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'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.

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.

Better summary:

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

Isn't lower calorie consumption in general correlated to longevity? (Assuming no major malnutrition)

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.

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

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 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.

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.

"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 !

And a doubling in the rate of waking up blind.

We are very early in the semaglutide world, exciting times ahead!

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.

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