Ezetimibe Reduces Alzheimer's Disease Risk (study)

#82

The Editors in Chief of the journal certainly don’t think it’s a “horrible paper”- as they picked that very paper to write the editorial for their journal issue, commenting: “That uncertainty does not detract from the importance of this remarkably thorough and compelling paper.”

So who is correct? The reviewers and editors in chief - all research scientists in biology/medicine, most with their own labs? Or the cardiologist/biostatician? I could understand a more nuanced disagreement. But “pretty horrible paper” is largely the polar opposite pov.

The 3 nematode strains used (living nematodes, not just nematode cells by the way) are standard models for AD researched and provided by a national lab designated by the NIH.

I actually agree, that animal models in AD in general are not of much value. But that’s a weakness ingrained in all AD research - not just this paper. Therefore papers using animal models in isolation can be dismissed, until the substance involves human level data.

I can only reflect what I can find online on the database:

it seems to be a more general database, having access to patient data from US based health insurers (medication claims data as well as diagnosis) and is marketed as a research tool for observational studies. Nowadays there are a handful of better, government databases available (2 in the US, 1 in UK, China, South Korea) - but they require a somewhat lengthy vetting process and cooperation with a national research institute (i.e. most published observational research is done on different data).

With analytical strategy I wager you’re talking about more details about the regression analysis, statistical tests used and potential sensitivity analysis? I agree that the authors should have been more detailed in describing that part. Though that doesn’t mean that 1.) they didn’t do it or 2.) they don’t know what they are doing - as it’s a very long paper already, the reviewers/editors may have just told them to cut it short (i.e. the reviewers know about the details and approved for publication based on that)
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As the editors note, the authors are remarkably thorough in their methodological approach - therefore to contrast it again:

commonly some researcher has a pet-substance or data from mice where the substance “works” - and is doing a an observational study to gather more evidence. Or he simply was doing regression analysis for potential effects of various substances on a condition. Fishing for associations. Simply by chance, you will find effects. Therefore in a next step you need to pin down the mechanisms. Which often is surprisingly difficult in AD.

The authors are doing the opposite. They are doing extensive work in-vitro in human cells and tissue surrogate, in human brain slices of AD and non-AD people and in nematodes to detail a potential mechanism. Next they calculate out of data for over 1.800 approved drugs, that EZ would inhibit that mechanism (modern AI driven models can do that easily) - which they test in nematodes and neuronal tissue. Their prediction: EZ should have an effect in AD, based on our novel mechanism. That’s no fishing for associations. But picking one candidate out of 1800 potential candidates based on comprehensive work - before doing the observational study. Combine that with the truly crazy effect size and cheap price and safety.
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Do I think, that EZ is the most promising candidate out there? No - I think that place is currently reserved for Lithium, in particular after we get the data of the LATTICE trial.

But if the observational part of the EZ study can replicated in another observational dataset it surely is a candidate above almost everything else - even if they find only half the effect size. The authors themselves are working on an RCT - but that would take a long time.

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#83

I’ll go with an emeritus academic professor of cardiology, biostatistics and epidemiology who has over 300 published articles in the peer reviewed literature.

The good news is that ezetimibe is unlikely to hurt anyone and might possibly be helpful in regard to dementia.

It’s not going on my list at this time. Eager to see a better study on this.

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#84

Instead of going with the combined editorial board and reviewers in the same area of research - all of whom are research scientists, most tenured professors or principal investigators with their own lab? The authors of the editorial themselves with multiple papers in CELL and NATURE each (not the sub-journals, but the main journal) and won numerous prestigious awards.

Again: I could understand a more nuanced disagreement. But having the polar opposite opinion is hard to reconcile. Then I’m faced with a group of known prestigious experts on one hand and one unknown prestigious expert on the other.

My parents are at high risk of AD due to APOE4 - I have to take what look sufficiently promising in a risk/reward calculation. Therefore: what else could I have a look at ? You seem to be so knowledgeable - could you name one (1) that I could have a look at? Just to prevent double standards from dominating those statements.

#85

Sure,

SGL2i
GLP1’s
Lithium low dose
Vitamin D optimization
Omega 3 index if ApoE4 positive of 10%
Telmisartan
Rapamycin only if have no impairment or very early mci.

There are more than this and some of them will end up being duds, but on a risk benefit I favor this approach in clinical practice.

I do however plan to cease responding further on this topic as I’m on the board for enjoyment and learning, and don’t think either is accomplished by the interaction.

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#86

If there is a benefit of Ezetimibe in AD, could it simply be a result of its ApoB lowering effect, since we now know that high ApoB is a risk factor for AD?

Same mechanism in which statins may potentially reduce risk of AD?

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#87

The study is quite impressive and I’d still like to see follow ups with other well known databases. My main concern is actually that the hazard ratio is so low to seem unbelievable. It’s near “cure” levels.

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#88

Most likely the non ezetimibe users are statin users (in the sub study on the CAD group). And other association studies didn’t find such protective effects for other lipid-lowering drugs vs AD.

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#89

I think we have to realize that Ezetimibe is a useful and inexpensive medication that probably reduces the risks of Alzheimer’s by some amount. Even if this effect is due to an improved circulatory system or better lipid profile, it doesn’t have many downsides. I don’t see any reason not to take it.

One of the best reasons to take Ezetimibe is that 10 mg of Atorvastatin + 10 mg Ezetimibe is superior to 80 mg of Atorvastatin in that it lowers ApoB and LDL by the same amount but also increases HDL and reduces statin side effects.

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#90

This has generated quite a robust discussion. It’s great to see folks on the forum reading carefully and thinking hard about the science. I think we’ve encountered a challenge along the way that eventually plagues many of our conversations – empirical observations lead to speculation, and speculation leads to an appetite for additional empirical facts, but we are very good at speculating and not very good at generating new empirical facts. We often hit an impasse and simply need to wait for new data.

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#91

Great wisdom!

Worst case scenario, Ezetimibe improves lipids and through that mechanism improves rate of dementia. Best case scenario, this article we are discussing is correct.

My sense, looking at other literature on this topic, is that this paper is overly optimistic, and the size of the beneficial effect will be much less dramatic than claimed.

For myself, I’m taking ezetimibe and bempedoic acid with my ApoE4, but for optimization of lipids and not wanting agents that decrease cholesterol in the brain.

I honestly don’t know if ezetimibe outside of it’s lipid lower effect has any direct impact on likelihood of having dementia. I don’t think this article is sufficient to know. My hope is that the effect is real, I take this drug, but I’m not convinced yet.

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#92

Over 40 years of research and over $30B spent on AD research with basically nothing of consequence to show for it.

I think this is what drives a certain level of skepticism on this topic.

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#93

Looking at their Table 4 and their cited systematic review, it appears that none of the trials of ezetimibe (specifically) were looking at dementia: they were looking at acute or subchronic cognitive adverse effects of the “brain fog” variety. Also, nearly all the trials were in EZE+statin vs. statin alone; since statin alone appears to lower dementia risk, it would require an exceptionally large cumulative patient population and long duration to pick up the marginal effect of adding EZE.

You’re right, though, that the observational study in the lead study in this thread ( PMID: 39263528 is weak: they’re comparing EZE users to either age-matched controls from the general population or users to CAD patients, without regard to whether the comparison group was taking lipid-lowering therapy. The right comparator group is people with similar clinical characteristics on other LLT, matched for other risk factors and ideally for achieved LDL-C or apoB.

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#94

I don’t think that’s correct. They used “a time-dependent regression model to adjust for the observation time interval” but I don’t see that they adjusted for confounders: they “just” matched EZE users to controls for (some) clinical characteristics.

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#95

The whole thrust of the paper is that there is a mechanism unrelated to EZE’s known MoA: that it inhibits protein:protein interaction between hexokinase-1 (HK1) and 14-3-3G/γ proteins, thereby preventing HK1 dissociation from the mitochondria and aggregate formation. Because this is based on the structure of EZE itself, a metabolite or induced factor (like PF4 in the Klotho case) is unlikely to have the same effect, even supposing that the metabolite or induced factor could itself get into the brain.

So if EZE doesn’t even make it into the brain, it can’t do that, and everything in the paper except the pharmacovigilance analysis is moot. Granted the low quality of the latter, I wouldn’t try to pull on that multiply-broken chain.

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#96

The authors used the PharMetrics-Plus IQVIA longitudinal database to strengthen their hypothesis that ezetimibe lessens the chance of dementia. While an RCT could be years off, it would be interesting to learn if other longitudinal databases (Optum Clinformatics Data Mart, MarketScan by IBM, Kythera Open Claims Database, and the UK IQVIA Longitudinal Patient Data) similarly support their hypothesis. Such database studies would produce results much sooner than an RCT.

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#97

Desertshores, that’s a good list. I’m interested in 3 items you listed if you have time to respond: Memantine, Ginkgo Biloba and Galantamine. I use Galantamine and find it mildly useful and I’ve tried Ginkgo Biloba and noticed nothing. However, in particular I want to know your opinions of memantine from your personal experience. Thanks.

#98

Many of the supplements I take are on a trial basis. There are exceptions, but for the most part if I don’t find any measurable results or feel that there are subjective results, I stop taking them.

As I said before, if it’s not broken you can’t fix it. That causes a null result of the supplement/drug being tested.

Memantine:
“Its primary use in treating moderate to severe dementia of the Alzheimer’s type, memantine has shown potential therapeutic benefits in various neuropsychiatric disorders. According to a review by Lu and Nasrallah, memantine has been found effective as monotherapy in conditions such as autism spectrum disorder, binge eating disorder, and attention-deficit/hyperactivity disorder (ADHD).[4] It has also been used as an augmentation therapy in posttraumatic stress disorder (PTSD) and generalized anxiety disorder (GAD), where it enhances the efficacy of other medications.[4]”

I took Memantine for 200 days, looking primarily to see what effects it might have on my aging brain, increased focus, etc.
Result? I noticed nothing. So apparently nothing Mematine fixes needs fixing. No side effects were noted.

Galantamine:
“Is used for the treatment of mild to moderate dementia of the Alzheimer’s type. It is a cholinesterase inhibitor that works by increasing the concentration of acetylcholine in the brain, which helps improve cognitive function in patients with Alzheimer’s disease.[1-2]”
The most commonly prescribed therapeutic dose of galantamine for the treatment of mild to moderate dementia of the Alzheimer’s type is 16-24 mg per day, administered in divided doses."

I am currently taking 16 mg a day.
Result? Again I notice nothing except an increase in memorable dreams. Side effects; increase in memorable dreams.

Ginkgo Biloba:
Ginkgo biloba extract (GBE) has been shown to have positive effects on cerebral blood flow in several studies, suggesting it may indeed increase blood flow to the brain.

Evidence for Increased Cerebral Blood Flow
Quantitative MR Perfusion Imaging Study
A pilot study using dynamic susceptibility contrast-enhanced magnetic resonance imaging (DSC-MRI) found:
A mild increase in cerebral blood flow (CBF) in the left parietal-occipital white matter after GBE administration
A small but statistically significant increase in global CBF ([1])
Effects on Cerebral Oxygen Supply
I take Ginkgo Biloba (GBE) primarily as a preventative measure, primarily for its potential cognitive benefits. Since I sometimes use antihistamines, which can deplete choline levels, I also supplement with choline to counteract this effect. Since I don’t measure choline, I must take this on faith. I have felt no subjective effects.

Ginkgo biloba extract (GBE) is used therapeutically to enhance peripheral and cerebral blood flow.

Mechanisms of Action:

Vasodilatory Effects:
Ginkgo biloba extract (GBE) is used therapeutically to enhance peripheral and cerebral blood flow. Compounds such as flavonoids and terpenoids contribute to its vasotropic effects.
Modulation of Neuroinflammation

GBE reduces the expression of proinflammatory cytokines and other inflammatory mediators in the hippocampus. This anti-inflammatory action may help improve cerebral blood flow.

Cognitive Function:
A 6-week GBE regimen in middle-aged women improved working memory performance and altered prefrontal cortex activation during memory tasks.
Neuroprotection

GBE and its constituents (e.g., Ginkgolide B) exhibit neuroprotective effects in cerebral ischemia models, potentially due to enhanced cerebral blood flow.
Dosage and Administration

Typical dosages in studies range from 120–240 mg per day.
One study utilized 60 mg twice daily for 4 weeks.

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#99

At 85, I may not be alone in having noticed a gradual cognitive decline. I see it mostly in speed of new learning and retention. This is a very subjective assessment,of course, with no measurable basis. Have you come across a more objective standard useful for gauging results?

With your cognitive experiments, have you narrowed your list? If so, which interventions have you settled on as likely the most helpful?

Have you compared galantamine alone with memantine + galantamine and with memantine + donepazil?

#100

No.
I am not currently taking memantine or galantamine.
I was experiencing unexplained brain fog and loss of short-term memory.
Memantine and galantamine really helped. Since I was taking both, I really didn’t know which one was the most effective.
It took about two months to get results. After four months, everything seemed to return to normal, so I quit taking them. One reason I don’t take galantamine is the effect it has on my sleep, excessive dreaming mainly.
At ~84, my mind is mostly normal. The main thing I notice is a slowing of processing speed. This manifests in my inability to find objects in a clutter as fast as a normal brain would.
My ability to do things like crossword puzzles and sudoku puzzles has never been better.
The main supplements I take for maintaining brain functioning are:
Vinpocetine, Huperzine A, and Ginkgo Biloba.

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#101

@desertshores Curious if you’ve tried HMB.