The list of potential benefits of GLP-1 drugs is only getting longer, with a new review of mostly preclinical studies linking these popular diabetes and weight-loss medications to limiting the molecular hallmarks of dementia.
The review by researchers at Anglia Ruskin University in the UK looked at 30 published studies conducted in cell cultures and lab animals.
Specifically, they assessed the effects of four different GLP-1 drugs on the harmful buildup of amyloid-beta and tau proteins in the brain, which characterize Alzheimer's disease.
Of the preclinical studies examined, 22 showed a reduction in amyloid-beta plaques, and 19 showed a reduction in tau tangles. These abnormal masses of protein are thought to damage and kill neurons in Alzheimer's (though other suspects are emerging).
We're a long way off being able to say that GLP-1 drugs such as Ozempic and Wegovy may reduce the risk of dementia, especially when the review only turned up two small in-human trials.
But it seems growing evidence from cell and animal models of the disease suggests there's some kind of connection here.
"This new review provides one of the most comprehensive analyses so far of how GLP‑1 drugs interact with the underlying mechanisms of Alzheimer's," says physiologist Simon Cork.
"Our study highlights several biological pathways by which GLP‑1 drugs may influence Alzheimer's, including reducing inflammation, improving insulin signaling in the brain, and altering enzymes involved in the production of amyloid‑beta."
GLP-1 drugs get their name from the glucagon-like peptide-1 (GLP-1) hormone that they mimic. Technically, they're GLP-1 receptor agonists, because they work on the same cell receptors as GLP-1 to activate the same response – slowing digestion, prompting insulin release, and limiting appetite.
These drugs are commonly known by brand names including Wegovy, Ozempic, and Mounjaro, but what's more important are the active ingredients: semaglutide, liraglutide, exenatide, and dulaglutide were the four examined here.
Liraglutide was the active ingredient most extensively represented across the review and proved the most consistent in reducing both amyloid-beta and tau back to safe levels.
Exenatide had the smallest effect across all of the data analyzed, though it still showed an association with reduced amyloid-beta and tau in some studies.
Two small clinical trials were also examined, though they reported mixed results.
Brain cell metabolism was preserved in one trial, and the other found reduced amyloid-beta in extracellular vesicles, but neither trial found that GLP-1 drugs reduced the build-up of amyloid-beta in the brain or helped stave off cognitive decline.
"Whilst human studies demonstrating an impact on cognitive decline are still lacking, the current evidence points towards these drugs having a preventative effect, rather than in patients with established cognitive impairment," says Cork.
Previous research has found that people on GLP-1 medications are less likely to develop dementia in some cases.
However, other studies involving people with early Alzheimer's or mild cognitive impairment have yielded negative results: One published last year showed no connection between semaglutide and a slowing of cognitive decline.
We also know that both obesity and diabetes – the two conditions that GLP-1 drugs are developed to target – have their own links to dementia. Teasing out the different mechanisms at play and the subsequent effects on dementia risk is going to take a while.
Exactly how GLP-1 medicines might protect against toxic protein build-up and dementia needs further investigation. The researchers suggest that reductions in inflammation and protein production, and improved insulin signaling, may be involved.
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"With more than three‑quarters of preclinical studies showing reductions in amyloid‑beta or tau, and early signals emerging from studies on humans, GLP‑1 drugs remain strong candidates for future Alzheimer's prevention trials," says Cork.
"Larger, early‑stage clinical trials are now needed to determine whether these promising signs actually translate into tangible benefits for patients."
The research has been published in Molecular and Cellular Neuroscience.