#21

A study I posted earlier (possibly on another thread?) showed that taking ezetimibe at least 4 hours apart from vitamin E prevented the inhibition of vit E absorption, so it would make sense that the same would be true of ALA. I now take my ezetimibe at night, since I put ground flax seed and walnuts in my morning smoothie (both rich in ALA). Also another study showed no inhibition of EPA or DHA, so if you take fish or krill oil, it shouldn’t be a problem.

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#22

Saudi-Egyptian paper and animal model but still interesting when combined with the AD finding above: Repurposing ezetimibe as a neuroprotective agent in a rotenone-induced Parkinson’s disease model in rats: Role of AMPK/SIRT-1/PGC-1α signaling and autophagy 2024

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#23

Also an Egyptian paper so might not be of high quality, and it’s an animal model but: Ezetimibe protects against Gentamycin-induced ototoxicity in rats by antioxidants, anti-inflammatory mechanisms, and BDNF upregulation

We know that hearing loss is a modifiable risk factor for Alzheimer’s disease. This paper suggests ezetimibe might be protective:

The threat of hearing loss has become a universal reality. Gentamycin (GM) can lead to ototoxicity and may result in permanent hearing loss. This study aimed to elucidate whether the hypolipidemic drug Ezetimibe (EZE) has a possible underlying mechanism for protecting rats from GM-induced ototoxicity.
EZE can safeguard inner ear tissues from GM via antioxidant, anti-inflammatory, and antiapoptotic mechanisms, as well as upregulation of BDNF mechanisms.

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#24

Editorial from last month commenting on this paper: Hiding in Plain Sight: FDA-Approved Cholesterol Drug Ezetimibe as a Treatment for Alzheimer’s

The authors note that, while the controls (nearly 1 million subjects not taking ezetimibe) were well matched to ezetimibe recipients for age, gender, and established ADRD risk factors such as hypertension, diabetes, and kidney disease, the groups were not matched for cholesterol levels. It would not be unreasonable to assume that the patients prescribed ezetimibe had initiated it due to relatively high serum cholesterol levels, so these researchers point out that double-blind randomized trials of newly enrolled patients would have to be conducted to establish a causal connection.

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#25

Perhaps we shouldn’t be splitting our 10mg tablets to 2.5 mg…

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#26

You could try dutasteride for a similar benefit profile (balding, BPH) with different side effects (less side effects I hear). Look for Kyle Gillett MD for more on dutasteride / finasteride. I have an interview with Kyle coming out soon on hormone health.

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#27

This is most likely excellent advice, and if/when I start taking ezetemibe (EZ), I would do the same. However, I’d be remiss, if I didn’t mention that from a strict black box perspective, this is not entirely kosher. The good results of EZ are in people who took no special measures - as far as we know - to preserve vit. E or any fatty acid away from EZ. This opens the possibility - however remote and illogical it may seem - that therein might be some essential aspect of the positive effect, and going out of one’s way to change that ordinary practice of most patients to our own of taking EZ away from these nutrients might obviate the very effect we are counting on. In other words, the inputs into the black box have changed, and to expect the same outputs is making an assumption about what’s going on inside the black box, which we assuredly do not have a clear picture of - we don’t know by what mechanism EZ achieves that particular effect on AD. Now, perhaps we can say it doesn’t matter and we are confident that in this particular case changing the inputs should not affect the outputs, and this may very well be right. But. The fact remains, that in order to assure the same outcomes, we must try to duplicate the inputs as closely as possible, or be so sure of how this works that the black box is in effect a glass box.

Bottom line, the recommendation on how to take EZ is probably quite sensible, but we cannot be 100% sure without running a study to show that the outcomes would be the same. YMMV.

1 Like
#28

If you are referring to the initial EZ paper you can rest peacefully. The authors thoroughly prove the specific mechanism by which EZ is impacting AD. That is: they demonstrate, that it’s that particular mechanisms impacting AD. And that it is a specific target of EZ (not just by computer simulation, but also actual lab work).

That’s the amazing point about their study. Identifying a potential mechanisms that is very AD specific and getting data from mice and neuronal cultures on that. Computing that EZ is an inhibitor of that mechanisms. Proving that in the lab. And from an observational dataset confirming a large effect of EZ on AD (which nobody noticed previously).

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#29

Not wanting to burst everyone’s bubble here … but Ezetimibe might get across the gut a bit, but there is no indication it gets across the BBB. So drill a hole in your head and trickle in some ezetimibe, that might work (except the hole in your head), but short of this, it’s fascinating, but ultimately not useful in clinical practice. I like ezetimibe and use it myself, but I don’t see its utility for AD based on this research.

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#30

I’m unfortunately not yet familiar with EZ pharmacology - but according to the paper it does cross the BBB at a certain rate. I wasn’t yet able to track down an independent reference for that.

And given the big gamble that researchers took - picking EZ out of over 1800 drugs that they simulated with and betting: this will impact AD… it’s very unlikely that it’s an association just by chance. In particular given it’s dramatic effect size. Even half the effect size would be massively better than the anti-bodies currently being marketed.

1 Like
#31

The size of effect isn’t the issue - the issue is, in vivo does it get into the brain? If not, the finding is irrelevant, unless we have a form that crosses the BBB.

Here is what Vera-Health.ai says on this:
Ezetimibe is primarily designed to inhibit the intestinal absorption of cholesterol and is used to lower LDL-C levels in the bloodstream (ASHP). However, its ability to cross the blood-brain barrier (BBB) is not well-documented in the provided references or typical pharmacokinetic profiles.

The blood-brain barrier is a highly selective permeability barrier that separates the circulating blood from the brain and extracellular fluid in the central nervous system (CNS). It is known to restrict the passage of most drugs, especially those that are not lipophilic or do not have specific transport mechanisms. Ezetimibe, being a lipid-lowering agent that acts in the gut, does not have a mechanism or structural properties that suggest it would cross the BBB effectively.

Moreover, strategies to enhance drug delivery across the BBB often involve structural modifications or the use of delivery systems like nanoparticles, which are not applicable to ezetimibe as per its current formulation and use. The focus of ezetimibe’s action is on the peripheral cholesterol metabolism rather than CNS effects, which further supports the notion that it does not cross the BBB in significant amounts.

In summary, based on its pharmacological action and the nature of the BBB, ezetimibe is unlikely to cross the blood-brain barrier. This aligns with its intended use and mechanism of action, which are centered on cholesterol absorption in the intestines rather than any CNS activity.

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    Some of the most important areas that have recently redefined the BBB are reviewed and how they can be applied to the development of CNS therapeutics are discussed.

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Non-invasive approaches to brain delivery, particularly for biopharmaceuticals, some of which are now in clinical testing, are discussed and analysed and their potential in the treatment of CNS disorders is analyzed.

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#32

Actually I’m referring to the mechanism of how EZ taken orally ends up helping against AD. And obviously the whole chain from mouth to brain. That’s what matters. That’s why In Vivo > In Vitro. There are tons of molecules and processes that work in vitro that never pan out in vivo.

In this case Black Box = everything that happens between mouth and brain. We may know this piece or speculate about that piece, but the totality is inside an opaque black box. We see inputs, and we see outputs, but inside the black box it’s invisible - we can speculate though!

2 Likes
#33

Okay: re-reading the paper - the authors use computational approach to predict the BBB properties of the 6 final candidates they narrowed their computations down to. Presumably because originally nobody gave it much thought to look for BBB penetrance in a drug targeting a specific mechanism in the gut (note: EZ is entering the blood stream with a dose depended blood level)

Given a lack of specific studies on BBB that is a legitimate strategy. With modern models and computer power it’s possible to calculate the ability to cross based on size, structure and polarity of a molecule.

Their result can be independently confirmed by publicly accessible databases e.g. https://go.drugbank.com/drugs/DB00973 (DrugBank is generally considered reliable)

According to calculations by DrugBank there is 90,74% probability, that EZ can penetrate the BBB. That’s pretty high as far as molecular predictions are concerned.

6 Likes
#34

Interestingly DrugBank gives a 95.99% probability, that rapamycin can penetrate the BBB but this has been the subject of a lot of debates here.

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#35

After a rather exhaustive search using six different AI search engines, of which three are medical-specific, I can find no evidence that Esetimibe crosses the BBB barrier.

Summed up in this reply:
“No evidence suggests ezetimibe or its metabolites cross the blood-brain barrier.”

“Ezetimibe has a molecular weight of 409.4 Da. [1-2]
The ability of a molecule to cross the blood-brain barrier (BBB) is influenced by several factors, including molecular weight, lipid solubility, and plasma protein binding. Generally, molecules with a molecular weight less than 400-600 Da and high lipid solubility are more likely to cross the BBB via passive diffusion.[3] However, despite its relatively low molecular weight, ezetimibe does not cross the BBB effectively. This is likely due to its high degree of plasma protein binding (>90%) and its pharmacokinetic properties, which include extensive glucuronidation and minimal oxidative metabolism.[1-2][4]”

I take ezetimibe, but it wouldn’t be on my top ten list for Alzheimer’s prevention

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#36

It’s a pretty big unknown - but yes, drip ezetimibe onto brain, seems pretty solid. Taken orally seems a problem. Not ready for a craniotomy this week to mitigate my ApoE4. Maybe next week.

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#37

Come on - are serious? Is this joking? Is this your true assessment of this study?

Of course it’s not an RCT.

But you seem to dismiss this study entirely. In that case you pretty much have to dismiss everything we have in the toolbox to prevent AD.

1 Like
#38

I’m curious.

It seems you have very high standards of scientific evidence.

What is you top 10 - or top 5. Based on higher scientific evidence than EZ? Note: that needs to be pretty much RCT based.

I’m all for being skeptical in biomedical science, guided by rigorous standards.

But of course you gotta avoid double standards. If you truly dismiss this study, there isn’t much left in AD research.

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#39

Not at all. Ezetimibe could not cross the BBB and still have beneficial effects. For instance through the gut brain axis and the vagus nerve.

That’s the bet that Novo Nordisk is making with their big trials (2x3000 patients) of oral semaglutide for Alzheimer’s disease. We know (and they know) perfectly well that semaglutide doesn’t cross the BBB. Oral semaglutide maybe even less so. I was told that Novo Nordisk researchers do believe that other mechanisms can be neuroprotective.

Anyway, ezetimibe seems to be a safe bet. We need more papers though. Not that this paper is bad, but the majority of published papers are wrong (either outright fraud or just mistakes done by the author). I know two researchers (MIT and Imperial College London) looking now at ezetimibe + low dose statin vs high dose statin for dementia. Hopefully we’ll have more clarity on this “soon” (meaning, in academia, a couple of years…).

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#40

Sadly, there is no evidence that ezetimibe signals the brain in any fashion that I can find. Whereas with GLP1’s we know this happens as functional PET scans show remarkable effects with GLP1’s via the vagus nerve even without brain penetrance.
However, looking at the pharmacological activity of ezetimibe, I see nothing to suggest it has this effect.
I would be a reasonable statement to say that something studied on brain cells that works requires the substance (apart from Gut-Brain axis effects - which ezetimibe has none that I can find) to actually get in with the brain cells. In this instance, I don’t believe it does.
Anyway, I take ezetimibe, but it isn’t on my list of things to prevent AD.

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