Ezetimibe Reduces Alzheimer's Disease Risk (study)

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We have some papers that suggest a mechanism @DrFraser:

Recent German paper in Nature: Exploring the neuroprotective potential of Nrf2-pathway activators against annonacin toxicity 2024

Surprisingly, we found evidence that ezetimibe, an approved drug for hypercholesterolemia, prevents the transcriptional upregulation of 4R-tau triggered by annonacin insult.
Overall, treatment with the selected Nrf2-pathway activators, particularly with the p62-activators, ezetimibe and licochalcone A, limited the neuronal death and neurite degeneration induced by annonacin.

Ezetimibe attenuates functional impairment via inhibition of oxidative stress and inflammation in traumatic spinal cord injury 2023

Our findings demonstrated that EZE administration attenuates inflammation in microglia by regulating the AMPK/Nrf2 axis.

Ezetimibe Reduces Alzheimer's Disease Risk (study)

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

Ezetimibe, a NPC1L1 inhibitor, attenuates neuronal apoptosis through AMPK dependent autophagy activation after MCAO in rats 2018

Drug Repurposing Patent Applications July–September 2024

Ezetimibe reduces aggregation and endoplasmic reticulum stress in both human-cell and Caenorhabditis elegans models of Alzheimer-like aggregation

[desertshores]

I don’t dismiss the study of Ezetimibe. I take Ezetimibe to reduce low-density lipoprotein cholesterol. If it has additional benefits, fine.

The list below are the ones I take that I think show promise for delaying or preventing dementia and Alzheimer’s. But, that is not the primary reason I take them. Most have other benefits.
There are no extended RCTs that I can find, so all of the evidence for any of these preventing Alzheimer’s is weak. Rapamycin probably is the best choice just because anything that delays aging probably delays Alzheimer’s.

Rapamycin
“Rapamycin has shown promise in reducing Alzheimer’s disease (AD) neuropathological hallmarks in mouse models ([1])
Studies demonstrate beneficial effects in AD mouse models, including:
Prevention or reversal of cognitive deficits
Reduction of amyloid oligomers and tauopathies”

“Rapamycin may delay the development of AD by reducing β-amyloid (Aβ) deposition, inhibiting tau protein hyperphosphorylation, maintaining brain function in APOE ε4 gene carriers, clearing chronic inflammation, and improving cognitive dysfunction. It is thus expected to be one of the candidates for the treatment of Alzheimer’s disease”.

Sildenafil or Tadalafil
“Recent Studies: A 2024 Cleveland Clinic study linked Sildenafil use with a reduced risk of Alzheimer’s in insurance data analysis and lab experiments with human neurons.
Reduction Rates: The reduction in risk wasn’t necessarily 70%. Studies suggest a 30-69% lower chance of developing Alzheimer’s for Sildenafil users compared to controls.”

Memantine
“Memantine, an NMDA receptor antagonist, is already approved for moderately severe to severe AD and is being investigated for its potential in earlier stages due to its ability to counteract cellular damage from pathological NMDA receptor activation by glutamate.”

Ginkgo Biloba.
Increases blood flow to the brain
“All-cause dementia incidence decreased with higher numbers of Ginkgo biloba prescriptions in MCI patients”

Vinpocetine
'Vinpocetine Increases blood flow to the brain and protect brain cells (neurons) against injury
Vinpocetine is a synthetic derivative of the Vinca minor alkaloid vincamine and has been studied for its potential benefits in preventing or delaying the onset of Alzheimer’s disease."

Methylene blue
Methylene blue for Alzheimer’s prevention and possible reversal

Galantamine
“Compared to placebo, galantamine (when given at a total dose of 16 mg to 24 mg/day) slows the decline in cognitive function, functional ability, and behaviour at six months in people with dementia due to Alzheimer’s disease.”

“Rapamycin and Alzheimer disease: a hypothesis for the effective use of rapamycin for treatment of neurodegenerative disease - PMC
Rapamycin Responds to Alzheimer’s Disease: A Potential Translational Therapy - PMC
Evaluating the effect of rapamycin treatment in Alzheimer’s disease and aging using in vivo imaging: the ERAP phase IIa clinical study protocol - PMC
https://sci-hub.se/10.2165/00023210-200216120-00003
Neuroprotective effects of vinpocetine, as a phosphodiesterase 1 inhibitor, on long-term potentiation in a rat model of Alzheimer’s disease - PMC
https://sci-hub.se/10.1016/j.bbr.2020.112512
Ginkgo biloba Extract in Alzheimer’s Disease: From Action Mechanisms to Medical Practice - PMC
Association Between Ginkgo Biloba Extract Prescriptions and Dementia Incidence in Outpatients with Mild Cognitive Impairment in Germany: A Retrospective Cohort Study - PMC
Plant-Based Nutraceutical Interventions
against Cognitive Impairment and Dementia:
Meta-Analytic Evidence of Efficacy of a
Standardized Gingko biloba Extra
https://sci-hub.se/10.3233/jad-141887
https://pubmed.ncbi.nlm.nih.gov/39498781/”

[Guest]

To give an important qualifier:

For AD research all you can take serious is human data. The vast majority of clinical trials in general fail - despite previous positive data in animals to get approval for the trials. In AD it’s particularly bad, as we do not have animal models that develop human type AD.
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Rapa has no relevant data in humans to speak of.

The Sildenafil observation study uses the opposite approach of the EZ study - fishing for associations and then trying to prove a mechanism (which they were not yet able to pin down). The EZ paper design is a much stronger approach in that respect.

Memantine is already used in AD patients and at least so far in observational studies it has a much smaller effect than EZ in it’s study. The only point to make it compete with EZ would be RCTs - do these exist?

GB - same as Sildenafil: fishing for associations. That’s a “simple” observational strategy inferior to EZ. The main upside is the dose depended effect size that they were able to tease out. Therefore I would put it on the same level as EZ - though EZ still got the upside of being a “clean” drug with a single, AD specific mechanism.

Vinpocetine does provide symptomatic relieve during it’s administration in AD. But it does not prevent AD conversion? We have a lot of those drugs for AD. They just don’t prevent disease progress.

MB - is there even observational data on that? Apart from being a lot more problematic as a drug than EZ.

Galantamine - the linked meta analysis is interesting; most of the included studies were unblinded clinical trials. The data is suggestive - a 2,86 difference on ADAS-cog (which is either 70 or 85 on the full scale) is okay; better than the antibodies currently marketed. This would be the only one that I would put above EZ. That’s based on the trial designs, though the effect size is clearly smaller.

All in all your list contains one drug that would be on the same level and one better than EZ - based on trial designs.

[Guest]

You do realize that’s true for many symptomatic treatments of AD - i.e. no specific trial to prove that it penetrates past the BBB (i.e. by doing lumbar punctures etc.)? And they are still approved based on an idea of their mechanisms and the fact they actually just work in symptom relieve.

Again: do you seriously think the authors got lucky, to pick by random chance out of more than 1800 candidates a drug… …that just happens to have a massive impact on AD in and subsequent observational study? After predicting this effect based on an AD specific mechanisms.

And lacking trial data for BBB they actually provide computations based on accepted standards that predicted BBB crossing (BEFORE they did observational analysis) - corroborated by an established medical database and their own independent calculations.

This is not fishing for associations. It’s not an RCT either of course. But you’re building up impossible standards in a situation where we do not have any effective therapy officially approved for AD !

So out of curiosity: what therapies are you actually recommending?

[DrFraser]

You can read my blog and I’m open minded, but I’m also a scientist who spent a lot of time getting education in pharmacology. We want mechanisms to be possible at least. I don’t have a horse in this race, but ezetimibe isn’t on my list yet, and nothing in the comments on this topic has made me see it otherwise. In vivo and in vitro, especially with neurologic issues requires either indirect signaling or penetrance of the drug to the CNS.

Anyway, my new YouTube Channel DrApoE4 will start having discussions on this topic. Just starting up on this.

The wonderful thing with this community is getting exposed to a lot of ideas, and having to filter which ones I apply to clinical practice, as I have to justify my recommendations to my patients, and which ones to sit back and wait for more information.

It doesn’t require high levels of proof, so the standard isn’t that high - but I have concerns here, as my assessment is that the benefit would occur if you got ezetimibe into your brain. I personally don’t think ezetimibe gets into the brain … so the study is fascinating, and maybe a neiman pick binder that crosses the BBB would be a great candidate. Doesn’t mean the literature isn’t useful, it’s just not something I’m going to recommend to a patient stating that I think it would decrease risk of dementia. I have other better candidates right now.

[Guest]

I’m afraid my time is as limited as yours - so reading blogs is something I would do if you can give a link to a specific post.

Would you be so kind to do that?

Alternatively: would you please name an intervention that is worthwhile in your eyes? Just the name would be sufficient - I can do a quick read up myself.

[DrFraser]

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.

[LukeMV]

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.

[Guest]

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

[DrFraser]

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.

[desertshores]

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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@Guest

Rapa has no relevant data in humans to speak of.

We have: The MSA trial showed that sirolimus does not engage with brain mTOR in humans (those with MSA at least).

@Guest

The Sildenafil observation study uses the opposite approach of the EZ study - fishing for associations and then trying to prove a mechanism (which they were not yet able to pin down).

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

[Guest]

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.

[Guest]

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.

[Tim_NAWROT]

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.

[Guest]

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).

[DeStrider]

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.

[amuser]

What a bizarre reply.

[DeStrider]

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.

[medaura]

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.