The unexpected ways Ozempic-like drugs might fight dementia

National Geographic

15 hours ago

She can see the difference. Yazhou Li, a neuroscientist at the National Institute of Aging in Bethesda, Maryland, studies the effects of different drugs on brain impairments including traumatic brain injury, Alzheimer's disease, stroke, and Parkinson's disease. Working in the laboratory of neuroscientist Nigel Greig, Li and her colleagues test drugs on injured​ cells in dishes, run mice and rats through mazes, look at their brains. They are trying to find out if treatment with certain drugs might reduce the devastating effects of dementia or brain injury.
And the latest drug they're testing? Seems to work. The damage is 'much more intense without treatment, and much more subdued with treatment,' Li says, though she cautions, 'the animals aren't, like, suddenly normal.' But after injury or in models of Alzheimer's or Parkinson's, mouse brains show less inflammation when the animals are given this drug. They move better and solve mazes faster than animals that don't receive the treatment.
What's surprising is the drug in question. Li has been dosing the mice with one of the GLP-1 agonist drugs—the ​​suddenly-everywhere class of drugs that includes Ozempic, Wegovy, and Mounjaro. Originally designed to treat diabetes and help with weight loss, GLP-1 (glucagon-like peptide 1) agonists are being tested against a number of diseases as scientists explore their wide-ranging effects—and pharmaceutical companies look to make even more profits from the burgeoning wonder drugs.
The drugs are currently in their silver bullet phase. No one doubts that they reduce insulin resistance, effectively treating ​t​​​ype 2 diabetes. But ​t​​ype 2 diabetes isn't just an insulin or blood sugar disease—it has many other possible effects. One of them: a higher risk of dementia as patients age.
And as Li and a cohort of cognitive researchers are discovering, GLP-1 drugs might help reduce that risk. But how they work, how well they work, and who exactly will benefit from them are harder questions to answer. Diabetes and dementia
Insulin is a vital molecule. After a person eats, beta cells in the pancreas release insulin into their blood. The hormone hits cells throughout the body, making them move glucose transporters to the cell membrane—opening the door for sugar to enter cells, which drives down glucose levels in the blood.
The brain, however, ​​is a sugar hound​, using as much as 20 percent of ​​the glucose ​we produce. Glucose transporters are always present on brain cells, keeping the doors permanently open to sugar. But this doesn't mean insulin isn't important for our brain.
In the brain, insulin is 'more of a growth factor,' says Christian Hölscher, a neuroscientist at the Henan Academy of ​Innovations in ​Medical Sciences and chief scientific officer at Kariya Pharmaceuticals, a drug company developing GLP-1 agonists to treat neurological diseases. It 'supports and drives gene expression linked to cellular growth, cellular repair, energy utilization.' In other words, it doesn't make cells take up sugar. Instead, it has another important task—helping to keep brain cells fully functional.
This means if the brain becomes resistant to insulin—as it does with diabetes—the results can be catastrophic. 'Synapses [the connections between brain cells] burn through tons of glucose,' Hölscher explains, 'so if anything compromises that, then you will see the effects quite clearly.' Neurons will stop maintaining their synapses. 'Synapses stop working, and eventually they disappear, and then you're well on your way to Alzheimer or Parkinson's,' Hölscher says.
A brain losing connections is a brain in distress, and inflammation abounds. 'There's inflammation in the brain with virtually every acute or long-term neurodegenerative disorder,' says Greig. Inflammation and insulin resistance in the brain are all linked to Alzheimer's disease, Parkinson's, and dementia.
It's a connection that clinical neuroscientist Michal Schnaider Beeri has seen firsthand. The director of the Herbert and Jacqueline Krieger Klein Alzheimer's Research Center at Rutgers University in New Jersey has been following a large cohort of Israeli men for decades, looking at risk factors for issues like heart disease. As the years go by, she has seen something else: Those who developed ​t​ype 2 diabetes in midlife were nearly three times more likely to develop dementia. 'Diabetes, per se, is related to faster cognitive decline, mild cognitive impairment, and high dementia risk,' she says.
Perhaps due to the drastically different roles of insulin in the body and the brain, insulin resistance in one doesn't always mean insulin resistance in the other. 'There are plenty of studies now that [show] in individuals with Alzheimer's disease, they have insulin resistance solely in their brain,' says Elizabeth Rhea, a neuroscientist at the University of Washington in Seattle. Which means they don't have ​​high blood sugar​, or require diabetes medicine. ​To make matters more complicated, insulin resistance in the brain isn't detectable with a blood test—it requires brain tissue, something that's basically impossible to get from live patients.
For diabetics, the good news is that not everyone with insulin resistance in the body has to panic about their brains. But the difficulty of detecting brain insulin resistance also means that it can wreak havoc unnoticed for years, until the effects are severe enough to become apparent. ​
By then, it's often too late, says Natalie Rasgon, a neuroendocrinologist at the ​ Ichan ​ ​Icahn ​School of Medicine at Mount Sinai ​in New York City ​and director of the Center for Neuroscience in Women's Health at Stanford University. 'When you have a neurodegenerative disease, the train has left the station,' she says. 'You could try to mitigate the course [of the disease], but it's not a curable disease.' Saving at-risk neurons
Scientists have known since the 1990s that insulin can improve the lives of cells affected by Alzheimer's disease, fighting against the clumps of insulin-blocking, synapse-clogging beta-amyloid that build up outside of diseased cells. More insulin could help the brain fight back. A few puffs of nasal insulin, it turns out, can improve memory in people with Alzheimer's, as well as in healthy older adults. 'Even with relatively short exposure times, just a few weeks, you could shift the needle on cognition or short-term memory and some biomarkers,' Hölscher says.
The connection between improved insulin signals and cognition became visible in Schnaider Beeri's aging men. The researcher and her colleagues began to realize that brains with Alzheimer's looked different not only based on whether the patients had diabetes, but on whether they'd ever been treated for it. For patients who had been in treatment, their brains sometimes showed 'a little less' damage than the team expected. Schnaider Beeri's conclusion: 'Maybe the drugs for diabetes are doing something to [the] pathology of Alzheimer's.'
Other scientists and drug companies were quickly coming to the same conclusion. Surveys across more than ​one ​million patients indicated that diabetics on metformin (Glucophage) and sodium-glucose cotransporter-2 inhibitors (drugs like Jardiance) developed dementia less frequently. Ozempic and the brain
As much as GLP-1 agonists like Ozempic and Wegovy have gained cultural relevance as weight-loss drugs, they were originally approved to treat diabetes. The GLP-1 receptor in cell membranes binds hormones released after meals, stimulating the production of insulin. Drugs that activate the GLP-1 receptor, then, also promote insulin release.
GLP-1 receptors are found in the brain, where they help brain cells grow and maintain their connections. And researchers like Greig, Li, and their colleagues have shown that the GLP-1 agonists do reduce brain injury in animal models ​​of​ stroke, traumatic brain injury, Parkinson's, Alzheimer's, and ALS.
Meanwhile, when it comes to humans, Rasgon and her colleagues showed in 2019 that 12 weeks of liraglutide (Victoza)—another antidiabetic medication—improved connections between the memory-critical hippocampus and other brain regions, whether the participants were insulin resistant or not. ​Even better​, a 2020 Italian study showed that liraglutide could improve memory scores in diabetes patients.
Schnaider Beeri is in the midst of a study funded by the Alzheimer's Association—due to end in 2027—that gives diabetic patients combinations of the GLP-1 agonist semaglutide (Ozempic, Wegovy), as well as intranasal insulin in older adults who are already cognitively impaired, to find out how well the treatments might rescue their brain function.
Other scientists are pooling data from large cohorts—often from studies by pharmaceutical companies eager to find new markets for already popular drugs—to examine how many people who received GLP-1 agonists went on to develop dementia.
In an Eli Lilly-funded study known as REWIND, dulaglutide (Trulicity) reduced mild cognitive impairment rates by 12 percent. In a study funded by Novo-Nordisk, the Dutch pharmaceutical company that manufactures Ozempic, people treated with GLP-1 agonists ended up with an 11 percent decrease in risk for dementia. 'I think it's good enough to keep looking,' says Christian Torp-Pederson, the cardiologist at Nordsjællands University Hospital in Denmark ​who ​​helped lead ​the study. Go slow, go steady, do studies
With GLP-1 agonists already helping millions of people manage diabetes and weight loss, the added bonus of lowering the risk of dementia might seem like yet another reason to start taking one. But for otherwise healthy people, the science is not as clear-cut.
First, the effect on cognition in nondiabetic brains might be too minor to matter. 'The majority of patients in the GLP-1 studies, they had a prior myocardial infarction or similar,' Torp-Pedersen says. 'So they were quite sick. And it is in this group we see a benefit.'
And not every study even sees the same benefits, notes Riccardo De Giorgi, a psychiatrist at the University of Oxford in England. Some show differences in inflammation, others in cognition; some studies show no changes in cognitive function at all after treatment with a GLP-1. ​​​​
'This topic has become so extremely popular, people obviously are getting quite excited,' De Giorgi says, adding, 'but sometimes that means doing things a bit quickly and maybe looking for a big, sensational title—a big message in the news, rather than doing some small, incremental, step science.' He is working on a study with a single injection of semaglutide in healthy patients. 'We are trying to establish whether these medications have any effects on…reward, impulsivity, emotional processing, memory and so on,' he says.
Whether a particular drug has any effect will depend on if it gets into the brain at all, Rhea notes. The brain is protected by the blood-brain barrier—a thin layer of cells that carefully filters everything passing from the bloodstream to the brain. It has transporters for some molecules and allows others through—but many need not apply.
Rhea and her colleagues have shown that while some GLP-1 agonists whoosh into the brain, others, like tirzepatide (Mounjaro, Zepbound), never cross at all. It's possible, she says, that for cognitive benefits, existing drugs might need to be tweaked to emphasize their effect on the brain versus the body.
Of course, it would be helpful if scientists knew exactly how GLP-1 agonists were having an effect on dementia risk. Maybe insulin resistance is driving neurodegeneration, and GLP-1 agonists just make insulin signals better. 'I believe when these drugs are moving in the brain, insulin resistance is reversed, which in turn enhances cognition,' Rhea says.
Others, like Greig and Li, think inflammation is the cause of cognitive decline. 'The inflammatory process in the brain is a double-edged sword,' Greig says. 'It's essential to be triggered for the healing process.' Immune cells in the brain turn on in response to injury. But they need to turn off or they'll do more harm than good. In neurodegenerative diseases, he says, the immune cells might be stuck in a pro-inflammatory state. It's possible GLP-1 agonists might quiet these cells, keeping them from damaging the very neurons they're meant to protect.
Schnaider Beeri thinks damage to blood vessels in the brain could play a role. Insulin receptors sit on blood vessels. Insulin resistance could be 'impairing the vessel function. It could be impairing the vessel structure,' she explains. People with ​t​​ype 2 diabetes are also more susceptible to strokes and brain bleeds—which can in turn kill brain cells. As GLP-1 improves insulin signaling, the vessels could be able to function again.
The answer to how GLP-1 agonists affect the brain could, of course, be all of the above. Insulin resistance could increase inflammation, which could impair blood vessels and eventually damage cells. Blood vessels could develop insulin resistance, cause cell damage, and inflammation could be the result. GLP-1 agonists could influence all of these processes.
And while some GLP-1 drugs have been on the market for decades, scientists still aren't sure of the long-term effects, Rhea adds. It's far too soon to recommend that the average person start taking one as a hedge ​to ​protect their brains.
'That type of question appeared first with statins, you know, to lower cholesterol: 'Why don't we put statins in the drinking water?' We could put GLP-1s in the drinking water,' Torp-Pedersen says. But we don't put pharmaceuticals in the drinking water for good reason: 'We have yet to find a drug that's never dangerous.'
GLP-1 agonists have plenty of unpleasant side effects: Nausea and constipation are common. ​​​​And those are the ones we know about. As more and more people take Ozempic, Wegovy, Zepbound, and the like, rare side effects—like pancreatitis or even sudden blindness—will probably become increasingly apparent.
Even if it never makes sense for the average American to take GLP-1 agonists like they would take daily vitamins, the upside is considerable: An increasing body of research shows how these drugs might make a crucial impact in how we manage and mitigate the brutal effects of neurological disease. According to Alzheimer's Disease International, more than 55 million people were living with dementia in 2020—and that number will roughly double every 20 years. Having a drug on the shelf that might lessen the effects of an increasingly prevalent enemy would be a win-win. But there's still plenty of work to be done by ​​​​​lab scientists and clinicians alike​ before anyone can celebrate.
This article is part of Your Memory, Rewired, a National Geographic exploration into the fuzzy, fascinating frontiers of memory science—including advice on how to make your own memory more powerful. Learn more.