Can GLP-1s Lower My Dementia Risk?
A two-year drug trial examining whether GLP-1s could slow progression of Alzheimer’s disease has shown disappointing results.
The drug company Novo Nordisk’s EVOKE/EVOKE+ Phase 3 trial studied whether the drug semaglutide is safe and effective at treating mild cognitive impairment (MCI) due to Alzheimer’s disease.
Semaglutide is a GLP-1 receptor agonist better known under its brand names Ozempic for the treatment of type 2 diabetes and Wegovy for the treatment of chronic weight management.
EVOKE/EVOKE+ was a large-scale, randomized and placebo-controlled clinical trial. These types of trials are the gold standard when it comes to safety and the ability to determine whether a treatment is effective or not.
The trial enrolled over 3,000 adults ages 55–85 who had MCI or mild dementia due to Alzheimer’s disease. The participants’ disease was confirmed through the existence of amyloid plaques in their brain. They received either semaglutide or a placebo (pills without any medication).
Alzheimer’s disease is a degenerative brain disease and the most common cause of dementia. More than 7 million Americans have Alzheimer’s disease, which kills more people than breast cancer and prostate cancer combined.
Most available Alzheimer’s drugs treat only the symptoms. Two newer drugs, lecanemab (brand name: Leqembi) and donanemab (brand name: Kisunla) treat the disease itself. They are anti-amyloid drugs, meaning they work by slowing down amyloid plaque accumulation. Both are given as IV infusions and are only approved for use in people with MCI and mild dementia due to Alzheimer’s disease.
If the EVOKE/EVOKE+ trial had shown that semaglutide helped reduce MCI, it would have offered a new, easier option because it’s given as a pill, not an IV infusion. “The anti-amyloid [drugs] are good, but it’s a subset of people who are eligible for those drugs,” said neurologist Ronald C. Petersen, MD, PhD, director of the Mayo Clinic Alzheimer’s Disease Research Center and the Mayo Clinic Study of Aging in Rochester, Minnesota.
Lecanemab and donanemab are expensive, given only via IVs in a clinic, and only available for certain patients. “They’re very good; we’re using them all the time,” Dr. Petersen said. “But clearly there’s a broader swath of people with Alzheimer’s disease who may have benefited from this [GLP-1] class of drugs had it been successful.”
Disappointing Results
As such, the Alzheimer’s community was eagerly awaiting the trial’s results. But on November 24, 2025, Novo Nordisk announced that the two-year primary analysis of the results showed semaglutide wasn’t any better than a placebo. The planned one-year continuation of the trial was canceled.
“This is disappointing,” Dr. Petersen said. “Maybe I was too optimistic about it, but I thought we were going to see some kind of a clinical signal” that that GLP-1s would be able to help patients beyond type 2 diabetes and obesity.
Semaglutide has been shown to benefit cognition in the brain in animal studies. It’s also been shown to have anti-inflammatory effects. Inflammation can be a part of Alzheimer’s and other neurogenerative diseases, Dr. Petersen explained. In addition, obesity and higher glucose levels are risk factors for cognitive impairment, and maintaining a healthy lifestyle is recommended to prevent or delay dementia.
In Los Angeles, neurologist Zaldy S. Tan, MD, MPH, is director of the memory and aging program at Cedars-Sinai Medical Center. He, too, was disappointed in the trial results. His memory and aging program is a risk-reduction clinic for people with higher risk for developing dementia due to family history or having the APOE4 gene variant, which is the strongest genetic risk factor for late-onset Alzheimer’s disease.
Given the popularity of GLP-1s, particularly in California, his team had been telling patients to watch for the EVOKE trial results. “Some of our patients are already on GLP-1s, so we were thinking maybe it would have the additional benefit of reducing their risk for dementia. That was a bit disappointing to see that it did not pan out even with this large trial,” he said.
Looking Ahead: GLP-1s and Dementia
Dr. Petersen is looking forward to hearing more details about the EVOKE results. “Were there any cognitive measures that may have shown a signal? What about the biomarkers? I’m not willing to put it all to rest right now and say we’re done with that class of drugs. Let’s look more deeply at it.”
Dr. Tan agreed that this isn’t quite the “nail in the coffin” to abandon GLP-1 research in dementia. He pointed out that semaglutide is one of the GLP-1s that isn’t able to cross the blood-brain barrier, meaning not much of the medication penetrates into the brain, where it’s needed most.
He highlighted the GLP-1 drug dulaglutide (brand name: Trulicity), which is a weekly injection to treat type 2 diabetes. Dulaglutide has been among the most effective GLP-1 medications at crossing the blood-brain barrier. “Perhaps that will be another way to look at this is to look at other GLP-1s that have higher brain penetration than semaglutide,” Dr. Tan said.
The EVOKE trial results illustrate how complex Alzheimer’s disease is, Dr. Tan said. “It’s not just insulin resistance; it’s not just inflammation. It’s really a combination of multiple mechanisms at play that ultimately result in Alzheimer’s disease,” he said.
Thus, he believes future successful prevention or treatment for Alzheimer’s will be a combination of medications—drugs that will work together to attack the various pathways of how Alzheimer’s occurs in individuals. “That’s really the cure that we’re all waiting for,” he said.
