Weight-loss jabs linked to reduced risk of 42 conditions including dementia

[monkeybus]

theguardian.com/society/202...

Yes, I realise these newer generation diabetes medicines aren't the same as the likes of Metformin or pioglitazone, both of which you can get prescribed for our disease.

But these new drugs have already been rolled out for weight loss, and now they are being touted as cure-alls for all manner of maladies, from addiction, through neurological diseases to dementia.

As I am fond of saying, fresh, unique research into our disease is/will always be thin on the ground on account of so few of us have this disease. Plenty of weight issues around and about, especially in America, often accompanied by diabetes.

This could well be good news for us lot. These drugs are being (safely?) prescribed more and more, affordable as well.

I shall file this under my "We are all cured" pile. Thank me later.

The number of times I have cured us all, I should at least be in line for a Nobel by now.

[tetris]

> Yes, I realise these newer generation diabetes medicines aren't the same as the likes of Metformin or pioglitazone, both of which you can get prescribed for our disease.

I'm seeing that metformin might actually make AMN worse. From "Activated AMPK inhibits PPAR-α and PPAR-γ transcriptional activity in hepatoma cells", Sozio et al., Lipids in American Journal of Physiology, Gastrointest Liver Physiology 2011 (pmc.ncbi.nlm.nih.gov/articl... ):

> We concluded that the AMPK activators AICAR and metformin inhibited transcriptional activities of PPAR-α and PPAR-γ, whereas inhibition of AMPK with compound C activated both PPARs.

So, metformin down-regulates PPARα, and PPARγ which is bad for AMN. On that note, I'm completely cutting out metformin starting now.

[tetris]

> Yes, I realise these newer generation diabetes medicines aren't the same as the likes of Metformin or pioglitazone, both of which you can get prescribed for our disease.

Pioglitazone treats AMN because it is a PPARγ agonist (it makes the peroxisome more active) and it crosses the blood-brain barrier relatively easily. It looks like tirzepatide/Mounjaro/Zepbound does upregulate parts of the PPAR pathway, but doesn't effectively cross the blood-brain barrier. From "Exploring the molecular mechanisms of tirzepatide in alleviating metabolic dysfunction-associated fatty liver in mice through integration of metabolomics, lipidomics, and proteomics", Jinliang Liang et al., Lipids Health Dis., 2025 (pmc.ncbi.nlm.nih.gov/articl... ):

> In the PPAR signalling pathway, the expression of FA transport proteins (Cd36), fatty acid-binding proteins (Fabp2, Fabp4), and perilipins (Plin2, Plin4, and Plin5) associated with lipid accumulation were significantly increased. This was consistent with the lipidomic results showing increased FA and TG in the HFD group. Furthermore, the upregulation of FAO related proteins such as Cpt1a, Acaa1b, Ehhadh, and Cyp4a10 suggests that the liver is attempting to counteract lipid accumulation by increasing FAO.

and

> Through comprehensive metabolomics, lipidomics, and proteomics analyses, we identified that the PPAR pathway plays a crucial role in lipid metabolism regulation and the progression of MAFLD. Specifically, in comparison with the NCD [normal diet] group, the expression of proteins associated with PPAR pathway activation was markedly elevated in the HFD [high-fat diet] group, including Cd36, Fabp2, Fabp4, Plin2, Plin4, Plin5, Capt1a, Acaa1b, and Cyp4a10 (p < 0.05) [43].

However, tirzepatide crosses the blood-brain barrier very slowly, and only in small amounts. From "Brain uptake pharmacokinetics of albiglutide, dulaglutide, tirzepatide, and DA5-CH in the search for new treatments of Alzheimer’s and Parkinson’s diseases", Elizabeth M Rhea et al., Tissue Barriers, 2023 (pmc.ncbi.nlm.nih.gov/articl... ):

> The percent of injected 125I/14C-IRAs taken up per gram brain tissue (%Inj/g) is shown in Figure 5a except for 125I-tirzepatide that did not exhibit significant BBB transport.

and

> These results suggest that longer-lasting IRAs such as semaglutide and tirzepatide can enter the brain slowly and in relatively small amounts through the extracellular pathways [...].

So, tirzepatide's reduction of dementia risk is probably mostly indirect and outside of the brain.

Update: But see the ADDF's evaluation of semaglutide (healthunlocked.com/amneasie... ).

[mariagno]

I have been on Mounjaro for 18 months. I have lost 60 pounds and feel great. It hasn't changed AMN but my quality of life has improved.

[monkeybus in reply to mariagno]

That's a whopping 26 kilos. Nice work, has to do you good to shed all that weight.

[3WheelWonder in reply to mariagno]

Congratulations!

[tetris]

The Alzheimer's Drug Discovery Foundation evaluated semaglutide/Ozempic/Rybelsus, one of the weight-loss jabs the article mentions (alzdiscovery.org/uploads/co... , linked from alzdiscovery.org/cognitive-... ):

> Half-life: 7 days

> BBB: Potentially not penetrant but does accumulate in brain in regions not protected by BBB.

Both of these attributes are comparable to tirzepatide, whose half-life is 5 days. Semaglutide and tirzepatide are both glucagon-like peptide-1 (GLP-1) agonists, so tirzepatide probably accumulates in the same brain regions that semaglutide does.

The ADDF's semaglutide evaluation mentions that 4 trials are ongoing to assess semaglutide's effectiveness at treating Alzheimer's (the most common form of dementia):

• A trial to see if semaglutide makes tau levels in the brain go down in Alzheimer's patients (isrctn.com/ISRCTN71283871 )

• 2 trials to assess semaglutide's effectiveness in early Alzheimer's (clinicaltrials.gov/study/NC... , clinicaltrials.gov/study/NC... )

• A trial to characterize semaglutide's immunological and biological effects in Alzheimer's (clinicaltrials.gov/study/NC... )

If semaglutide is found to be an effective treatment for Alzheimer's Disease, maybe it could be effective for AMN patients, too.