tdlr: This is a Novo Nordisk-funded study focusing on predictive biomarkers rather than real-world dementia cases. Novo Nordisk's actual dedicated clinical trials for Alzheimer's completely failed to show that semaglutide stops cognitive decline.
"A predictive biomarker is like a "check engine" light on your dashboard. It warns you that there is a risk of a future problem. In this study, the researchers only checked if the drug turned off the "check engine" light (by measuring blood proteins), rather than testing if the car was actually driving properly (by testing the patients' actual memory and brain function)."
Always do FIRST analysis on studies. Or have AI do it for you. I used Gemini to dig into this:
"Novo Nordisk funded this study, and several of the researchers are employees or minor shareholders. While corporate funding doesn't automatically mean the data is fabricated, it does mean the company is highly motivated to find and publish data that makes their blockbuster drug (semaglutide, marketed as Wegovy, Ozempic, and Rybelsus) look like a preventative treatment for a wider range of conditions, expanding its market and driving up profits."
"Funding: The study was funded by Novo Nordisk A/S.
Investigation: Researchers conducted a post hoc analysis using data from the randomized, placebo-controlled SELECT trial. They applied the Dementia SomaSignal Test (dSST)—a 25-protein risk score—to non-fasted serum samples collected at baseline and at week 104 to estimate 5-year and 20-year all-cause dementia risk in patients receiving semaglutide (2.4 mg) versus a placebo.
Results: Semaglutide significantly attenuated the progression of the dementia risk signature. Compared to the placebo group, the 5-year predicted risk increased 2.5-fold less (a 26.0% lower predicted event rate) and the 20-year risk increased 1.67-fold less (an 8.8% lower rate). Semaglutide also lowered the odds of patients moving into a higher dementia risk category by 36%.
Subjects: The analysis included 2,970 older adults aged 65 and older (mean age of ~69.7 years) who had overweight or obesity and cardiovascular disease, but no history of diabetes. The cohort consisted of 814 women (27.4%) and 2,156 men (72.6%).
Time: The study evaluated data over a 104-week (2-year) follow-up period. The analysis was published on August 8, 2026."
And then map the weakness to each respective letter if you want to dig deeper.
So has anyone managed to separate the effects of semaglutide from the effects of weight loss?
If this is caused by the weight loss, it is a little disappointing that public health didn't act quicker - lots of people have been overweight for a century now, so literally 10's of millions of people could have been saved from dementia had action been taken 100 years ago.
I have some individual anecdotal evidence. I spent a long time, basically a year, relatively heavy but on a very small dose of GLP drugs due to tolerability issues, and my labs improved dramatically, to a degree we redid them out of disbelief, even without weight loss. I believe one of the suspected underlying causes is reduction in fatty liver despite constant body weight and composition, and also inflammation reduction directly through GLP influence in other areas of the body.
I'm not great evidence because N=1 and all the confounders, but I found that it absolutely made me much healthier without weight loss. I then went on to increase the dose slowly and have lost a bunch of weight and my labs improved even more, which I attribute mostly to the body mass reduction.
Similar experience here on minimal dose of GLP-1. There is definitely something going on here other than "you are just losing weight and that's really why your healthier".
With my labs at my current weight you can not tell that I am a type 2 diabetic. Previously, when I was at this very same weight in the past - all my labs indicated I was prediabetic.
With all the research into dementia and its causes, if there was a simple strong link to overweight I can't imagine that would not stand out in the data and be well known by now.
Edit: although, there are well-known links between overweight and a lot of negative outcomes, and yet people are still too fat.
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That is the question now. Some studies have some early evidence that GLP-1s might reduce inflammation markers a little more than weight loss alone.
Giving GLP-1s to normal weight people doesn’t work well because they can have to work harder to maintain their weight. That can be a real problem as people get older where maintaining muscle mass is important for quality of life and longevity. I remember how hard it was to keep some of my grandparents at a healthy weight, so adding a GLP-1 to a non-obese elderly group is a no-go for study purposes. Going to be hard to separate these effects out.
My assumption was that GLP-1's don't suppress appetite so much as suppress the compulsion to eat when not necessary/more than necessary?
It’s both. That’s why it’s so effective.
What should public health have done differently?
Treat junk food like cigarettes
People have tried. Any time the government tries to do anything a substantial portion of the electorate throws a childish hissy fit and tries to make out that the Bolsheviks are coming to make their fries less tasty for no good reason.
Unfortunately in most countries the blocker is politics, not the desire of public health officials to do anything. See the current US admin going after vaccines while declaring open season for peptides.
Semaglutide was invented in the early 2000s. Weight loss is an extremely complicated and societally mediated problem that we didn't have a 'cheat code' like this for until recently.
Even more so. Not absolute weight loss but the effect of loss of the systemic inflammation due to a surplus of visceral fat which has significantly more systemic effect than subcutaneous fat or other types of loss of mass.
that is the interesting question. also the effects of weight loss vs. the effects of disengagement with the engineered to be addictive "food products" side of the western diet.
What is interesting about it?
Proper sleep, eating less (including liquid calories), and exercising have been the mainstream medical advice for many decades.
Obviously, most people can’t accomplish that for whatever reason, so another solution was needed.
> What is interesting about it?
did western society engineer a junkfood-industrial-complex so addicting and so en-sickening that it ultimately required a sort of junk food methadone to wean itself off?
I mean kinda yeah
Alzheimers dementia is sometimes called type 3 diabetes, so it may be both.
Well, if you consider that is much cheaper to eat trash than healthy, and that food companies' only interest is in maximizing profit, you have what we have.
I don’t consider that since it’s simply not true.
When I grew up relatively poor we never ate out or ate junk food because it is ridiculously expensive in comparison. We made our food from cheap ingredients. To save money.
Yes it takes more time and is far more work and is less convenient. US society has valued convenience over everything else for a few generations now. Cheaper it is not.
I don't buy that. You can buy a steak and a potato for two for less than a bag of Doritos. A banana costs far less than a candy bar. A bag of mixed nuts will provide many meals.
Price out a bag of rice, a bag of beans, etc.
> food companies' only interest is in maximizing profit
Pleasing your customers is how profit is maximized.
Besides, I bet if you were faced with two stores, one that charges $x for A, and another that charges $(x-1) for A, you'd patronize the latter store.
Where are you getting a steak and potato for 2 for less than a bag of Doritos? Is it a 50 lb bag of Doritos?
Maybe it's 4oz of very lean tough steak and a single small russet potato with no fat, and the two mentioned are five year olds.
But... the profits!
Dementia aside, there are plenty of very obvious reasons we should have been discouraging obesity and encouraging healthier eating and lifestyle habits.
Lobbies and general government ineptitude have been a problem longer than obesity and that one needs to be solved first.
>> If this is caused by the weight loss, it is a little disappointing that public health didn't act quicker
I imagine people hundred years in the future will think of our current society rightfully as dumbfucks. But should we be surprised? 50 years ago women didn't have voting rights; homosexuals were incarcerated in western societes; all because of moral and power implications of some powerful men. Not much different with Semaglutide.
>50 years ago women didn't have voting rights
Where are you? In the US, women have had full voting rights for over 100 years.
I think you need to read up on why the civil rights act was necessary and the things it fought for. Woman's suffrage was fought for a long time ago, but that does not mean it was universally applied.
Many many times in US history we've said something is true, but put some big asterisks after them. Slavery is over (except it's definitely still permitted in the US), it's illegal to discriminate based on race (except we allowed redlining for generations and arguably are still fighting it), rape is illegal (unless it's your spouse, then it was legal until '93. And a lesser crime still in much of the country).
Voting is no different. Heck, one might argue we still don't have universal suffrage. People who want to vote but because we've put barriers like underfunding stations, long lines, not giving time off to vote, etc. we're clearly preventing some types of people.
No, black woman (among many other minorities) certainly didn't. I guess that part isn't taught in american schools as thoroughly as it should be.
Then teach us.. when did they got voting rights?
I'm a big semaglutide proponent after being on it for a year. I know research says it helps with inflammation, arthritis (separately from weight reduction), and all sorts of magical things.
I lost 40 pounds in a year(230 to 190) at age 50. Great! I also went from being active and fat(weightlifting with some cardio) to basically having no energy. In the last year I've had arthritis appear in several joints. I'm awake several times a night to pee(yeah, prostate is acting up but I still void completely. The semaglutide is like a diuretic for me at night.). I get waves of hypoglycemia like feelings where I feel weak and spaced out. I'm afraid to get off of it because now my joints can't handle the extra weight. My doc recommended going to every other week now that my BMI is normal but as far as I can tell that advice isn't backed up by any research. Anyway, it's a powerful drug that works well but is not without side effects.
You are a proponent, but your outcomes seem worse?
Losing 40 pounds where sometimes it feels like this weight is impossible to lose. That's what makes it worth it.
I'm on the pill version, which allows me to adjust the dosage on a more day-to-day level. It also doesn't need a fridge, so it allows me to travel more easily. There's a level that works best for me long-term, and it's quite a bit less than typical.
Is it kind of the stuff where the benefits outweigh the side effects? I'm just scared of the unknowns with the drug with such overwhelming positive research. Maybe, I'm a paranoid person but I'm unable to believe that such a powerful drug isn't without any side effect, clinically proven.
What dose? Have you considered lowering it?
If you're overweight or especially if you're T2D I highly encourage you to discuss GLP-1 with your doctor. If you're T2D then get research retatrutide which looks to be an actual cure for T2D by clearing liver fat. It should be released early next year but research-use is available and what everybody is taking. Companies like finnrick do public testing of research peptides and a good place to gather names.
I’m on tirzepatide right now from Eli lily, and I’ve been very interested in Reta, but I can’t say that I jump at the chance to inject something into myself that hasn’t been tested directly on the actual thing I’m about to put into my body. I know there are testing companies that will test certain sources but it’s not like they’ve tested the vial you get. If there’s some kind of pathogen or bacteria or whatever in the vial you get, well, there’s no recourse: it was “for research use only”. That seems like an unacceptable risk, but I see so many people on the internet claiming miraculous results. Maybe if I knew someone in real life, but I know those biohacking subreddits and such are astroturfed to no end by companies looking to sell sketchy peptides.
That's a common and very acceptable concern and there's not great answers for it. Mostly a place will do multi-vail testing for purity, sterility, endotoxin and heavy metals. The idea is that the sample is sufficient to show safety. Many are rightfully dubious of this but still thousand and thousands of people taking it.
Semaglutide cleared my liver fat and fixed my moderate NAFLD in a matter of months. Why is retatrutide necessary?
Retatrutide has a specific mechanism for clearing liver fat (glucagon) which makes it one of the most effective ways to treat T2D. This is the 3rd agonist not found in semaglutide or tirzepatide.
Are you implying the medicine did it or does the medicine just make you eat less which cleared it? Like is there an MOA of the drug itself?
Yes the medicine does it. It's attacking T2D via several pathways, but in the case of Reta the glucagon is doing the heavy lifting of clearing liver fat.
This extra receptor is why Reta is a triple agonist unlike semaglutide (single glp1) or tirzepatide (glp1+gip double agonist).
Semaglutide clears liver fat? I had no idea. I’m curious to know more about your protocol
Isn't lower calorie consumption in general correlated to longevity? (Assuming no major malnutrition)
That's a big percent for something that is completely devastating. This is objectively good news.
Although it's encouraging, they do mention that the reduction in the BMI also have an effect (they take it into the consideration by lowering the β −0.092 to β −0.066 (P < 0.001)).
Just skimming through it, it's possible there are direct benefits, but it could also be other environmental factor. This study will most likely generate others that give us more insight in the future.
This is interesting. Diabetes is a well-known risk factor for dementia.
As is being sedentary - there are probably lots of interconnected factors in play, and GLP-1 receptor agonists seem to help with more than one (perhaps even many) of them.
Unpicking the exact chains of causation is likely going to be extremely complex, but the general picture continues to look good.
We should probably be studying people who wear smart watches and collecting the activity levels to control for that.
But if GLP-1 makes you more active, who am I to complain. There's the reason they approve stomach stapling surgeries on morbidly obese people. They are so compromised that anything that gives them a chance to be more active offsets some of the risks of surgery, and the risks of inaction.
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Western disease and sugar heavy diets broadly speaking, which Semaglutide is a countermeasure against. Not yet a vaccine, but in due time (probably via gene therapy). Fructose also helps cancer metastases and spread.
https://www.sciencealert.com/common-sugar-appears-to-loosen-...
First of all it’s a nice study. The dosages they always give are way too high and mice are rarely a reliable model.
But you’re also ignoring the fact that the same study shows that glucose inhibits the behavior.
So your claim that the study indicates its sugar is incorrect. The study indicates a possible impact from fructose which is countered by glucose, so the real issue is the fructose to glucose ratio.
Table sugar providing equal fructose and glucose molecules is acquitted by this study.
> Western disease and sugar heavy diets broadly speaking
No, just being sedentary. There's no such thing as acquired diabetes in physically active people.
To "actshully" you (because there are no absolutes in biology) pro-triathlete Lionel Sanders got his hba1c up to prediabetic range (5.9)
https://www.tri247.com/triathlon-news/elite/lionel-sanders-t...
Also age plays a pretty significant role. I know older asians who regularly walk who still got T2D. You could argue that walking isn't physically active enough... but they'd argue otherwise. It's all relative.
Doubt you can eat just pure fructose for 30 years and ”move” and avoid diabetes.
People kick around the idea of the "personal fat threshold". E.g. caucasians seem to be better at carrying fat than, say, Southeast Asians. White people seem to be able to better store fat without metabolic side effects; SEA seems to get T2D at a much lower bodyfat percentage.
Sugar heavy diets is everywhere IF people can afford to have them if you look at the data. There is no such thing as Western vs Eastern in this sense.
Note I am not Western
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I don't see anything RFK-like in that comment.
Just pattern matching as an autistic human. Similar results were seen on a ketogenic diet (and to some extent, intermittent fasting). What do they have in common? Sugar intake reduction. Is it surprising sugar potentially fuels cancer, contributes to dementia, etc? It shouldn’t be. It’s indirect and a casual connection.
There is no health benefit to a high sugar or Western diet, only downside. I think calling it poison is hyperbole, but it’s definitely not healthy, based on all available evidence. I expect to see longitudinal scale results over the next decade as everyone starts taking GLP-1s.
(I take a glp-1, they’re an amazing drug class, it changes how your brain operates, charlie day waving arms in front of a whiteboard meme here)
Thats due to caloric restriction. A high fat diet isn't going to helpful as well. To think that people cut sugar but continue to eat far too much meat and fat... yikes.
in older adults *with obesity *and cardiovascular disease without diabetes
Read a interesting piece recently that Semaglutide reduces inflammation, and very likely the weight-loss and a lot of the other emerging benefits are likely the effects of reduced inflammation.
> and very likely the weight-loss and a lot of the other emerging benefits are likely the effects of reduced inflammation.
That’s not correct. GLP-1s interact with satiety (fullness) circuits and reduce appetite. They also have minor effects delaying gastric emptying, meaning the stomach stays full longer.
There is some early data suggesting that they might reduce some inflammation markers slightly more than weigh loss alone, but losing weight and controlling food intake without GLP-1s reduces the same inflammatory markers. The question now is if GLP-1s have additional anti-inflammatory influence.
I don’t know why someone would claim all of their effects are downstream of inflammation. Some people get stuck in modes where they think inflammation is the cause of everything and can’t comprehend causal effects going in the other direction.
"Semaglutide attenuates a proteomics-based dementia risk signature "
ie : clinically meaningless.
The company behind this, Novo Nordisk is increasingly desperate, as tirzepatide destroys the semaglutide revenue stream and the consequent job losses decimate the company
Their operating profit was up 11% on a margin of 44% according to their recent quarterly release, and they beat EPS by 23%. They were in a little trouble in the stock market a few years ago as competitors came online, but they are doing pretty well right now.
They have launched new semaglutide oral products which are growing faster than previous products, and they have multiple drugs in the research pipeline in late phases.
Can you elaborate on your claims? As it currently stands, I’m only reading meaningless drivel from you.
Absolutely magical drug ! It makes you thinner, younger and now smarter !
We are very early in the semaglutide world, exciting times ahead!
If it reduces inflammation and causes weight loss, I find it impossible to believe you can just stop and not get rebound on both.
Which to me just sounds like every other addictive drug. Paradise while you’re high, and eventually you pay for it.
For sure we still need to find out many related outcomes.
Last year it become known that it increases (high relative risk, low absolute risk) non-arteritic anterior ischemic optic neuropathy (NAION), ie sudden, sometimes permanent vision loss.
https://www.ema.europa.eu/en/news/prac-concludes-eye-conditi...
To save others the click: It increased the likelihood to 1 in 10,000 in adults with type 2 diabetes.
Diabetics are already more prone NAION. This studies contribution was to show that diabetics on GLP-1's are MORE prone. It does not show that the general population is more prone when taking GLP-1's.
I didn't check to see if other studies prove that.
It is well known that forcing a sudden drop in chronically high average blood glucose (like, from 200+ to a normal ish range) with insulin can cause vision loss. I wonder if it's the same mechanism?
It tends to happen when:
1) You must have a crowded optical disc as a precursor (low cup to disc ratio). Genetic and can be tested
2) You have stiff veins/arteries due to poor metabolic/cardio health
3) when blood pressure drops too much, blood flow can get cut off to the optical nerve temporarily due to reliance on high blood pressure due to 2
4) Due to loss of blood flow, optic nerve swells and closes blood flow into the eye due to 1
It's also true that having a crowded optical disc is pretty much a required precursor condition to suffering NAION.
Which you can get checked for via a $50 optical scan.
No crowded disc, very little risk.
(Cup to Disc ratio of 0.2ish or less starts to present risk)
In addition to being closely associated with the conditions semaglutide treats, NAION is quite rare.
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Not only that but high intakes of added sugars and fast-acting, high-glycemic carbohydrates are linked to an increased risk of cognitive decline and dementia. Excess simple sugars, particularly fructose and sucrose, promote insulin resistance, chronic inflammation, and vascular damage that impair brain function and accelerate neurodegeneration. So with other words, you diet is a major contributing factor here. The medical establishment and big pharma simple ignores the fact that the biggest health risk for a human being is the "modern" high sugar diet that Kellogs introduced in the US and spread to the western world (even to Asia at some extent).
Which sort of affirms the mantra, "If you can't prove causation, try to prove correlation." This because you can market correlation to unsophisticated readers and imply causation.
Didn't even bother looking into it because there's obviously not enough data yet to say anything substantial about GLP-1s and Alzheimers. But your comment should probably be the top.
I’m not an expert on this, but haven’t GLP-1’s been used for quite a while on more limited scopes? So maybe there’s a cohort of people that could approach statistical significance.
GLP-1s have been used for over 20 years. There likely is enough data to say something, even if it's not water tight.
Doesn’t socialized medicine mean that big brother already knows the answer to these questions? Why isn’t NHS or whomever more useful on these issues?