@DrFraser So statins such as Atorvastatin increase Alzheimer’s and Dementia risks?

1 Like

Yes I agree with this point. It is my current opinion, and I’m happy to be swayed on this, but for folks with ApoE4’s (and I’m one of these) we want maximal cholesterol in the brain and not the periphery. We simply don’t have a trial to answer the specific question. Personally I’ve gone over to bempedoic acid and ezetimibe from atorvastatin/ezetimibe.
I agree with @Guest that there is certainly some penetrance even of the hydrophilic statins, but less. For my patients with ApoE4’s, I want them either off of statins, or on rosuvastatin. If money is no issue, taking agents that don’t cross the BBB seems the cautious approach.
@DeStrider Good question - I think the net benefit outways harms on a population basis - but specifically with individuals with ApoE4’s, I suspect there is net benefit, due to improving vascular risk, but I’m certainly of the belief that there will even be more benefit for those with ApoE4’s to optimize their lipids with agents that don’t affect cholesterol levels in the brain.

5 Likes

Have you tested desmosterol levels in ApoE4 patients taking pitavastatin? Pitavastatin is classified as weakly lipophilic, but behaves rather differently peripherally from other statins, while having excellent CVD outcomes. Many people who are statin intolerant seem to do well on pitavastatin, fwiw.

1 Like

No I haven’t but all statins knock down cholesterol precursors, so I’d expect similarly to see these low.

AI says:
Regarding your question about desmosterol , it is important to note that desmosterol is an intermediate in the cholesterol biosynthesis pathway. Statins, including pitavastatin, work by inhibiting the enzyme HMG-CoA reductase, which is upstream in the cholesterol synthesis pathway. This inhibition leads to a decrease in the production of cholesterol and its precursors, including desmosterol.

4 Likes

I’ve always thought that keeping blood flow the brain was important.
Ginkgo biloba has been proven to enhance blood flow to the brain.
Of course, nitric oxide enhancers also do this.
Two other supplements shown to do this are Vinpocetine and Bacopa Monnieri.

Apparently, Ezetimibe “potently disrupts HK1::14-3-3G adhesion, reduces disease-associated aggregation, and activates autophagy.”

This is a different mechanism than simply increasing blood flow to the brain.
A supplement I mentioned earlier is fulvic acid; it also reduces disease-associated aggregation, but there is no mention of autophagy.

Neuroprotective effects of Ginkgo biloba extract
https://sci-hub.se/10.1007/s00018-003-3080-1

Fulvic Acid Inhibits Aggregation and
Promotes Disassembly of Tau Fibrils
Associated with Alzheimer’s Disease
https://sci-hub.se/10.3233/jad-2011-110623

Effects of pharmacological
modulators of α‑synuclein and tau
aggregation and internalization
https://sci-hub.se/10.1038/s41598-020-69744-y

7 Likes

I’m sure you’re right, but I’m old (66), and from lifelong experience of reading medical papers, I have developed an almost superstitious rule of thumb, that unless specifically tested, it’s not safe to make assumptions about how things work in the body, even if the mechanism seems completely logical, as in this case. Anyhow, here is an interesting paper about how pitavastatin helps preserve the blood brain barrier (which naturally declines with age), and the pleiotropic effects on dementias including AD. I’m not saying this is a reason to take pitavastatin! It’s just a possibly interesting effect:

Pitavastatin Ameliorates Lipopolysaccharide-Induced Blood-Brain Barrier Dysfunction

Pitavastatin Ameliorates Lipopolysaccharide-Induced Blood-Brain Barrier Dysfunction - PMC.

1 Like

Discussed here: Ezetimibe Reduces Alzheimer's Disease Risk (study)

3 Likes

Ah - sorry. I just scanned this central discussion and didn’t notice it.

And I do think, that this study is underappreciated in this forum. Yes, it’s not an RCT. But it also is “not just” an observational study.

This was not a brute force screen of 1800 drugs - where by pure chance you may find drugs that are associated with reduced Alzheimer’s. The authors are highly methodical - first building an argument for a particular mechanism (going after the proteins, which stick amyloid together into plaque) in vitro and animal models. And computing which known drugs due to their molecular structure can inhibit those proteins.

They made a bold prediction: “Out of those 1800 drugs, we will find a sizeable effect of Ezetimibe on Alzheimer’s” (note: Alzheimer’s specifically - not just vascular dementia). A drug that so far didn’t give cause to think, that it would impact Alzheimer’s. It would be really very unlikely, that they just got lucky. Particularly as in the observational study design they found a dramatic effect size - not just some mild effects as we observe in the antibody RCTs.

This is data in humans. Not simply in-vitro. Not animals models. And it’s more than a simple observational study. It’s a prediction based on a mechanism that is plausible and tested in-vitro/animals before the drugs screening. The effect size is enormous - it’s not about normalizing an elevated AD risk in people taking Ezitimibe for a certain condition.

Seriously: given everything else discussed here, Ezitimibe should be seen as a prime candidate.

4 Likes

I agree with you and that’s why I’m taking ezetimibe :slight_smile:

3 Likes

I also agree and that’s why my parents and I all take Ezetemibe. :slight_smile:

(I’m working on my wife, her family and my siblings).

4 Likes

What? Not the neighbors too? :wink:

7 Likes

I tried talking to my parents’ neighbors, but the cats, horses and deer didn’t want anything to do with it.

The racoons were interested though. But they take all the supplements they can find without doing proper research first. :wink:

I may be talking about health a little too much in the office as I now have the nickname ‘Dr. Chris’ amongst some of my colleagues.

7 Likes

Well, with time I found that the less I talk about health to friends, aquaintances, coworkers and strangers, the better. First, people have a lot of misconceptions about health, and do not appreciate having their convictions challanged. Diet, exercise, drugs, supplements, vaccines, healthcare, lifestyle. It’s endless. You’ll get animosity and suspicion for your efforts. So I say nothing. “Carnivore, man, only way”, “OK”, “vegan, man, only way”, “OK”, “vaccines, government control”, “OK”. And so on.

Many people hate, hate, hate to have their beliefs questioned, some even on this site. There are some members I simply don’t engage with, because they’ll just get hostile. I don’t get it, because it seems to me your most important allies are those who are willing to ask questions about your beliefs backed by good arguments, studies, and evidence. I want someone to spot the flaws in my protocols… priceless. I have biases, and I need outside opinion to notice them. All of us have biases.

What I have learned in my 66 years on this earth, is to never give financial advice, and only provide health related opinions when specifically asked, and even if specifically asked, I may opt out. The only place I will express health related opinions, are sites like this, dedicated to the topic. By the way, more often than not, people ask only to have their biases confirmed, otherwise, they’ll ignore your advice, so all you did is waste your breath and often get hostility in return even though they asked.

So I don’t say anything about such topics IRL. It’s like religion - I’m not out to convert anyone, or convince anyone. You do you. Whatever floats your boat. Life is so much simpler and people like you a lot better when you don’t feel compelled to air your views as if you had some kind of a truth bank.

At least that’s the conclusion I’ve reached after all these years, lol🤷.

5 Likes

Yes. I help my parents who are thankful for my advice both on health and finances. My wife will listen to some supplement advice but has a taboo about meds. I handle the household finances but she has her own accounts to play with.

The problem with financial advice is that you need to know when to stop and start it. By the time some people get the advice, think about it and then finally commit, it may be already too late. So, yeah, don’t give financial advice other than buy an index fund like VOO or QQQ and hold. That’s almost bulletproof long term.

As for health advice, most people don’t know enough to be able to act on it. I told a younger coworker that I was lowering my cholesterol and he told me ‘I thought cholesterol was good for you?’. So now I just talk about the basic 4 supplements for deficiencies - Omega 3s, vitamins D and B12, and Magnesium. If we really get going, I’ll branch off to lipid lowering (for those who’ve had a stroke or heart issue) or amino acid replacement (Glynac and Taurine).

I have a friend who used to be a pharmacist and we can have good conversations about meds.

Then there are the rare few that talk about Rapamycin.

4 Likes

When asked for health advice, now I just send this page: Roadmap - How To Look Young & Feel Strong – Dr Brad Stanfield

Written by a doctor, evidence-based (even though I disagree with some points), and starts with the basics (diet, exercise, sleep, stress). I don’t think a single person I sent it to has taken the time to read it. So I’m glad I didn’t lose time explaining these things to them :sweat_smile:

(And yes, for financial advice: “Just buy VOO or VT”)

6 Likes

I’ll gently disagree … if the biochemical mechanism is known for the class then one needs to consider what is likely and make logical decisions based upon what information we have. If one chooses to say that unless you have the exact situation being discussed specifically investigated, then you’ll be able to draw sensible conclusions very rarely.

There are so many clinical questions I have on an individual basis with considering multiple variables, the balance of the data and making a judgement what makes the best scientific sense.

I almost never have a study that specifically answers the question being asked.

So in conclusion, with a lot of experience, I do feel it is the most sensible approach to extrapolate when there is a good mechanistic situation to do so. Otherwise, I’d be paralyzed in indecision, and all my patients would fire me.

@adssx I refuse to buy VOO, I always buy EVOO :wink:

8 Likes

Guys, I’ve bought NVIDIA at $9.87 a share… just sayin….

3 Likes

By suppressing this complex, researchers have shown it’s possible to dramatically reduce the toxic effects of Alzheimer’s-causing proteins, boosting the cell’s natural defenses through enhanced degradation of hazardous proteins.

This mechanism regulates proteostasis across tissues by modulating TGF-β signaling, a pathway involved in cell growth, differentiation, and tissue homeostasis. This breakthrough opens exciting new possibilities for the development of new therapies that could slow or even prevent diseases like Alzheimer’s, offering hope for a future of healthy aging.

This is sensationalist (i.e. bad) science reporting.

There is no breakthrough happening here.

The authors first did an in-vitro essay for a certain mechanism involved in protein regulation. That is: it’s not AD specific. Their “animal model” are nematodes - tiny worms. By creating a transgenic version of that worm, they find that reducing that mechanism leads to better survival of the worm under amyloid-beta overload.

This study is purely hypothesis forming. And likely a null results for humans.

  1. Animal models in general have a very low predictive value for success of human clinical trials. And this animal model in isolation (and that’s what this paper is about) is essentially irrelevant. It’s not mice or non-humand primates. Another problem: there are no good animal models for Alzheimer’s. Because no animal naturally develops something similar to AD. Unlike ASCVD or cancer, which happens in many animals just as in humans.

The best we have are certain transgenetic mice, engineered to develop some form of amyloid overload, causing neuro-toxicity. But in detail it’s not really how we believe that AD is caused and progresses in humans. Animal models have a low predictive value as is. And it’s even worse in AD. Therefore: don’t get exited for AD, until you got data in humans.

  1. We don’t even know if this mechanism is a drug-able target. The authors are silent on that. They are not giving a substance to inhibit the mechanisms. They are using transgenic worms. And given how central the mechanisms supposedly is for protein regulation (according to the authors) it may actually no be a feasible strategy, even if it’s drug-able - due to numerous downstream effects on protein synthesis and catabolism. Humans are a LOT more complex than tiny worms. Because again: this mechanism is not AD specific, but impacts general protein regulation of hundreds of proteins.
    .
    .
    .
    This paper is a far cry from the ezetimibe paper. Which has impressive data in humans that go beyond a simple observational study. A very AD specific mechanism. And an existing, very safe drug, that targets the specific mechanism.

For AD it would be wise, to only post papers, if there is some form of human level data involved as part of the paper.

4 Likes

Good points as always. Thanks for the feedback!

1 Like