Really appreciate how precisely you've laid out the CypA MMP-9 cascade here, it's a much sharper mechanistic story than the usual "rapamycin is good for autophagy" framing. One thing worth flagging on the "conditional, not inevitable" point: most of the direct evidence for mTOR inhibition protecting BBB integrity comes from models where the barrier is still intact, true primary prevention. There is newer work in ischemic stroke and vascular cognitive impairment models showing mTOR inhibition can also reduce pericyte constriction and support barrier function after injury has already started, not only before it. If that generalizes to APOE4 biology, it would mean rapamycin isn't only useful for carriers who start early, it could still be doing meaningful work for people whose BBB is already somewhat compromised. Worth tracking for anyone trying to figure out how late is too late to start.
Have read more and noted 6mg suggestion and to consider drug levels. Do you track progress eg white cells with any specific blood tests other than FBE blood tests?
During the first couple of years on rapamycin, my neutrophils were usually out of range low (not by much - but lower). My body seems to have adjusted now as no longer trending low. No other markers were affected. Common sense with rapamycin use is to skip it if you are going to be exposed to potential infection risk (minor surgeries, dental cleanings etc) and if I cut my skin, I'm diligent about immediate cleaning and disinfecting. I keep a Z-pak on hand but have never had to use it.
The protocol Dr. Green used was once weekly 6mg. He believed every APOE4 carrier should be on this starting mid-life and before any cognitive symptoms occur.
Did you discuss this with Dr. isaacson and if so what was his opinion? I don’t recall him mentioning it in recent podcast but it seems like rapamycin should be recommended for us! Where do you suggest ordering it?
As mentioned, the appointment with with Dr. Isaacson's team, not him directly. I'll bring it up at my next appointment. Regardless of what his thoughts are, I won't discontinue rapamycin. It's likely he has no opinion until there is more human data and I haven't the time to wait. As for ordering it - since Dr. Green passed away, my PCP prescribes it for me. She knows my APOE status and my history using it. There are numerous online sources including AgelessRX.
Really appreciate how precisely you've laid out the CypA MMP-9 cascade here, it's a much sharper mechanistic story than the usual "rapamycin is good for autophagy" framing. One thing worth flagging on the "conditional, not inevitable" point: most of the direct evidence for mTOR inhibition protecting BBB integrity comes from models where the barrier is still intact, true primary prevention. There is newer work in ischemic stroke and vascular cognitive impairment models showing mTOR inhibition can also reduce pericyte constriction and support barrier function after injury has already started, not only before it. If that generalizes to APOE4 biology, it would mean rapamycin isn't only useful for carriers who start early, it could still be doing meaningful work for people whose BBB is already somewhat compromised. Worth tracking for anyone trying to figure out how late is too late to start.
Well done, Karin. Thanks. Note: everolimus might be even better than rapamycin, because of the shorter half-life, but we need more research.
I assume this is a prescription? Is it a pill? Any known side effects?
Have read more and noted 6mg suggestion and to consider drug levels. Do you track progress eg white cells with any specific blood tests other than FBE blood tests?
During the first couple of years on rapamycin, my neutrophils were usually out of range low (not by much - but lower). My body seems to have adjusted now as no longer trending low. No other markers were affected. Common sense with rapamycin use is to skip it if you are going to be exposed to potential infection risk (minor surgeries, dental cleanings etc) and if I cut my skin, I'm diligent about immediate cleaning and disinfecting. I keep a Z-pak on hand but have never had to use it.
Great article and references Karin , may I ask purely as information if a 1mg dose is used generally if someone decides to use rapa weekly ?
The protocol Dr. Green used was once weekly 6mg. He believed every APOE4 carrier should be on this starting mid-life and before any cognitive symptoms occur.
Did you discuss this with Dr. isaacson and if so what was his opinion? I don’t recall him mentioning it in recent podcast but it seems like rapamycin should be recommended for us! Where do you suggest ordering it?
As mentioned, the appointment with with Dr. Isaacson's team, not him directly. I'll bring it up at my next appointment. Regardless of what his thoughts are, I won't discontinue rapamycin. It's likely he has no opinion until there is more human data and I haven't the time to wait. As for ordering it - since Dr. Green passed away, my PCP prescribes it for me. She knows my APOE status and my history using it. There are numerous online sources including AgelessRX.