#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.

6 Likes
#101

@desertshores Curious if you’ve tried HMB.

#102

I have a container of powdered HMB. Unfortunately, I should have bought the capsules. It ruins the flavor of everything I put it in, so I have not really taken very much of it.

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#103

Yeah I’d been warned so I got capsules but only take them once in a while. Need to put them in pill organizers so I actually take them.

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#104

Random Chinese university and journal but bad news: Mendelian randomization analysis of lipids traits and lipid-lowering drug-targets in relation to cognitive status 2025

Mendelian randomization reveals no causal link between lipid traits and cognition;
NPC1L1 inhibition genetically linked to higher cognitive impairment risk;
Ezetimibe’s cognitive effects may be independent of lipid-lowering action;
Findings highlight caution when prescribing ezetimibe to cognitively impaired patients.

Predicting Alzheimers & Dementia (and minimizing risk)
#105

That looks like p-hacking to me if they used 9 drug targets + lipids, and on top of that multiple different outcomes and six different datasets (and found a genetic correlation in three):

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#106

I wonder how much care we need to put into interpreting Mendelian randomization studies due to linkage disequilibrium types of effects. The rarer is any given mutation that drives the result, the more likely it would tend to be packaged with some other mutations that impact things we care about. If mutation A that causes lower LDL-C comes along with mutation B that causes X, should we conclude that lowering LDL-C also lowers X? We should not unless there is a sensible mechanistic story and observational evidence showing some relationship between LDL-C and X independent of the MR study.

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#107

It’s possible. Might explain why it’s published by the “Department of Anesthesiology” (lol) of a university in the random “Journal of Affective Disorders”. If it was of higher quality it would be published in Brain by a Stanford team. I’m sure other teams looked at ezetimibe MR and dementia and found nothing and didn’t publish anything.

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#108

Null results are still valuable results. They should be published. If they have them, but didn’t publish, that’s a pity. I am not aware of it either way.

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#109

Actually I was wrong, some good researchers published this null result in a good journal: Lipid lowering and Alzheimer disease risk: A mendelian randomization study 2019

University College London + Cambridge + Karolinska + Utrecht so Tier 1. In Annals of Neurology, Tier 1 as well.

Results:

NPC1L1 (encoding the target for ezetimibe)
Models for HMGCR, APOB, and NPC1L1 did not suggest that the use of related lipid-lowering drug classes would affect AD risk. In contrast, genetically instrumented exposure to PCSK9 inhibitors was predicted to increase AD risk in both of the AD samples (combined odds ratio per standard deviation lower LDL-C inducible by the drug target = 1.45, 95% confidence interval = 1.23–1.69). This risk increase was opposite to, although more modest than, the degree of protection from coronary artery disease predicted by these same methods for PCSK9 inhibition.

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#110

That’s fantastic, and very encouraging. Great harm is done when null findings are suppressed, as it distorts what we know and obstructs hypothesis generation. Unfortunately publishing incentives don’t always align.

Concerning about PCSK9i and AD though.

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#111

Huge sigh :frowning:
I have one apoe4 and I take repatha
Oh well, I guess my chances of an MI are greater than AD, so….