Semaglutide and Alzheimer’s Disease

4 min

Semaglutide was approved in 2017 as an injectable diabetes drug under the brand name Ozempic; in 2021 a higher dose of the same drug (brand name Wegovy) was approved for weight management. In 2024 the FDA approved Wegovy to reduce the risk of heart attack and stroke in overweight or obese adults with cardiovascular disease. It is currently being tested in patients with scleroderma, polycystic ovary syndrome (PCOS), and even alcohol use disorder. I don’t believe the science yet supports a conclusion that semaglutide protects against dementia, but I do think it’s worth a step back to look at how the drug works, why it is being studied for several different disorders, and what the prospects might be for dementia treatment.

As background, glucagon-like peptide 1 (GLP-1) was discovered in the 1980s. Over the following two decades, researchers came to understand more about the hormone’s role in the release of insulin and the regulation of blood sugar. Given our national epidemic of type 2 diabetes, it was understandable why that would be the first focus of pharmaceutical developers. In 2005 the FDA approved exenatide (Byetta), the first diabetes drug that mimicked the effects of GLP-1.

Since then, there have been several new GLP-1 agonists (drug formulations that act like the hormone). In addition to Byetta, these now include dulaglutide (sold as Trulicity), liraglutide (Victoza), lixisenatide (Adlyxin), and now semaglutide (Ozempic, Wegovy, and Rybelsus). All have side effects, most but not all of which are mild – and it’s important to remember that with any new drug it’s not possible to know the long-term effects.

These drugs all act on the remarkably complex process of how and why we eat. Although we may experience hunger as a rumbling of the stomach, it’s much more complicated than that, involving not just the stomach but the pancreas, the gut – and the brain. GLP-1 receptors in the brain are key to those feelings of hunger and fullness, and semaglutide acts on those receptors to control appetite. It also slows the rate at which the stomach empties into the intestine, regulates the release of insulin from the pancreas, and seems to boost lipid metabolism, which can help lower cholesterol.

The drug’s potential for treating patients with brain disorders is one of the most interesting areas of GLP-1 research. Type 2 diabetes is a known risk factor for Alzheimer’s disease – the link is not completely understood, but researchers have noted some similarities in the brains of individuals with type 2 diabetes and those with Alzheimer’s disease, including insulin resistance in the brain’s nerve cells.

In a small study in the U.K., about 200 patients with mild Alzheimer’s disease were treated for a year, half with the GLP-1 drug liraglutide and the other half with a placebo. Results released in the summer of 2024 showed that those who received the liraglutide performed better cognitively – and lost significantly less volume in the parts of the brain that control memory, learning, language, and decision-making – than those who had received the placebo. The lead researcher on the study attributed the success of the trial to reduced inflammation and insulin resistance in the brain as well as improved communication among nerve cells. Given how closely related liraglutide and semaglutide are, it’s reasonable to hope that they might share some of these neuroprotective effects.

I am very interested in seeing the results of a much larger-scale study now underway at nearly 400 locations in the United States. In that study, called EVOKE Plus, more than 1,800 patients with mild cognitive impairment or early-stage Alzheimer’s disease are being followed for more than three years – half are being treated with semaglutide and the other half with a placebo in a fully blinded study. We won’t have results of that study for several years, but it’s the kind of long-term, rigorous clinical trial we need to come to informed conclusions about semaglutide and the brain.

An article in the August 1, 2024, issue of the journal Neuropharmacology reviewed many recent findings and concluded that GLP-1 drugs were “a revolution in the making” for their neuroprotective effects and their potential as treatment for neurodegenerative diseases including both Alzheimer’s and Parkinson’s diseases. That’s a revolution I’d like to see, and I hope future evidence emerges that supports it.

Andrew Weil, M.D.

Sources
Alzheimer’s Association. (July 30, 2024). “GLP-1 Drug Liraglutide May Protect Against Dementia” [Press Release] aaic.alz/releases-2024/glp-drug-liraglutide-may-protect-against-dementia.asp

“A Research Study Investigating Semaglutide in People With Early Alzheimer’s Disease (EVOKE Plus).” ClinicalTrials.gov identifier: NCT04777409. Updated 2024-08-22. Accessed September 21, 2024. clinicaltrials/study/NCT04777409?term=EVOKE%20Plus

Hölscher C. “Glucagon-like peptide-1 class drugs show clear protective effects in Parkinson’s and Alzheimer’s disease clinical trials: A revolution in the making?” Neuropharmacology. 2024 Aug 1;253:109952. doi: 10.1016/j.neuropharm.2024.109952. Epub 2024 Apr 25. PMID: 38677445.  pubmed.ncbi.nlm.nih./38677445/

Reich N, Hölscher C. “The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: An in-depth review.” Front Neurosci. 2022 Sep 1;16:970925. doi: 10.3389/fnins.2022.970925. PMID: 36117625; PMCID: PMC9475012.  pubmed.ncbi.nlm.nih/36117625/