi.nlm.nih.gov/articles/PMC7486698/
That doesn't make sense. If Rapamycin down regulates inflammatory pathway which is causing oxidative stress and hence apoe4 production in the brain and resulting ptau production and amyloid plaques, how would that not be beneficial to someone with cognitive decline which is being caused by the downstream effects of said inflammatory pathway, which is the whole point of taking Rapamycin, right? I mean, that's the whole point and action of any of the diet and lifestyle interventions in any protocol which is targeted to lower this type of inflammatory cognitive decline, type 3 Alzheimer's, I believe, is how Dale Bredesen identifies it. Anything that increases autophagy and mitochondrial efficiency in the body is going to help reverse cognitive decline, to a certain extent, if not entirely, or prevent it. In other words, Rapamycin is an inflammatory mitigator, which prevents inflammation in those without it and removes inflammation in those with it, making room for the body and brain to start healing.
I believe his opinion was largely formed by this paper: https://pubmed.ncbi.nlm.nih.gov/21980451/
here the detail: https://pmc.ncbi.nlm.nih.gov/articles/PMC3182203/
Yes, I understand that there is research, like the papers you have attached, which seem to show little effect of Rapamycin post cognitive decline. But again, like I said earlier, the effect of any type of healing or reversal is based on how much damage has already been done. In the mouse model of Majumder et al, the extent of damage done to the brains of the mice not treated until after the fact may have crossed the line of not much return. There are many other apoe4 specific mouse studies which show that Rapamycin does indeed help to reverse cognitive decline after the fact, not just prevent. Here is one by Caccamo et al, 2010: https://pmc.ncbi.nlm.nih.gov/articles/PMC2857107/
APOE4 impairs autophagy and Aβ clearance by microglial cells (Rapamycin treatment corrected Mitochondrial Membrane Potential in APOE4-expressing cells.)
https://pmc.ncbi.nlm.nih.gov/articles/PMC11958439/
mTOR inhibition enhances synaptic and mitochondrial function in Alzheimer's disease in an APOE genotype-dependent manner.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11494852/
I side with Dr. Green's theory on this one. The APOE4/CypA mechanism isn't proven in humans, but that doesn't make it irrelevant. Preventive medicine is often based on animal and observational evidence while human outcome data develop - and often RCTs will never happen when there's no financial incentive. I agree that fatty-acid composition matters enormously for brain and BBB health. But is there evidence that fatty-acid intake actually suppresses the APOE4–CypA–NFκB–MMP9 pathway? I haven't seen it. Rapamycin has been studied for a while now - and I'll take my recent normal ptau217 at almost 74 as evidence I'm doing something right. Been on rapa since 2021 @ 6mg with NO side effects. And others have come to recognize the potential role of rapamycin for AD prevention. https://pmc.ncbi.nlm.nih.gov/articles/PMC12220712/