When you hear the word Ozempic, weight loss immediately comes to mind. Belonging to a class of drugs called GLP-1 agonists, the drug has taken the medical world (and the internet) by storm by helping people manage diabetes, lower their risk of heart disease, and lose weight quickly.
The drug may also protect the brain from dementia. In a clinical trial involving more than 200 people with mild Alzheimer’s disease, daily injections of the GLP-1 drug for a year slowed cognitive decline. In a series of tests assessing memory, language skills, and decision-making, participants who took the drug were sharper for longer than those who took a placebo, which was a similar-looking, nonfunctional injection.
These results are the latest from the Evaluating Liraglutide in Alzheimer’s Disease (ELAD) study, led by Dr. Paul Edison of Imperial College London. The study, which began in 2014, builds on years of mouse studies that have shown that liraglutide, a GLP-1 drug already approved in the United States for weight loss and diabetes management, protects the brain.
In Alzheimer’s disease, nerve cells die and the brain gradually loses volume. In this experiment, liraglutide slowed that process, causing about 50% less volume loss in several brain regions associated with memory compared to a placebo.
“We are in a time of unprecedented hope, with new therapies in various stages of development that could slow or prevent cognitive decline from Alzheimer’s disease,” Dr. Maria C. Carrillo, chief science officer and medical affairs officer for the Alzheimer’s Association, said in a news release. “This research provides hope that more options are on the horizon that could alter the course of the disease.”
The results were presented last month at the Alzheimer’s Association International Conference.
Back to basics
The search for a cure for Alzheimer’s disease has been fraught with failure. Most treatments aim to break down toxic protein clumps that build up inside the brain. Breaking them down is thought to prevent nerve cells from dying.
Some have had limited success. Last month, the U.S. Food and Drug Administration approved a drug that breaks up clumps in people who are already experiencing symptoms in the early stages of the disease. A few weeks later, the European Medicines Agency refused to approve another drug that targets clumps, saying the benefits of delaying cognitive decline were not balanced by the risk of serious side effects, including brain swelling and bleeding.
Other scientists have looked elsewhere, particularly at diabetes. Insulin helps keep the brain healthy, and type 2 diabetes is a risk factor for developing Alzheimer’s disease. Could the brain be protected by manipulating the body’s metabolism instead of directly breaking down the brain’s protein clumps?
Introducing GLP-1 drugs. These drugs mimic the hormones released in the stomach after a satisfying meal, tricking the brain into thinking it is full. In other words, these drugs not only affect the gut, but also change brain function.
In mice models of Alzheimer’s disease, daily injections of liraglutide for eight weeks prevented memory problems. Their nerve cells also thrived. Synapses, the junctions that connect brain cells, were still able to quickly form neural networks, especially in areas damaged by the disease. Surprisingly, toxic protein clumps were reduced by up to 50 percent, and inflammation was reduced.
Liraglutide wasn’t just effective on neurons. Another study in a mouse model of Alzheimer’s showed that it rapidly modulated the metabolism of a specific type of stellate brain cell that supports neurons. These cells don’t form neural networks, but they help provide energy. In Alzheimer’s, the cells don’t function normally, but liraglutide reversed the decline. In the mice, the drug improved the cells’ ability to support neurons, allowing them to thrive and connect with other neurons. The brain was also able to better utilize its main fuel, sugar, to create new neurons in areas important for memory.
But as the field disappointingly knows, mice are not people. Many promising treatments on mice have failed in clinical trials, earning these efforts the nickname “the dream graveyard.”
trial
Edison was tasked with extending the study from mice to humans. In 2019, he and his colleagues laid out detailed plans for a clinical trial to measure the effects of liraglutide in people with mild Alzheimer’s disease. The study, called ELAD, was to be randomized and double-blinded—the gold standard for clinical trials. In this case, neither the doctors nor the patients would know who was getting liraglutide or a placebo.
They recruited 204 people to receive daily injections of liraglutide or a placebo for a year. Before the trial, each person underwent an MRI scan to map the structure and volume of their brains. Another scan recorded brain metabolism, and a series of memory tests detailed cognition. These tests were repeated at the end, with a safety check in between to check for side effects.
The study had several goals. One was to determine whether liraglutide increased brain metabolism in areas heavily affected by Alzheimer’s disease—areas involved in learning, memory, and decision-making. Another was to examine brain volume, which decreases as the disease progresses. Finally, cognitive tests of memory, comprehension, language, and spatial navigation were assessed.
People who took liraglutide had nearly 50 percent less brain volume loss, especially in areas related to reasoning and learning. “The slower brain volume loss suggests that liraglutide protects the brain in the same way that statins protect the heart,” Dr. Edison said.
Liraglutide also improved cognitive function. When comparing pre-test, midpoint, and final scores, those who received the drug declined 18% more slowly than those who received a placebo. However, the drug did not affect brain metabolism.
Side effects were relatively mild, the most common being nausea. More serious side effects were not specifically listed, but occurred in 18 patients, but were likely unrelated to the treatment, according to Addison.
To be clear, the team presented their results at a conference and have not yet been formally verified by other experts in the field. But they do help build evidence that GLP-1 drugs slow cognitive decline. A study in Sweden in June conducted a mock trial that assessed cognition after giving people with type 2 diabetes GLP-1 or two other types of drugs. Using health data records from more than 88,000 participants who were followed for four years, the GLP-1 drugs were more effective than the other two diabetes drugs at curbing dementia risk.
We don’t yet know how liraglutide protects the brain. Studies in mice suggest it may work in several ways, including by reducing inflammation, clearing toxic protein clumps and improving communication between neurons, Edison said.
But the idea is gaining momentum. A late-stage clinical trial of semaglutide (the chemical in Ozempic) called EVOKE Plus is underway. The study will take about three and a half years and is expected to enroll 1,840 people with early-stage Alzheimer’s disease. It is expected to be completed by the end of 2026.
“The advantage of repurposing drugs that are already approved for other conditions is that it provides data and experience from previous studies and real-world use, so we already know a lot about their actual effectiveness and side effects in other conditions,” Carrillo said.
Image credit: Maxim Berg / Unsplash
