back
367 comments
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.

> So has anyone managed to separate the effects of semaglutide from the effects of weight loss?

In general? Yes. For this specific thing? We haven't even really shown the effects matter for humans.

> 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.

Public health has been banging the drum on obesity for decades now. But humans on the whole aren't built to be able to resist hyper palatable calorie dense cheap foods.

It’s in broad terms weight loss related. More specifically blood glucose and insulin regulation which can be out of whack even if you’re not diabetic on paper. This is why you’ll see people claiming they’re not diabetic but still saw improvement from Ozempic and friends. Their insulin and glucose regulation was spoke. in casual terms “fucked”.

GLP-1 receptor agonists such as semaglutide act partly through the brain to reduce hunger, increase satiety, and lower spontaneous energy intake. Sustained caloric reduction produces weight loss, including loss of visceral fat around the abdominal organs and ectopic fat stored in tissues such as the liver. These fat depots are metabolically active and contribute to insulin resistance through excess fatty-acid delivery, inflammatory signalling, and disruption of normal insulin action.

As they shrink, muscle and liver tissues become more responsive to insulin, so the pancreas no longer needs to secrete as much insulin to maintain normal glucose levels.

This reduces the compensatory hyperinsulinaemic state that can exist for years before diabetes develops and decreases the probability that impaired glucose regulation will progress toward overt type 2 diabetes.

Those changes propagate into the cardiovascular system.

Better insulin sensitivity and lower visceral and liver fat are commonly accompanied by lower triglycerides, improved blood pressure, reduced systemic inflammation, and better endothelial and vascular function, thereby reducing several mechanisms that contribute to atherosclerosis and cerebrovascular injury.

GLP-1 receptor agonists also have a direct metabolic action independent of weight loss: when glucose is elevated, they enhance pancreatic insulin secretion and suppress inappropriate glucagon secretion, improving glucose control without forcing insulin secretion when glucose is low.

The overall effect is therefore a combination of an immediate GLP-1-mediated improvement in appetite and glucose regulation followed by progressively larger downstream effects from weight and fat loss, which together reduce the metabolic and vascular abnormalities associated with cardiovascular disease and, over much longer periods, potentially with dementia risk.

My wife has hardly lost any weight from Zepbound but she went from having such intense back spasms she could maybe walk a few hundred feet at a time to being able to easily handle a week at the Disney World parks on foot. Before she had to rent a motorized scooter. Absolutely life changing for her.
All my immediate family members are obese. I'm not (BMI 24.5, borderline overweight at the high end of normal, highest lifetime BMI was 29.5), but that's through strenuous, exhausting effort over decades. I also exercise regularly, though I've learned over time how disconnected exercise is from weight management.

At my weight, I'm not a candidate for going on a GLP-1. I'm sure I could find an unethical doctor to prescribe it if I looked hard enough, but I don't want to have the downsides hidden from me.

My weight has been steadily ratcheting up over the years, since I don't have as much room in my life as I used to for living with the discomfort of caloric deficit. If that continues, I will probably become a candidate for GLP-1s, like my immediate family members, just after a decade or so of possibly unneeded striving.

Lots of people are in situations far worse than mine, so I don't feel unlucky — but it would be nice if there were a clearer path forward. While lowering risk for Alzheimer's is not a priority for me, other effects of GLP-1s sound extremely enticing — especially reports of reduced food craving.

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.

> So has anyone managed to separate the effects of semaglutide from the effects of weight loss?

I was looking for that in particular. The study does say:

"To assess whether the observed effect was mediated by weight reduction, we performed a sensitivity analysis adjusting for change in BMI from baseline to week 104. In this adjusted model, the treatment effect coefficient was attenuated from β −0.092 to β −0.066 (P < 0.001), corresponding to a reduction of 28% in the estimated effect size. This attenuation indicates that 72% of the treatment-associated difference in 20-year dementia risk persisted after accounting for BMI change, suggesting that mechanisms beyond weight loss contribute to the observed proteomic signature modification."

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.

It’s been no secret that being fat is terrible for us. It’s getting people to actually eat less is the hard part.
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.
What should public health have done differently?
GLP-1s seem like a night and day difference in intervention adherence though. For various obvious and non-obvious reasons, it’s very hard to produce an intervention that people will adhere to to make the test group lose weight.
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.
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.
There are some effects of GLP-1s which definitely cannot be explained by weight loss. For example, some patients report that they lost their compulsive habits - gambling, shopping etc. In some, the effect is so extreme that it flips into outright anhedonia, an inability to enjoy anything.

GLP-1s are ultimately treatments that act on our neurohumoral regulation, and hormones tend to have a lot of functions all around the body. Claude would say that the expected "blast radius" of fiddling with hormones is much bigger than that of just losing weight.

Alzheimers dementia is sometimes called type 3 diabetes, so it may be both.
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.

Diabates can harm the brain either indirectly, through vascular damage, or directly through nerve cell degeneration. The latter is a less studied mechanism and can explain the benefit from GLPs. But I agree, it's not different than a low calorie diet. In the modern times of abundance and sedentary lifestyle, fasting makes wonders. So, if you have even one vascular risk factor, just cut your calories in half, just stop eating. Your body will thank you.
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.
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.

I'm a strong proponent of GLP1. But a change in one marker is at best an okay signal. But the only thing one cares about is real changes in rates. Who cares about markers that don't translate to real clinical outcomes. That's the whole damn problem with everything from stupid "this makes you younger" claims and the tragedy that is the history of Alzheimer research.

I wish they compared straight-up weight loss without disease. In this specific population, the bias has a known direction: unintentional weight loss in older adults is a well-documented dementia prodrome = weight starts dropping years before diagnosis. So placebo-arm weight losers are enriched for people already on the downward trajectory, and any comparison matched or adjusted on BMI change-diff inherits that, making the drug look better than it should in this study design.

And the 5-year OR 0.74, and no BMI-adjusted coefficient is given for it. The 5-year calibration is dominated by near-term inflammatory/metabolic pathways — exactly what weight loss moves, so it plausibly attenuates much more than 28%.

I think the conclusion is not warranted at all: that semaglutide does more than its weight loss explains, not the same or less. Which is also the commercially valuable claim. And note that Novo funded the study, AND two authors are Novo employees/shareholders.

In short, I like GLP1s, but I'm not convinced by this study that GLP1 treatment reduces dementia incident rates meaningfully compared to normal health weight loss.

This is interesting. Diabetes is a well-known risk factor for dementia.
Isn't lower calorie consumption in general correlated to longevity? (Assuming no major malnutrition)
Very american thread and comments.

At most I was 24 BMI and I felt like a fat bastard during COVID. Work from home in sweatpants and I got up to 24 BMI. 77-78kg, 182cm. I just did not weigh myself so I actually did not notice I had gained! But I did and decided to do something about it.

But I lost the weight pretty quickly.

I grew up at 60-65kg and that is where I feel at home in my body. I feel like myself basically. I should add I am 35, so certainly no spring chicken.

"omg how did you lose it"

Very easy.

1. Weight loss is done through diet, not exercise. Exercise is great for the body, but not a primary weight loss.

2. If you work an office job you do not need 3 full meals a day. Eat a light breakfast, a full lunch and a light meal for dinner.

3. On the weekends, fast. If you are committed, this weekend, buy like 4-5 litre of sugar free/diet soda, flavoured water zero calories, and caffeine pills. To distract yourself, play a high dopamine grind game like Diablo IV, PoE, Borderlands, WoW/FFXIV, CS, Valorant etc.

Just drink, do not eat. Hunger is temporary and will last like 1h for me, then the body "gives up". Do a 24h or 48h water fast, you will drop 5kg easy and feel way less bloated. Repeat next weekend...

Set an alarm every 2-3h to get up and walk. Get your 10k steps in everyday by walking outside.

"omg that's unhealthy"

Yes, ofc but it is more healthy than being overweight or close to overweight, agreed?

"you can only do this because ur a Swedish chad and you have walkable cities!!"

I'm a degenerate gamer. lol

That's a big percent for something that is completely devastating. This is objectively good news.
Semaglutide reduces appetite.

The less appetite you have the less you eat crap. The less crap you eat the healthier you are.

There's a little more to it than that obviously but this is the reason that they're finding all these "unexpected" things improving when people take semaglutide. Most food eaten by most people with access to semaglutide is crap, that makes you unhealthy. Eating less crap improves lots of factors.

But the good news is, eating less crap makes you less unhealthy independent of other factors too.

Better summary:

Two years of semaglutide treatment appears to substantially slow the worsening of a blood protein signature associated with future dementia risk

Some researchers have (informally) taken to calling certain forms of dementia "type-3 diabetes", so I think this sounds at least plausible. It's far from a foregone conclusion or anything, but there's at least some evidence that dementia might be a metabolic issue, so it would make sense that something that improves metabolic health would also improve brain health.
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.

I swear, Semaglutide is reverse Asbestos.

It's something we found and started using to one specific problem, but it later turned out that it has lots of other, extremely wide-ranging consequences. Except that in this case, these consequences are positive.

I hope that people will study the emotional impacts of these drugs.

I wonder if that may be the root of a lot of these changes we are seeing and might provide more clues into what might be possible with them.

"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

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.
Reading about GLP-1 medications reminds me of the movie Limitless. Being on them sounds great, getting off of them not so much.
in older adults *with obesity *and cardiovascular disease without diabetes
Absolutely magical drug ! It makes you thinner, younger and now smarter !
We are very early in the semaglutide world, exciting times ahead!
And a doubling in the rate of waking up blind.
This is one of those fake stats, where

if among people not taking it you would see 4 out of 100 get dementia within 5 years of when you started measuring,

if they were taking it you'd instead see 3 out of 100 get dementia within 5 years,

and the number is either a projection ("predicted risk") because they didn't actually study it for 5 years,

or the number is a p-hack because they checked every possible thing they could with the 5-year data they had and this was the only interesting thing that they found ("post hoc analysis"),

or both (the projection of a p-hack), which I suspect because they also tell you about the 20-year risk,

and it is a study sponsored by the manufacturers of the drug,

being suggested to cure a disease diagnosed by checklist (rather than any physical test.)

Will that keep it out of the headlines? No, it was written to become a "free" ad that will be published by the people they send enormous amounts of money to, but by their "news" departments.

The best thing we can do for the progress of medicine in the US is to make direct-to-consumer advertising of prescription drugs illegal again. There would be no use for this if the media hadn't been bribed to become cheerleaders for any old shit. It's illegal everywhere in the world other than the US and New Zealand.