Dr. Heather Ferris: This is Your Brain on Ozempic

With scientists studying if new semaglutide weight loss drugs could potentially treat dementia, many have questions about the potential impact of Ozempic and Wegovy on the brain. Is it the benefits of a lifestyle intervention for people with risk factors like diabetes or obesity, or are these drugs doing something more for brain health? 

University of Virginia Endocrinologist Dr. Heather Ferris joined Being Patient founder Deborah Kan on Brain Talks to shed light on the current research on the impact of semaglutide drugs on brain health.  An Associate Professor and endocrinologist at the University of Virginia, she specializes in caring for older adults with diabetes. Ferris’s research lab focuses on understanding how changes in brain cholesterol and insulin signaling can impact cognitive decline and the development of Alzheimer’s disease. 

Watch the full live talk or read the conversation below:

Being Patient: What exactly are semaglutide drugs?

Dr. Heather Ferris: They are part of a class of drugs called GLP-1 receptor agonists. GLP-1 is a hormone that your gut makes after you eat a meal. It’s one of these hormones that tells your body nutrients are present. It helps to give you that signal that you’re full [and] that you’ve eaten, and it also helps to stimulate your pancreas to control your blood sugars. 

These drugs are mimicking that hormone and they’ve been made longer acting— so they stay in your system for a longer period of time. They’re designed to do those two things: to stimulate that pancreas so that it controls blood sugars better over even when you’re not eating, and then also to tell your brain, “I’ve eaten. I’m full. I don’t need to eat more.” That’s why they’re used, both for diabetes and weight loss.

Being Patient: When it secretes this hormone that basically says, “Okay, I’m not very hungry,” does it also impact other systems, such as how we metabolize glucose within our systems?

Ferris: The glucose itself doesn’t tell you you’re full. It doesn’t [do that] just like we don’t differentiate if you’re eating protein or a carbohydrate. Your brain doesn’t say, “Oh, I feel more full,” in the moment because of one or the other. Later on, you do because they stick around for different amounts of time. These hormones from your gut feed back to your brain to say nutrients are received.

Being Patient: How do semaglutide drugs work for people with diabetes?

Ferris: Type-two diabetes is sort of a combination. You’re not making enough insulin, and insulin is not working as well as it should because you’re resistant to insulin. So, weight loss helps reduce insulin resistance. Weight loss helps in managing diabetes, but this also has a direct action on the pancreas.

It’s signaling to the pancreas to make more insulin because the blood sugars are elevated, and that helps to overcome that resistance. It’s interesting when we use these medications at lower doses, [because] they’re really effective at bringing blood sugars down. Then, at higher doses, we start to see appetite suppression and people starting to lose weight. So, we have this immediate response that’s impactful for diabetes. 

It’s a really smart drug. We give people insulin injections all the time, but those can cause low blood sugar. The way it works at the pancreas [is that] it only makes your pancreas make [produce] insulin when the sugars are high, so it doesn’t cause low blood sugar. That’s why we can use it in people without diabetes as well.

Being Patient: Both obesity and diabetes are risk factors for Alzheimer’s disease. In a lot of cases, Alzheimer’s disease is called type-three diabetes because of this relationship. For people with obesity who are concerned with Alzheimer’s risk, would it be a good option to consider Ozempic or Wegovy to help reduce that risk?

Ferris: What’s right for any individual is always a discussion with your physician. That’s going to be different from person to person, but we know that, in general, people who lose weight have less of these chronic disorders— heart disease, neurodegeneration, [and] diabetes. We also know that lifestyle change is really hard. 

“It’s interesting when we use these medications
at lower doses, [because] they’re really
effective at bringing blood sugars down.
Then, at higher doses, we start to see
appetite suppression and
people starting to lose weight.”

Our brains and bodies were not built for this environment where we have so much around us. We’re designed for an environment of scarcity. There’s no reason why your body would say, “Oh, you have too much nutrition. We should stop now.” Because it may go away, and that used to be the case. There [were] harvests and then famines. Our bodies are designed to hold on to calories. 

When you gain weight, all those hormones are saying, “Okay, this is great. This is my new happy weight,” and then when you lose it, your body starts fighting you. That’s why weight loss is so hard, and people tend to “yo-yo” back and forth. 

It’s because as you lose weight, those hunger signals increase, so things like semaglutide drugs help suppress that drive to eat. People talk about the “food noise”; it takes away that food noise— thinking about food because [you] haven’t eaten in a while. It dampens that down for people and makes it more sustainable.

Being Patient: Tell me about glucose metabolism. The way that I understand it, glucose is a main source of fuel for our brains as we age. I’ve been told we don’t metabolize glucose as efficiently as we did in the past as we get older. Would these drugs possibly help boost the efficiency of metabolizing glucose, which we know would be good for our brain?

Ferris: There’s a couple of different pieces to that. We make less insulin as we age. Our pancreases wear out like our knees do, so this boost helps. Insulin, what that does is it unlocks your cells and lets the glucose in so that it can be used. So, it’s definitely helping in that aspect. Whether it’s helping at some of the other parts of glucose metabolism is a little bit trickier to understand. 

“Our brains and bodies were not built
for this environment where we have so
much around us. We’re designed
for an environment of scarcity.

Your mitochondria are very important for breaking down glucose. [They] also accumulate damage with age. There are lots of other steps, but clearly, you get the boost from more insulin, and then you also get that boost from reducing insulin resistance. That just has a lot of toxicity. The same fats that are causing insulin resistance are generally not healthy for your cells. I think the benefits are manyfold. 

Being Patient: What do we know about Alzheimer’s prevention and semaglutide, and what more do we need to find out?

Ferris: I’d say the strongest data that we have right now is in people with diabetes. These drugs have been around for over a decade now, and we can go and look into the epidemiologic evidence and see: these are the people with diabetes who took these drugs, and these are people with diabetes who didn’t. The ones who took these drugs have less cognitive decline. That right there obviously is a tremendous outcome, but this is in people with diabetes. 

So, studying people without diabetes requires more prospective, looking forward studies. Those are starting to happen. Very recently, just last month, there was a study released with an earlier generation called liraglutide. Rather than a once-weekly drug like Ozempic, this is a daily drug that is, again, used for either diabetes or obesity. They had 100 people in each group, and these were people who had early Alzheimer’s disease. The paper actually hasn’t been fully published. It was just announced at a meeting, so I haven’t seen all the data yet. 

Then again, these were people without diabetes who had had cognitive decline and were thought to have Alzheimer’s disease. They saw less brain atrophy in the people [who] took the liraglutide and some reduction in cognitive decline. Interestingly, there was no difference in glucose metabolism.

Being Patient: Why do you think there was less brain atrophy? Are there any hypotheses you would have to explain that?

Ferris: There’s been a lot of work in mice and in cells and dishes to suggest that these drugs protect neurons from cell death. The confusing part about those studies is that there are not much of these drugs that actually get into the brain.

I told you that these drugs signal to your brain to stop eating, but that part of your brain called the hypothalamus that controls appetite is really a very special part of the brain. It sees the blood circulation much more than the rest of the brain. These drugs are really large. They don’t cross the blood-brain barrier very well for all the rest of it. [What] we don’t know is: is there enough getting in there to really hit? 

The receptors for GLP-1 are in the brain, so they should be there for some reason, but these drugs don’t get in very well. It’s still an open question as to whether the benefits that we’re seeing are from the drug directly getting into the brain and affecting neurons and increasing their survival, for example, or again, if it’s just healthier metabolism overall, and that is benefiting the brain in some indirect way.

Being Patient: What is the direct link between metabolism and brain health? What do we know in terms of metabolism?

Ferris: Again, I’ll reference a clinical trial that I think demonstrates it really well. In Finland several years back, they had a clinical trial where they had patients [who were] all older adults at risk for developing dementia. They didn’t have it, but they had risk factors. 

Half of those patients [were] put into an intensive lifestyle intervention. They got nutrition counseling, went to the gym, and had supervised exercise several days a week. Their nutrition counseling was through group teaching. They had social interactions, which we know is really important for the brain, and then they had them do some brain games, too. 

“It’s still an open question as to whether the
benefits that we’re seeing are from the
drug directly getting into the brain and
affecting neurons and increasing their
survival… or if it’s just healthier metabolism
overall, and that is benefiting the
brain in some indirect way.”

This intervention was for two years, and at the end of two years, they saw that the people in this intervention group had a 20 percent less cognitive decline than the controls. Again, this is always the hard part about anything related to nutrition and metabolism— it’s not just one piece. Is it the food? Is it the exercise? Is it the social interactions? It’s really hard to separate these things out, but we know that these lifestyle interventions can have a pretty similar degree of effect as what we were seeing from the anti-amyloid antibodies.

Being Patient: We have a follow up question from our audience. How does ApoE status influence metabolism, especially among people who have two copies of ApoE4?

Ferris: I’m going to answer the flip first, which is that we know that people with ApoE4 benefit from these lifestyle interventions just as much as people without, and actually maybe even more—[which is] great news. 

ApoE is a cholesterol-carrying molecule that’s part of LDL cholesterol in your periphery. We do see changes in cholesterol in people with ApoE4 compared to [E2 or E3]. In the brain, ApoE is the main thing that transports cholesterol. In your blood, you actually have a bunch of different APOEs that all work together, so it’s a little different. The main effects on metabolism are probably these changes to cholesterol, and definitely that’s the main effect in the brain.

Being Patient: Do we know about the long-term impact of taking these drugs? What do we know about long-term efficacy and safety?

Ferris: As I mentioned, they’ve been around for over a decade. Something unique about the diabetes space is that there was a diabetes drug in the past that caused heart failure. So, after that, the FDA mandated cardiovascular safety trials for all diabetes drugs, which means that they had to test these all-new drugs on tens of thousands of people. 

“The FDA mandated cardiovascular
safety trials for all diabetes drugs, which
means that they had to test these all-new
drugs on tens of thousands of people.”

They’ve actually been studied long-term in very large groups of people, so much bigger studies than your typical drugs that get approved. So, we know that they’re quite safe. They reduce your risk for cardiovascular disease [and] they reduce your risk for kidney disease if you have obesity or diabetes.

Being Patient: What do we know about once you go off drugs like Ozempic or Wegovy?

Ferris: Unfortunately, what we know about stopping the drug is that those hunger signals tend to come back. Some people are able to wean themselves off these medications. Sometimes, it’s the help they needed to lose weight so they could become more active, and then that facilitated a big change in their lifestyle. In general, we think of these as long-term medications. This is not fixing the underlying problem, per se, because our bodies just strive for these higher weights.

Being Patient: For Alzheimer’s prevention, maybe it will just be one piece of that puzzle, right? A lot of scientists out there believe now it’s gong to be more of an HIV type of treatment, where you’re targeting different risk areas and managing them to decrease your risk. I’m assuming the research you’re doing is not a “silver bullet.” Is it more about how we minimize this type of risk that is associated with Alzheimer’s disease?

Ferris: In the end, you don’t care how much plaque you have in your brain, right? You care whether you can remember your grandkid’s name. That’s where I see these drugs fitting in. There’s actually not a super great correlation between how much plaque you have and how much memory loss you have. Obesity and diabetes are those things that make lower levels of plaque maybe more symptomatic. So, if we can reduce those symptoms, then that’s our end goal. 

Being Patient: What’s the correlation with obesity, diabetes, and plaque? For example if you’re on a semaglutide drug, does that mean that you’ll possibly have less plaque or formation, or is it preventing you from reaching the tipping point?

Ferris: I don’t think we really know that. I think it’s much more plausible that it’s just preventing us from that tipping point. It may have some impact on plaque and tangle development, but that’s not where most of us see its primary action.

Being Patient: The research is obviously coming in, and there’s more data to be found. If semaglutide drugs are proven successful through future studies, where do you see them fitting into Alzheimer’s prevention?

Ferris: I mean, I don’t think that it’s a medication that everybody should be on. We’re all potentially at risk for developing dementia at some point in time, and we can’t all be taking this medication. Right now, we don’t have the best biomarkers. They’re coming but it’s not like cholesterol, where we have a really easy measurement. 

“In the end, you don’t care how much
plaque you have in your brain. You care
whether you can remember your grandkid’s
name. That’s where I see these drugs fitting in.”

For the foreseeable future, that’s going to be a little bit of a difficult question to answer. The trials that are being done right now with semaglutide are in people with mild cognitive impairment. These are people who are already showing some signs and we’ll be getting those results in the next year or two. 

These will be larger studies, and I think [they] will be really informative as to the population of people who do not have diabetes or obesity. Should we be using these drugs to slow things down? I think the lifestyle part is, without a doubt. As much as you can do— that works for everybody, and it’s safe. As much as possible, we should be instituting as many lifestyle changes as possible, but I don’t think we’re going to start prescribing these drugs to everybody with a family history.

This interview was edited for length and clarity.

Katy Koop is a writer and theater artist based in Raleigh, NC.