https://www.grantfrasermd.com/post/dont-lose-your-mind
I think this gives the beginning of my overview - there are a lot more candidates … but this is a start.
@LukeMV I think that I’d love to bring on other folks who have ApoE4’s … and I have a fair number in my practice. Just doing a Q&A around the approach can be quite useful. Sadly I’m very poor on time right now, but come March, I’ll be in a bit better shape.
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LukeMV
#48
Well aren’t you the party pooper, doc! We all WANT you to be wrong, so stop crushing all our hopes and dreams!
Just kidding, thanks a bunch for presenting all this info. Very excited to hear you’re starting a YouTube channel. I’ll certainly be hitting the subscribe button immediately. Maybe you can even bring on forum members as guests once in a while.
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Guest
#49
All he does is insisting that lack of specific experiments to prove BBB penetration of EZ invalidates the entire paper (while the authors do ameliorate that very question by calculations based on existing standards - verified by DrugBank).
While unfortunately not addressing my repeated comments on the unique study design of the EZ paper which sets it’s apart from typical observational studies (it’s not fishing for associations).
Now I have a link to a blog with a long list of interventions.
Would DrFraser therefore please tell me a specific intervention out of that long list, that he thinks is worth a second look? Is it Vitamin D? Telmisartan? I’m afraid I won’t have the time to read your entire blog.
Just a name is sufficient (or a specific link to a blog post to that worthwhile substance) - like provided by user desertshores
I think I’ll bow out - I’m sorry I put in any effort on this dialogue. If you don’t want to read materials put forth by a board certified anti-aging and regenerative medicine physician - okay. I’m going to move on from this topic until there is new information.
I was simply pointing out some considerations to assessing such studies that were mentioned, and the critical nature of assessing whether the in vitro can translate to the in vivo.
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Why are you so fanatical about Ezetimibe? You make it sound like you have discovered a very important Alzheimer’s prevention. I take it for cholesterol reduction, but as an Alzheimer’s preventative, it is just one more of hundreds of drugs and supplements that claim some association. Who cares if it crosses the BBB or not, though there is little evidence that it does.
So, bottom line: You are free to have your own beliefs.
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adssx
#52
We have: The MSA trial showed that sirolimus does not engage with brain mTOR in humans (those with MSA at least).
It’s worse than that. We have a Mendelian randomization preprint that shows that sildenafil might INCREASE the risk of dementia: Large Study Finds Viagra Is Linked to Almost 70% Lower Risk of Alzheimer's - #129 by adssx
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Guest
#53
Everyone can have their own opinions.
But there should not be an entitlement to their own facts in a science based discussion.
I’m generally using calm language. I do not engage in ridicule. I adhere to as good scientific standards as possible and try to explain those in my arguments. I’m certainly not, quote, “fanatical about EZ”.
But it is a promising candidate based on a quite unique paper, which is unfortunately not talked about as much as it should be. The paper design uses the reverse logic of what is normally done in observational papers (and with a very thorough methodology), which makes it a lot stronger than simply “fishing for association”.
Therefore I do object, if people strangely dismiss that finding by engaging in double standards.
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Guest
#54
You’re avoiding adressing arguments by citing your credentials. That’s logical fallacy.
You’re saying that you wouldn’t recommend EZ - because of a lack of evidence. That’s a valid standard of course - ultimately we need RCTs to have conclusive evidence.
But for my simple question to name a therapy that you do recommend you’re giving a general blog which you expect me to read in full it seems. Instead of giving a specific link to the respective blog post or just naming the substance.
I’m a tenured college lecturer, leader of a working group in a well known NGO and have a family. So I have to spend my time wisely as well. Asking me to figuratively “read my book” instead of giving a straight answer is not a good style of discussion.
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As for you final comment: the EZ paper is of course not just an in-vitro paper. It uses animal models as well as human observational data to confirm mechanisms and effects.
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Claiming insufficient time is not a valid reason to avoid answering properly. Scientific questions are inherently time-consuming, and critical feedback from academics / medical professionals like Dr. Fraser is valuable. Your comments falls below the forum standards. A lack of time should not excuse unclear or unhelpful responses in scientific discussions which are per definition complex. If you have a family or not is a non-issue.
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Guest
#57
As you hopefully noticed over the past few comments over these days I am actually spending time addressing arguments and concerns, when people dismissed the entire paper in blanket terms - saying that there are much more worthwhile therapies.
Case in point: I was giving direct replies to each of the substances and specific sources pointed out by user dersertshores.
However user DrFraser was not so forthcoming - first basing his entire argument around a very high standard for BBB crossing (which I addressed). And when pointing out the unique study design as a great strength and what he would recommend as a better substance… …he is instead pointing to a general blog and then disengaging. I even offered to do the necessary read-up about a worthwhile therapy if it could be named.
DrFraser does not seem to have read the actual paper - at least the statements like “in-vitro” is factual no the case as is the claimed lack of relevant pharmacological activity of EZ (the paper is testing and reporting that very activity of EZ in-vitro and in animal model - confirming the mechanism).
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Ok, guys. Remember to go easy on the people and hard on the science. Let’s refrain from personal attacks. @DrFraser is a valued member of this community and has dedicated a lot of time to this forum and helping people out. He’s provided a great deal of personalized help that’s gone above and beyond what a normal member does. That’s also why he’s a moderator here.
@Guest many of your comments are appreciated and I too am hopeful about Ezetemibe. I take it daily. We appreciate your contributions, but please let’s keep focused on the science. 
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I felt like this thread is coming close to engaging in personal attacks, and that’s one thing we try to avoid on this forum. We’re all in this together and should be working closely together to analyze the science for better outcomes.
It’s just a friendly reminder not to engage in personal attacks. But go ahead and trash the science as much as you like as long as you back it up.
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medaura
#61
I’ve listened to Attia’s conversations with neurologists and researchers and heard them seriously contemplate how drugs that do not cross the BBB can nonetheless have effects on the brain by acting on the peripheral vasculature. In some cases there’s a hidden intermediary that one wouldn’t even think of unless it can be pinpointed. Case in point, klotho, which doesn’t cross the BBB but activates platelet factor 4, which DOES, and apparently works wonders in the brain.
Consider also that people prone to Alzheimer’s, most notably apoE4 carriers like you and me, have a defective BBB more prone to leakage and penetration. On its own this is a disadvantage, but if we introduce drugs that could work better by crossing the BBB, it suddenly turns into an advantage.
Penny for your thoughts?
p.s., I’m skeptical of Ezetimibe as I am of anything in general but I see no reason why it couldn’t be true. So I’m agnostic, rather, and leaning on cautious optimism.
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medaura
#62
Too much time on hands, clearly
I’ve spent more time looking at this issue with Ezetimibe. I now see that in the VA study, both with and without CAD in Vivo … significant differences in dementia rates. This meets as good a criteria for consideration as GLP-1’s, SGLT2’s and Rapamycin, on a superficial review. I’d however look at my further comments on this after a researcher, biostatistician, epidemiologist reviewed this article.
If the effect is real, the only explanation I can come up with, is that it must cross the BBB, as the peripheral effects don’t make any mechanistic sense to any signaling to the brain like with the GLP-1’s, and interestingly in the study, seemed like more folks on ezetimibe developed coronary artery disease. This could be confounded by ezetimibe not lowering cholesterol in the brain (but then it’d not cross over the BBB) and the other folks doing worse, presumably principally on statins. However, the associations with statins and dementia don’t seem to indicate increased risk.
This is the beauty of the forum, getting exposed to things that aren’t in the mainstream and getting a chance to investigate.
The risk of this medication is very low, so adding it is sensible, but we need more data on this, as the current article has some significant flaws.
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medaura
#64
It’s also possible — and I say, merely possible — that there could be a hidden intermediary that we don’t even know about, an unknown unknown, unrelated to ezetimibe’s primary and studied mechanism of action. No one will know for sure save from RCT and even those might yield a false negative if it turns out that ezetimibe needs to be taken for many years or decades to have this neuroprotective effect and it might also be something that can help prevent, but no cure. We’re all merely debating what constitutes a reasonably well placed bet and what doesn’t.
Again, I picked NVIDIA at $9.87 
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That is a good thought. Just like alpha klotho doesn’t get into the brain, but induces platelet factor 4 which then crosses the BBB … who knows.
I secretly hate you for doing so well in the stock market. It is my nemesis.
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I thought your nemesis was your cat?
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My now expanded set of 3 cats fail to cause the same pain as my stock investing choices.
I’m an expert in buying high and selling low.
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