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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.

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.

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.

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.

> 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."

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.

What should public health have done differently?

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.

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

> If this is caused by the weight loss, it is a little disappointing that public health didn't act quicker

Public health has been trying to get obese people to lose weight forever, what are you talking about. We've known it's bad in enough other ways. It was just really, really hard (at a population level).

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.

But... the profits!

>> 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.

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

Given that the drug did not exist until only recently and it took decades to develop with the latest of technology, I don't see how this could have been possible. Stomach surgery has been around for 50 years though, but it's a bigger undertaking than an injectable drug.

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 have a very similar situation: on it for about a year, 220lbs to 180 at age ~40. Also very active: weight lifting / biking / swimming and - the sport that made me realize I needed to loose weight - rock climbing. I've always been very outdoorsy-adventurous, and climbing/mountaineering is the natural sort of "end game" for this lifestyle. My weight never really got in the way of anything else in my life (maybe my self esteem) but, this might offend some people, but climbing is a sport where you really cannot be even a little bit fat. It makes you painfully aware of your body weight. Most "good" climbers are built like bean-poles. I don't really need to be a "good" climber, just an "okay" and safe climber - I'm mostly interested in alpine trad below ~5.7. I still feel like I need to lose another 10lbs.

I was a fat kid growing up. I've had a BMI of 30±1 since age 12. I also have a family history of heart disease. Literally every male on my father's side for three generations has had a heart attack in their late 50s. We all have roughly the same body type. I already had hypertension in my mid 30s. Semaglutide has made me feel like there's hope.

Unfortunately, I can relate to the lower energy levels. While I'm no longer lugging an extra 40lbs around (a full pack!), I still bonk way faster. My gym sessions are way shorter. Luckily, I haven't lost much muscle mass, so I look great and it's been the "cut" I've never been able to achieve, but I'm sure if I ever wanted to "bulk" I'd have to go off it. I've found if I have a big trip or climb coming up, I have to take a way smaller dose the week, or even weeks, prior. I found this out the hard way when I puked on a climb in North Cascades. I just couldn't eat, and felt like shit the whole time.

The trick has been self managing my dose. I'm on compounded generic, so I can dose myself with my own needles. If I have a big trip coming up, I'll take like 25% of my maintenance dose for a week or two prior. This has been almost a superpower, because I'll get this massive burst of energy from the calorie intake. Im still not really sure if this is healthy, not the "taking 25%" part, but the fact that I feel like superman when I'm off it or on a low dose for a bit. Not sure what this says for someone who is basically taking semaglutide because their weight was holding them back from the activities semaglutide makes them too bonked to do anyways.

I had similar issues on Semaglutide, but I've found Tirzepatide much more tolerable. I've lost 165lbs, A1C has gone down to 5, I have more energy at 52 than I did at 32, and I am exercising like a maniac now. Maybe you could try 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.

I’m also active and fat. And to me being active is more important than losing weight; I’d rather continue to do those long 2000kcal bike rides on weekends than having a healthier BMI. I’ve heard stories of my own friends bonking during a ride and I decided that I wanted to err on the side of overeating. So semaglutide doesn’t interest me. You aren’t the only one I’ve heard who started to have no energy after being on semaglutide.

That said the dementia benefit mentioned in the article still intrigues me.

You are a proponent, but your outcomes seem worse?

I'm younger than you and only loss a about 25 lbs. I've now gone to a maintenance dose and seen my energy recover substantially, I do still think (anecdotally) that when I got off for a week I got even more energy but it's hard to judge.

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.

Try Tirzepatide or one of the other drugs. They each have their own side effect profile.

What dose? Have you considered lowering it?

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.

Semaglutide cleared my liver fat and fixed my moderate NAFLD in a matter of months. Why is retatrutide necessary?

I hope Retatrutide pans out but encouraging people to hop on research chemicals when we already have drugs that can get lots of T2D people into remission is a stretch too far. Let's wait for the actual medicines to be produced by legitimate manufacturers instead of ordering grey market peptides from some nameless whoever with zero liability. This is absolutely not on the right side of the risk-reward equation. Mounjaro is more than good enough.

> This is a Novo Nordisk-funded study focusing on predictive biomarkers rather than real-world dementia cases

You act like all this is hidden, but the title of the article and the list of authors makes this self-evident.

> Novo Nordisk's actual dedicated clinical trials for Alzheimer's completely failed to show that semaglutide stops cognitive decline

Sure, but the EVOKE studies were focused on something that could be sold as a product covered by insurance: semaglutide to those who had already developed Alzheimer’s. It is widely agreed the trial failed because it was a population already diagnosed with dementia. There’s lots of studies not funded by Novo that show semiglutatide has reduced the incidence of dementia in the diabetes population. Novo knows that running a general study on whether semaglutide reduces dementia in a non-diagnosed population is useless to their bottom line because insurance will never pay for everyone to take the drug.

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).

The fact that NN funded this study is very relevant but is not necessarily a negative as you make it out it to be. Perhaps that is not your intention but reading the comment made it look like that way.

1. It makes sense for companies that profit from their drugs to use their profits to also commission such studies.

2. Faking data or causing harm exposes these companies to total black swan events for which they will pay dearly so they often have incentives to release anything that might harm their patients.

Factoring out the ad corpus yelping, the interesting counterpoint is that suppressing the risk signal isn't a good thing if it doesn't suppress the risk.

Regarding “actual tests”: My team and I built a battery of longitudinal cognitive assessments useful for testing memory and brain function. (http://getNeuroUX.com)

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.

Much appreciated post, but can you keep the AI slop separate from the rest of it?

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.

This is one of the most distinguished peer reviewed journals on Alzheimer’s and dementia. Adults know not to make too much of a study of this scale and ambiguity. But considered as such, the paper is above suspicion.

So translated to human, does this basically mean then that semaglutide distorts dementia-predictions by altering the related biomarkers, rather than actually help with dementia?

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?

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.

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-...

Sure, but there is nothing in the world of the last 30-40 years that can compare to GLP-1s in terms of helping people consume fewer calories. This is a very coarse statement, but I'm confident in making it: there is nothing healthier than being skinny, and GLP-1s make people skinny in a way that is unique in modernity. Our modern food systems are optimized to encourage people to consume as many calories as they can, and GLP-1s are bulwarks against this system, if you will.

Semaglutide reduces appetite. Who could have known that eating less will have positive effects?

Maybe we should try consuming less in general and see what the effects are. Is there a semaglutide for my shopping habits? Maybe ban ads?

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.

> 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.

not really. these drugs only merely make you not overweight or obese, which was normal until around 1980 or so.

Alzheimer's disease is not a reduction in intelligence, don't be crass.

Doubling doesn’t mean much without knowing the base rate.

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...

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.