[gentle music] - Katie Gletty-Syoen: Hello, and welcome to the Village of McFarland Municipal Center.

My name is Katie Gletty-Syoen.

I'm the director of McFarland Senior Outreach Services.

And I'm so pleased to see you all here today.

Today, we're welcoming doctor Carol Van Hulle, associate scientist at the University of Wisconsin-Madison School of Medicine and Public Health, who is here through the Badger Talks, the speaker bureau for the UW-Madison campus.

For more information on this great free resource for the state of Wisconsin, please visit badgertalks.wisc.edu.

Now, I'm pleased to introduce Dr.

Carol Van Hulle, who will be presenting today on vascular contributions to dementia.

Dr.

Van Hulle received her PhD in psychology with an emphasis in quantitative genetics from the University of Colorado.

She is now an academic staff scientist with the Alzheimer's Disease Research Center at the University of Wisconsin-Madison.

Her research focuses on subject memory complaints and cerebrospinal fluid-based biomarkers for early detection of Alzheimer's disease.

Please join me in welcoming Dr.

Van Hulle.

[audience applauds] [laughs] Hello, welcome.

- Dr.

Carol Van Hulle: Hi, everybody.

I wanna thank you so much for coming out today, and I'm really grateful for the opportunity to speak to you.

I am Dr.

Carol Van Hulle, sorry.

[laughs] And I titled my talk, "Vascular Contributions to Dementia," but I really should have called it "Vascular Contributions to Dementia Risk."

So, we're gonna be talking today about things that might raise your risk of developing dementia, and hopefully things that will lower your risk for developing dementia.

So, I am a staff scientist with the Alzheimer's Disease Research Center.

I joined them in 2017.

Prior to that, I was studying child development.

So, I went from one end of the age span to the other end of the age span.

And my research does broadly focus on identifying early signs of Alzheimer's disease.

But the research at our center runs the gamut from basic science all the way through to dementia care and caregivers.

I like to start my talks with this slide because I'm very proud of the work that we do at the Alzheimer's Disease Research Center, but also because I wanna be very clear that I am speaking from the perspective of a researcher and a statistician.

I am not someone who has had experience caregiving for someone with dementia, and to my knowledge, I'm not living with dementia.

[knocks on podium] [audience laughs] As a stats person, also, I really love graphs, and I do have quite a few graphs throughout this presentation.

I will try to orient you to the graph so they make sense to you, but I want you to focus on the bars or the lines.

'Cause I'm not trying to fill your head with a lot of numbers.

I just wanna give you a quick snapshot.

That said, we are gonna start with a few numbers.

I always also like to start by acknowledging that dementia touches all of us.

Whether you are living with dementia or a caregiver of someone demential, or not, dementia is in our communities.

It affects our neighbors, our families, our friends.

It is a difficult disease that requires a lot of unpaid caregiving.

It is a very costly disease, and it is the seventh leading cause of death for people over the age of 65 in Wisconsin.

However, the number one leading cause of death for men and women over the age of 65 in Wisconsin continues to be heart disease.

So, for people who might be unfamiliar with the lingo, when I'm talking about vascular anything, vascular problems, vascular disease, I'm referring to blood vessels.

When I use a word that starts with cardio, I'm referring to the heart.

And when I use a word that starts with cerebral or cerebro, that pertains to the brain.

So, my immediate supervisor, Dr.

Cindy Carlsson, is a geriatrician, and I've heard her say off the cuff, you know, in casual conversation a few times, that people are much more motivated to take care of their brains than they are to take care of their hearts.

So, the good news is that you can do both at the same time.

So, for those of you who have to leave early or who fall asleep, the main message for today is that having healthy blood vessels contributes to having a healthy heart and a healthy brain.

And regardless of what else-- health issues you may be facing, having healthy blood vessels, especially in the brain, improves overall quality of life.

This is the outline for the rest of my talk, so I wanna start by defining dementia.

I wanna talk about some of the risk factors for dementia.

And then, I'll talk about vascular health and how it relates to Alzheimer's disease.

I'll talk a little bit about what we know about therapies that target vascular risk factors and cardiovascular health, and ways that we can improve vascular health in the heart and the brain.

So, what is dementia and how is dementia different from Alzheimer's disease?

This is a question we get a lot.

You probably already know the answer, but for those who don't, everyone likes to use this umbrella metaphor 'cause it is a really good metaphor.

Dementia is an umbrella term.

It is a general term for progressive loss of thinking, remembering, and reasoning skills to the point that it interferes with the person's ability to perform their daily tasks and to care for themselves.

There are many, many causes of dementia, including reversible causes, including sleep disorders and some vitamin deficiencies.

If you are concerned about your thinking skills or you are concerned about someone else's thinking skills, it's very important to go see a doctor and have a full physical to rule out some of these reversible causes.

However, the most common causes of dementia are the progressive and irreversible neurodegenerative disorders that are listed here on this slide.

The numbers at the bottom indicate the number of dementia cases that are due to these different neurodegenerative disorders, and you can see that Alzheimer's disease is far and away the most common type or most common cause of dementia, followed by vascular dementia.

And each of these different neurocognitive disorders has characteristic brain changes that go along with them.

But we've known since the 1920s that people who are diagnosed with Alzheimer's disease on autopsy also show signs of vascular dementia.

However, I think for a long time it was under the pervasiveness of poor cerebrovascular health and people with Alzheimer's disease was underappreciated.

So, I want to describe the brain changes that characterize Alzheimer's disease, in particular, because it is the most common cause of dementia and because it's the one that I study.

So, here we have a depiction of two brains.

The one on the left is a depiction of a healthy brain, and the one on the right is an illustration of the brain of someone with Alzheimer's disease.

And if we could take this little tiny red square.

If you can see that, and zero in on it, we would see the neurons.

That's that purple, those purple structures.

And in this healthy brain, you can see the neurons are kind of hanging out in what looks like clean tissue.

On the other side, when we look at that same area in a person with Alzheimer's disease, we see that around the neurons, we have these brown clumps that represent amyloid plaques.

And if you look closely, and it might be hard to see from where you are, there's purple squiggles inside the neurons.

And that represents tau tangles.

And these are the two hallmarks that define Alzheimer's disease.

Amyloid and tau exist in our brains naturally.

When amyloid becomes misfolded, it gets very, very sticky.

And that's why it forms into those plaques.

Tau exists in our neurons.

It helps our neurons communicate with each other.

When it becomes misfolded, it forms those tangles and it interferes with the communication between our thinking cells or our neurons in the brain.

And these two processes can be toxic, and that can lead to the death of neurons and other cells in the brain.

So, here we're looking at an MRI image.

And we use MRI to look at the structures of the brains of individuals.

And again, on the left, you see a healthy brain.

It's very full.

It's filling the whole skull cavity there.

Whereas the brain of the person with Alzheimer's disease, you can see there's a lot of space in and around the brain.

The arrows are pointing to an area called the hippocampus.

And the hippocampus is heavily involved in memory.

And it's one of the first areas where we see shrinkage or atrophy in Alzheimer's disease.

A lot of information that we have on brain changes related to all of these different, all the different neurocognitive or neurodegenerative disorders that I showed you earlier, come from studies of postmortem brain tissue.

And that's true for Alzheimer's disease as well.

We're still learning a lot from postmortem brain tissue.

But we have come an incredibly long way in being able to detect amyloid plaques and tau tangles in people while they are alive.

So, one of the primary ways we do that is through PET imaging.

So, the top here is a example of a PET scan for amyloid.

And you can see where it's labeled positive scan.

There's a lot of yellow and red.

That's an indication that this person has a lot of amyloid.

The other scan, you see mostly green and blue.

On the bottom is an example of a tau PET scan or a PET scan for tau tangles, and where it says positive scan, you see a lot of red right here in this area, kind of above their ears.

That's the medial temporal lobe.

And tau has kind of a very characteristic way of progressing as Alzheimer's disease progresses.

So, we start to see it here in this area above your ears first.

And then, as the disease progresses, the tau tangles spread throughout the rest of the brain.

We can detect tau tangles, or misfolded tau proteins and misfolded amyloid proteins in cerebrospinal fluid and in blood.

And so, this has really led to a lot of advancement in understanding Alzheimer's disease.

So, this is a kind of complicated slide.

I wanna walk you through it.

The top line there is just depicting normal aging.

Right, so we have thinking skills doing the side here, where high is good and low is worse.

And with typical aging, we all lose some of our thinking and skills and our memory.

I have terrible word-finding difficulties myself.

We forget names.

We might forget to pay a bill or something like that.

All of that is very normal.

The red line is depicting a decline in thinking skills due to Alzheimer's disease in this particular case.

So, what I want you to take away from this slide is that we start to see brain changes.

So, you can see the accumulating brain changes on the bottom kind of correspond to the decline in cognition and thinking skills on the top.

We see these brain changes start before we actually see any change in cognition or any deviation from typical aging.

And that typically star-- what that does, I should say, start with the accumulation of amyloid in the brain.

And then we start to detect tau tangles in the brain.

And then we start to see shrinkage in different areas of the brain, like I said before, typically in the areas related to memory.

And as those brain changes become more severe, then we start to see more severe symptoms of mild cognitive impairment and dementia.

So, the National Institute on Aging and Alzheimer's Association has guidelines for staging the brain changes that characterize Alzheimer's disease, starting with nothing, and then again we see amyloid, and then we have detectable tau.

And then we see tau begin to spread and spread and spread throughout the brain.

We also have in these columns guidelines for staging the symptoms of dementia that go along with Alzheimer's disease, from no impairment to subtle changes of impairment, where we think we're detecting subtle changes in people's cognitive ability or thinking skills, but they're not, like, diagnosable symptoms, to mild cognitive impairment, to dementia.

And we can try to map these things onto each other.

So, these gray boxes represent people whose symptoms match what we would expect based on their brain changes, and vice versa.

A study called the Alzheimer's Disease Neuroimaging Initiative, ADNI, it's a very famous study, decided to try to place all of their participants somewhere on this grid.

So, how many or what percentage of participants do you think fell neatly in these gray boxes, where their symptoms match their brain changes?

And your options are 40%, 60%, or 80%.

And you can just shout it out.

What do you think?

- Attendee 1: 80%.

- 80%.

- Attendee 2: 40%?

- 40%?

Yes, it's closer to 40%.

Less than half of individuals' symptoms match their brain changes.

Some people end up better, doing better than expected based on the brain changes that we see.

And we call that brain reserve or cognitive reserve.

And that's the ability to maintain function in the face of these brain changes.

Unfortunately, it's about, like, 10% to 15%, which means that another 45% or so individuals end up in this pink range, where they're doing worse than expected, based on just the Alzheimer's disease-related brain changes, and that's often due to co-occurring vascular dementia, or damage to blood vessels that is characteristic of some types of vascular dementia.

So, let's take a look at the blood vessels in the brain.

I really like this image.

These are an image of blood vessels in the brain of a living person.

This is a very difficult type of scan to do.

I like that it really shows the outline of the brain.

You can see how enriched the brain is with blood vessels, although, to be honest, it doesn't even do it full justice.

Our brains have used so much blood.

Our brains are a small part of our body, 2% of our body weight on average, but it receives an enormous amount of our energy and cardiac output.

We need healthy blood vessels, flexible blood vessels, to deliver oxygen and nutrients to the areas of our brain that need it.

We also need flexible and healthy and strong blood vessels to clear out waste from our brains so that misfolded proteins don't build up.

Sorry, I meant to mention the blood-brain barrier.

So, the larger vessels are on the outside of the brain, and then as they go into the substance of the brain, they get tinier and tinier and tinier until we get to the blood-brain barrier.

And this is the tiniest part.

And the blood-brain barrier protects the brain from toxins or bacteria or viruses that are in the bloodstream.

And it also aids in removing misfolded proteins, like amyloid plaques.

So, it's very important in maintaining the health of our brains.

The integrity of that blood-brain barrier is important to maintaining the health of our brains.

So, let's talk about some of the things that can go wrong with our blood vessels and contribute to risk for dementia, either solely due to vascular dementia or as a contributor to Alzheimer's disease.

So, I'm gonna go counterclockwise, starting with B here on top.

This arrow is pointing to an area where there was a stroke.

Strokes are a common cause of vascular dementia, although the symptoms of dementia don't necessarily show up right away after a stroke.

It can actually take up to a year after a stroke for symptoms of dementia to appear.

In A, those arrows are pointing to what we call white matter hyperintensities.

We call them that because they show up as bright white on these images.

These are MRI images, again, so we're looking at the structure of the brain.

White matter hyperintensities are thought to be indicators of damage to the white matter tracts in our brain.

So, the white matter tracts in our brain help the thinking cells communicate with each other.

And we think of the white matter as like the coating on a wire.

So, you need that coating on the wire for the electricity to get through properly.

We need good, healthy white matter tracts in order for our cells to communicate with each other well.

The bottom, C here, these arrows are pointing to areas of microbleeds.

They show up as little black dots on these scans.

Microbleeds can occur because of something called cerebral amyloid angiop-- angiopathy-- angiopathy?

That is the buildup of amyloid in the walls of the blood vessels.

And that can weaken those blood vessels and then lead to that bleeding.

And then finally, in D here, we have arrows pointing to-- these are called lacunar infarcts.

So, infarcts is another word for stroke or blockage.

Lacunar just is a reference to the smaller vessels.

So, this is blockage in smaller vessels in the brain.

There's also microinfarcts, which is blockages in even tinier little vessels in the brain.

And microinfarcts tend to be more diffuse throughout the brain.

These last three, A, C, and D, often fall under the umbrella term small vessel disease because they occur in those smaller vessels.

So, just like we can have thickening and stiffening of blood vessels to the heart, we can have thickening and stiffening of blood vessels in our brains due to the same plaques that build up in the vessels to our heart.

We can have hypert-- We can have high blood pressure in our brains, just like we do in our bodies.

That's called hypertensive arteriopathy.

And a really important but very hard to detect vascular risk factor is the breakdown of that blood-brain barrier.

And that can lead to harmful substances from the arteries getting into the brain.

And it can lead to buildup of misfolded proteins that interfere with the function of our brains.

All of these changes, by the way, that I'm talking about, happen quite naturally with aging.

They're very common in people over the age of, like, 85 or 90.

They usually aren't enough-- aren't severe enough to lead to dementia.

Currently, we do not have ways to develop these-- to measure these vascular problems in cerebral spinal fluid or in blood.

And that's a big barrier.

These MRI images are great, but they are time-consuming and they are costly.

And if you have metal in your head or certain types of implants, you can't have an MRI.

So, we're working very hard on finding alternate ways to detect these vascular brain changes.

So, I'm gonna pivot now and talk about some of the main risk factors for Alzheimer's disease.

And the absolute number one biggest risk factor for Alzheimer's disease and vascular dementia is age.

So, what you're seeing here on the bottom are age group divided up into decades, starting with ages 60 to 69 and ending with people over the age of 90.

The side is the proportion of the population that is living with dementia, either vascular dementia in green, Alzheimer's disease in teal, or any type of dementia in red.

And you can see when you start out in that 60 to 69 range, like, maybe 2% of the population is living with dementia.

By the time you get to 90, the percentage of people living with dementia has gone up quite a lot.

I do wanna point out, though, that top dot at 90-plus tops out at around 37% or 38%.

That's a lot.

But that means more than half of individuals in that age range don't have dementia.

So, age alone-- There's a sense, I think still, that if you just live long enough, you're gonna get dementia.

It's really not true.

Aging is definitely a risk factor, but aging alone is not going to cause dementia.

We are seeing a lot more people living with dementia, and that's simply because we are, in fact, living longer as people.

The oldest segment of the population, the segment that's most at risk for developing dementia due to age, is the fastest-growing segment of the population in many places around the world and in some surprising places around the world.

This is a good thing, in general.

We want people to live longer, but we want people to have-- to be healthy well into old age.

And you'll hear people now talk about healthspan in addition to lifespan.

To some extent, we're succeeding in living healthier as we age.

So, this is a graph.

It's bars instead of lines.

But it's similar to that graph I showed you before.

So, these are different age groups across the bottom.

And then the prevalence of-- or the percent of people living with dementia in each of those age groups is shown kind of on the side.

Yellow represents the number of people who were living with dementia in 2002, and blue represents the percent of people living with dementia in 2012.

So, this data was taken from the Health and Retirement Study.

This is a huge study.

And you can see that, in every age group, including the oldest age group, the number of people living with dementia actually declined over time as a percent of the population.

And this has been shown in different studies spanning different time periods.

So, that does give us some hope.

I apologize for how tiny the font is on this particular figure.

[chuckles] In 2020, the medical journal Lancet commissioned a review-- it's kind of a famous review now-- of the most important risk factors for dementia, and they assigned a percent value to each of those risk factors.

So, they said, "How much of dementia is due to this or that risk factor?"

The big gray path represents 60% of dementias that are due to factors that we can't change.

And those are things like our age, our genetics or family history, our sex, and our race.

So, women get-- develop dementia and Alzheimer's disease in particular more often than men.

And people who identify as African American or Latino develop Alzheimer's disease more often than people who identify as white.

These colored paths, though, represent what we call modifiable or potentially modifiable risk factors, and they include several cardiovascular risk factors.

Things like high blood pressure, obesity, high cholesterol, and diabetes.

Why is that?

Well, we have this idea now of the heart-brain axis, where cardiovascular diseases result in damage to or decline in blood flow to the brain.

This leads to damage to the blood vessels in the brain, which leads to cognitive impairment.

People who are cognitively impaired may not engage in typic-- in, you know, heart-healthy behaviors, which leads to greater cardiovascular dysfunction.

And we go around.

So, I wanna give a couple of examples-- an example from two studies showing the importance of blood flow and how that's related to Alzheimer's disease.

This is a study that was conducted at our center by my colleague, Dr.

Rivera-Rivera.

And he used an imaging technique called 4D-Flow.

And that measures the amount of blood flow through the larger vessels in the brain.

These are vessels that are found kind of at the base of the skull and the sides of the brain.

And he compared blood flow in these different vessels in people who had Alzheimer's disease, people who had mild cognitive impairment, older people who were cognitively unimpaired, and middle-aged people who were cognitively unimpaired.

And what he found was that the people with the lowest blood flow in those vessels in the brain were people who had Alzheimer's disease.

And, actually, we see a very consistent pattern, so that people with Alzheimer's disease have the least amount of blood flow in these blood vessels, followed by people with mild cognitive impairment, followed by older individuals who are cognitively unimpaired, followed by those middle-aged, unimpaired individuals.

He followed this study up with another study of pulsatility.

And this is kind of a measure of stiffness of the arteries.

And again, the people who have Alzheimer's disease-- this time, those are people who are shown in blue-- have the stiffest vessels.

Actually, the people with Alzheimer's disease in blue and mild cognitive impairment in red have kind of stiffer arteries than the older or the middle-aged cognitively unimpaired individuals.

But across all these vessels, people who are older have stiffer vessels than people who are younger.

So, again, these are things that happen with typical aging.

They don't always result in dementia or Alzheimer's disease, though.

So, how is it that these vascular factors change our risk for cognitive impairment due to Alzheimer's disease?

I want to talk about two different ways that this might happen.

One is simply that, if you have a lot of health problems, they just kind of add up.

It's like knocking the same glass off a table over and over again.

The multiple hits eventually overwhelms the brain's ability to repair itself.

And there's some evidence for this.

So, this graph comes from a study conducted in 2005 with a cohort of 8,800 individuals.

The study authors looked at four cardiovascular risk factors.

These were high blood pressure, diabetes, high cholesterol, and smoking.

And they found that it didn't really matter which of these different risk factors you had.

If you had more than one of them, your risk for developing dementia increased.

A more recent study came out of the Atherosclerosis Risk in Communities, or ARIC, study.

I don't know if people are familiar with the ARIC study.

It's another very famous one.

And they showed that midlife hypertension and the signs of amyloid plaques in later life and diabetes in later life all separately increase the risk of developing Alzheimer's disease.

On the other hand, good vascular health could be protective.

So, there was a study back in 2005 that showed that cognitively unimpaired people with better blood flow in their brains had larger hippocampal volume, that region related to memory where we see the first signs of shrinkage with Alzheimer's disease.

It stands to reason that if you're starting out with a healthier, larger hippocampal volume, then as it starts to shrink, you're still going to be able to maintain function 'cause you just started out with more.

Another possibility is that poor vascular health and plaques and tangles that are the hallmarks of Alzheimer's disease interact with each other so that they exacerbate each other.

And so, that the whole is greater than the sum of the parts.

And there's evidence for that as well.

So, this study was performed using the Wisconsin Registry for Alzheimer's Prevention.

And this is a large-- the other large longitudinal study, I should say, of Alzheimer's disease at the University of Wisconsin in Madison.

In this case, participants were divided into four groups based on whether or not they were amyloid positive, meaning they had a concerning amount of amyloid in their brains.

And that's indicated by being AB- or AB+ on this graph.

And then, whether or not they had the presence or absence of one other risk factor, in this case, either hypertension or obesity.

Here, the people in green are people who have-- are amyloid positive.

They have that concerning amount of amyloid, and they have one of these risk factors, hypertension or obesity.

And you can see that those people in green are declining the fastest on this measure of thinking skills.

This was a measure of verbal learning and memory.

And they're declining faster than if we just took the orange line, which is somebody who has, you know, just hypertension, and added it to the line, the blue line, which is somebody who had just amyloid.

So, there's some interaction going on there that's causing a greater decline than we would expect if we just kind of added those health problems up together.

So, to summarize, when we have reduced blood flow, either due to stiff vessels or clogged vessels, there's a decrease in delivery of oxygen and nutrients to the brain regions that need them.

We have impaired clearance of beta amyloid and other toxic proteins.

And there's an increased risk of blockages.

With weakening artery walls and weakening of the blood-brain barrier, there's an increased risk of bleeding and a reduction in the brain's ability to protect itself against outside toxins.

So, that was a lot, so I thought I'd throw in a little stretch break for everybody.

[audience chuckles] So, if you feel like it-- You don't have to, but if you feel like it, you can just raise your arms up over your head.

I always, like, do this with my fingers when I do this.

And then just twist real gently to one side and then real gently to the other side.

Ooh, I get a nice crack there.

And then just kind of float your hands down, just kind of shake it out.

[blergh] Okay.

Thank you for joining me.

All right, so, what happens when we treat cardiovascular-related chronic conditions?

Can we lower the risk for dementia?

There is a lot of interest in drug repurposing.

There's many advantages to drug repurposing.

It's very expensive and time-consuming to develop new drugs.

If we can capitalize on some investment that we made in the past, that saves us that time and that money.

But also, drugs that have been on the market for a long time already have a known risk profile that can help doctors decide whether their patient is-- should be getting that drug or not.

We have treatments for cardiovascular-related diseases.

We don't have treatments for any of these cerebrovascular health problems that I mentioned earlier.

We have a lot of observational or correlational data showing that poor cardiovascular health is related to these cerebrovascular problems in the brain and to higher risk for dementia.

So, it seems like a no-brainer, right, that if we treat cardiovascular health problems, we can reduce or prevent cerebrovascular health problems, which will in turn reduce or prevent the development of vascular dementia or Alzheimer's disease.

But efforts to show that cardiovascular-- treating cardiovascular-related diseases lowers the risk of dementia haven't been completely successful.

So, we'll start with the unsuccessful attempts.

And this involves statins.

Back in the early 2000s, researchers looked at people with and without statin and whether or not they had dementia or not.

And it looked, across several studies, as if statins had a protective effect against dementia.

People got really excited about that.

But the problem with those studies is that they looked at people at the same time, right?

So, they looked at, "Are you on a statin, yes or no, right now?

Do you have dementia, yes or no, right now?"

Later studies took a more prospective approach.

So, they took a bunch of people and said, "Are you on a statin, yes or no, right now?

"And then, let's follow you over time "and see if you develop dementia, or Alzheimer's disease specifically, later on."

So, there's a review that was published a few years ago of 17 studies that followed this prospective design.

Ten of those studies did show that there was a reduction in dementia among statin users.

Seven of those studies showed no relationship between statin use and risk for dementia or Alzheimer's disease.

So, it was almost evenly split.

Clinical trials of statins have been unable, to date, to show a reduction in dementia.

However, those same clinical trials also show no loss in cognitive ability, and that was a concern at one point in time.

People were concerned that putting someone on long-term statin use would actually increase their risk for dementia, and that does not appear to be the case.

So, one drawback-- Oh, I forgot to say.

A drawback of these clinical trials is that they tend to be short.

They're designed to show a cardiovascular benefit, not a cognitive benefit.

So, we have a new trial that UW is a site for.

This is a multi-site trial.

We are one of the sites.

The goal of this study is to enroll 10,000 adults who are over the age of 75 and randomly assign them to receive a statin or not.

And then, the outcome will be years free of dementia or years free from persistent disability.

So, we're still enrolling people in this study.

We plan to follow them for at least five years and hopefully longer, and hopefully show that being on a statin in older age will actually result in more years free from dementia or disability.

Now, we go to the success.

What has been successful is showing that reducing blood pressure reduces the risk for mild cognitive impairment or dementia.

And some of the best evidence for that comes from the SPRINT-MIND trial.

This was a very large clinical trial of 9,000 people who had high blood pressure.

And they were assigned care as usual or a more aggressive treatment.

Care as usual, meant keeping that top number, in the blood pressure numbers that they give you, keeping the top one to around 140.

The more aggressive treatment was dropping that down even more to 120.

The main outcomes were cardiovascular.

So, it was reduction in myocardial infarction, stroke, heart failure, and death.

And then, a secondary goal was to show a reduction in the incidence of mild cognitive impairment and dementia.

This trial was so successful at reducing the risk of stroke and heart failure and death that it ended early.

But they were still able to show that there was, in fact, also a reduction in the risk for developing mild cognitive impairment and dementia.

There's also interest in repurposing drugs for cardiovascular health in people who don't have cardiovascular health issues.

Can these drugs still improve brain health independent of any cardiovascular benefit they may provide?

So, there's been a couple of trials now, for example, metformin.

If we give metformin to people who don't have diabetes, Type 2 diabetes, do they nevertheless see a benefit when it comes to slowing cognitive decline?

Another example of this is a study of semaglutide, that you may know better as Ozempic or Wegovy.

Semaglutide is a medication that was developed for Type 2 diabetes.

And two studies were conducted.

EVOKE and EVOKE+.

So, these were clinical trials.

They each enrolled 1,800 participants ages 55 to 85.

They were ongoing in parallel.

And all of the people who were enrolled had mild to moderate dementia due to Alzheimer's disease.

In the EVOKE study, people were excluded if they had any signs of small vessel disease.

So, if they had any of those microinfarcts or microbleeds or white matter hyperintensities, they couldn't be in that part of the trial.

But they could be in the other part of the trial, EVOKE+.

So, basically, they had people with mild to moderate Alzheimer's, dementia due to Alzheimer's disease, with healthy brains, and people with mild to moderate Alzheimer's, dementia due to Alzheimer's disease, with unhealthy brains, at least in terms of the blood vessels in their brain.

Their goal was to slow the progression of dementia in people on semaglutide, or to show that that could happen.

The results from this study just very recently were presented at a conference a couple months ago, and there was no difference in progression between the two groups.

This was a very disappointing outcome, but it has not dampened interest in semaglutide as a potential treatment for Alzheimer's disease.

As in other drugs that have failed to have an effect in the mild-to-moderate dementia phase, we are looking at earlier phases of disease progression.

It's not just medication that people are taking an interest in repurposing.

There are also studies on supplements, particularly omega-3 and omega-6 fatty acids.

Now, you may remember there's been a lot of study of cardiovascular benefits for omega-3s in particular and fish oil.

And it kind of goes back and forth, right?

It was like, "Yay, fish oil," and then, "Boo, fish oil."

And now, I think it's "yay" again.

So, this is a study that my supervisor, Dr.

Cindy Carlsson, conducted.

And we had this eicosapentaenoic acid, which is an omega-3 fatty acid.

And you can think of it as a really concentrated dose of fish oil, even though it doesn't technically come from fish.

But we were hoping to show that being on this supplement for 18 months would improve blood flow in the brain.

Unfortunately, we were not able to show that.

Our group that was on the concentrated fish oil didn't improve-- or didn't have a difference in their blood flow in their brains, on average, than people who were taking this mineral gel placebo.

That has not dampened people's interest in omega 3-s and omega-6 fatty acids.

There are still a lot of trials of those supplements, and there are several trials of Ginkgo biloba, as well, and a few other supplements.

So, clinical trials have been done looking at the impact of treating cardiovascular risk factors.

However, often dementia is a secondary goal, which means it might be added after the start of the trial.

That happened several times.

Often the ways that dementia is measured is not the best way to measure dementia in these clinical trials, and they tend to be too short.

It takes a long time for dementia to develop, especially Alzheimer's disease.

We see those symptoms of amyloid burden 10, 15 years before we actually see clinical symptoms of dementia.

The best evidence we have right now is for controlling high blood pressure.

And additional studies are needed.

And I can feel your eyes rolling because we always conclude that, right?

Additional studies are needed.

We need additional studies, first of all, for those drawbacks that I just mentioned.

We need longer studies.

We need studies that are designed specifically for detecting a cognitive benefit.

But we also need studies that enroll people, a broader spectrum of individuals.

So, the typical study participant, especially in studies of Alzheimer's disease, looks like you guys.

[chuckles] It is-- Or an older version of me, right?

It is a-- Two-thirds of the people in both our longitudinal studies of Alzheimer's disease are women.

Most of our participants are white.

They have a college degree, they're middle-class, they live in an urban or suburban area.

And our participants actually tend to be healthier than the general population.

So, we need studies that are able to reach out to communities that are underrepresented.

Sicker people, older people, people from rural areas or lower socioeconomic areas.

In order to really understand Alzheimer's disease and vascular contributions to Alzheimer's disease, we need more people.

So, there are things that we can do to manage chronic conditions-- Besides managing chronic conditions, I should say, to improve brain and heart health.

This is called Life's Essential 8, and this was put together by the American Heart Association.

But these recommendations overlap entirely with recommendations for improving your brain health.

So, I'm not gonna spend a lot of time on this because these infographics are everywhere.

And you've probably heard a lot of this from your doctor.

And if you aren't hearing this from your doctor, get a new doctor.

[audience laughs] I do wanna point out a couple of things.

First of all, the American Heart Association has adopted that more aggressive approach to managing high blood pressure, so, keeping it down around 120.

I want to be very clear about what I'm about to say.

It is never too late to adopt a healthier lifestyle, but it's always better to start earlier if you can.

And that's especially true for high blood pressure.

We find that treating high blood pressure in midlife-- and midlife is defined as 55 to 65 years of age, typically-- treating high blood pressure in that age range or starting in that age range gives you the most bang for your buck.

So, if you know people in that age range, tell them to go see their doctor, get their blood pressure checked out, and if they need medication, start taking it.

The other thing is, when I hear "physical activity," I think exercise.

And I just can't find the joy in exercise personally.

But actually, physical activity doesn't just have to be exercise.

It can be gardening, it can be cleaning the house, it can be running around doing errands.

And there's been a few studies now on sedentary behavior, just sitting, that have shown that sitting for 10 hours or more really substantially raises the risk of dementia.

So, any amount of activity is better than no activity.

And sprinkling your activity throughout the day, even if it's a, you know, pretty moderate, low activity is gonna be beneficial.

There are a couple things I want to bring up just because that you're here and I feel like I need to spread the word, as somebody said earlier.

There are some specific risks-- or risks that are specific to dementia.

So, I get a lot of questions about drinking when I go out and give these talks.

Heavy drinking is really bad for your brain and for the blood vessels in your brain.

And I can't imagine it's particularly good for your heart.

But it's okay to drink moderately.

I recommend that people treat drinking as a treat, or, like we say in my household, as a sometimes food.

There's not really-- There's some studies that show a mild benefit to drinking red wine or something like that.

There's other studies that show no benefit.

So, again, if you like having a drink once in a while, that's great.

You don't have to give it up, but it's not like you need to start for the health benefits.

Hearing loss.

We are learning more and more about how hearing loss, especially hearing loss in midlife, is a risk factor for developing dementia.

So, treating hearing loss, we think, is really key.

Again, if you-- This is another area where you get the most bang for your buck if you start early.

So, if you are starting to have-- notice hearing problems, get checked out.

If you know somebody who's in that midlife range or you're in that midlife range yourself, go get your hearing checked.

If you need a hearing aid, try to get one and wear it.

[chuckles] There's a couple reasons why we think hearing loss is leading to dementia, but the main one is most likely that people with hearing loss become socially isolated.

And that's the last thing I wanted to mention.

We are seeing more and more that throughout disease-- Alzheimer's disease progression, being socially active, staying socially active improves quality of life across the board.

So, it's really important for us to stay socially active.

But it's also important for us to incorporate our friends, our family, our neighbors who may be experiencing some mild cognitive impairment or dementia, to stay engaged with them so that they are able to be socially active as well.

That is a real gift to people.

So, the last thing I'm gonna talk about is the multidomain approach.

Typically, when we study modifiable risk factors or these modifiable lifestyle factors, we study them one at a time.

So, we look at exercise.

Does exercise improve something?

Diet, does diet help anything, right?

We look at them, you know, like we're looking for a magic bullet.

The multidomain approach says, "We don't need to do that.

"Let's just make people as healthy as possible, "however we need to do that, all at once.

We will do all the things all at once."

So, this is the U.S.

POINTER study.

This was a multidomain study that was patterned after a similar study out of Finland called the FINGER study.

And in this study, 2,000 cognitively unimpaired individuals were enrolled, and all of these individuals were at high risk for dementia due to poor diet, lack of exercise, and one other risk factor, which includes elevated blood pressure, elevated LDL, the bad cholesterol, or a high A1C value.

Individuals were then randomized to a self-guided intervention or to a structured intervention for two years.

So, again, this is a little hard to read probably from where you're sitting.

The bottom part here is the self-guided intervention.

The self-guided intervention group got to identify their own goals.

They had six facilitated group meetings to talk about those health goals.

And they really didn't get a whole lot more than that.

They got some education, they got some online tools, and they got some health monitoring.

The people in the structured intervention group were given goals to meet in the areas of physical exercise, nutrition, cognitive and social activities, and they were provided with health coaching.

They went to 38 facilitated meetings to talk about their health goals and how they were doing.

The people who were in the self-guided group got a $75 gift card at each of those meetings to put towards their health goal.

The people in the structured intervention group-- I really like this detail-- got a monthly rebate.

Not the money, a rebate, up to $10 towards blueberries.

So, their reward for all of that was blueberries.

But it must have worked.

Cognitive ability or thinking skills was measured every six months.

And both groups improved over the two years.

So, the top line, those dark purple dots, represent the group that was on the structured intervention, and the lavender triangles represent the people who were on the self-guided intervention.

So, we expect people to do better on a test if they've been exposed to it repeatedly, right?

If you're taking the same test every six months, we hope that you learn how to do the test.

And we call this practice effects.

But even so, the structured intervention group actually improved more than the self-guided group.

This was a statistically significant difference.

Everybody was very excited about that.

But you can kind of eyeball it, right?

You can see that the difference isn't real big.

My takeaway-- and not just my takeaway, some other clinicians have weighed in on this-- is that even minimal intervention, a little bit of infrastructure, a little bit of incentive, has the potential to improve people's cognitive function.

And this is cognitive function in people who are, remember, at high risk for developing dementia.

So, if we can help improve people's health, if we can improve their cognitive function, we can contribute to that brain reserve or that cognitive reserve that helps people maintain function in the face of any other brain changes that may be going on.

So, here's my final takeaways.

First of all, it's never too early or too late to take care of your heart and your brain at the same time.

It's all the same stuff.

Definitely talk to your doctor if you haven't in a while about your blood pressure and whether it makes sense for you to be on that more aggressive approach to lowering high blood pressure.

And in general, do what makes sense for you.

There's a lot of infographics like this.

It's, like, ten steps to good brain health, Twelve steps to good brain health.

We're not all gonna do all those things.

That's not realistic.

So, it's important to kind of sit down and think, "What makes sense for me to do?

"What can I do to improve my health?

What am I gonna stick with?"

That's really important.

"What can I be consistent with?"

It's also important-- What I've learned from the U.S.

POINTER study and from the FINGER study and a couple other multidomain studies is that I think it really helps to have a team.

Have your doctor involved.

Maybe meet with a nutritionist if that's available to you.

Involve your family and your friends.

Have a support group to help you with your goals.

So, I have a couple of final slides that have nothing to do with vascular risk for dementia.

None of this information would be possible without study volunteers.

So, even though a lot of our study volunteers are kind of people like yourselves, we still need more of you.

[chuckles] We need so many more participants, especially for clinical trials.

If you've tried to be a part of a study before and you've been turned down, please check back.

We always have new studies starting at the University of Wisconsin in Madison.

And right now, a lot of effort is being put towards home assessments so that people can cut down on their travel or maybe not even travel at all for some of these studies.

A good place to just see what's out there is TrialMatch at the Alzheimer's Association website.

You can kind of-- You can use search terms to look for different things that you're interested in and see what trials are going on.

And endalznow.org is another place where you can kind of see what studies are available.

We have a ton of information at our Alzheimer's Disease Research Center website.

We have a fall community event every year, and that's recorded.

So, you can go to our website and you can listen to a wonderful talk from Kim Mueller, who is a language specialist.

Dr.

Nate Chin, who's a geriatrician with our center, hosts the Dementia Matters podcast.

I can't believe there are over 200 episodes already.

It's amazing.

They're really wonderful discussions.

We have an exercise class and a healthy living with mild cognitive impairment class.

And in April, we have our annual Solomon Carter Fuller Brain Health Brunch.

This is hosted by the African Americans Fighting Alzheimer's in Midlife study, but it is free and open to the public.

The University of Wisconsin has a new initiative called RISE-THRIVE.

And the goal of RISE-THRIVE is to invest broadly in healthy aging.

So, again, focusing on that healthspan rather than a lifespan.

And they are just getting up and running, but hopefully in the next year or two, they'll have a lot of exciting things going on and exciting public events.

So, I wanna leave you with this one last thought, 'cause I know we've talked about a lot of things that are kind of, you know, hard to hear and, "Oh, aging, blah, blah, blah."

So, this was a cartoon that somebody made in response to an article that purported to find the best age.

And in this cartoon, this person has brains in jars through the ages.

So, the first age is 18 to 24, and you probably can't read it, but that brain is labeled "Green."

And then there's ages 25 to 36, and that brain is labeled "Overrated."

And then there's ages 37 to 50, and that brain is labeled "Distracted."

And then there's 51 and up, and that brain is "Just right."

So, everybody in this room can rest easy.

Your brains are just right.

[audience chuckles] Thank you, everyone, for coming.

[audience applauds]