A Woman’s Journey | Modifiable Risk Factors for Dementia with Neurologist Rebecca Gottesman

A Woman’s Journey | Modifiable Risk Factors for Dementia with Neurologist Rebecca Gottesman


>>Good morning, everyone. I’m Rebecca Gottesman. I’m your third and final speaker today. Thank you so much for being here. And as I’m looking around the room, hearing these fabulous
talks, I’m turned, sorry. I was gonna turn my body. I’m amazed at the group that’s here and how attentive you all are. Really, everyone is taking everything in so I hope that I can continue to give you some useful information. So, I’m a neurologist,
I’m a stroke neurologist, but I study how stroke and
risk factors for stroke affect long term risk of
cognitive problems and dementia. So, I’m gonna talk about, you’re gonna hear some common
themes that we’ve heard about, both with cardiovascular disease, cardiovascular risk factors, inflammation, and, certainly, aging and how these relate to risk of dementia. And so, I’m gonna start with
the connection to aging. So, so, we have done a
tremendous job in science at treating acute illness, we’ve made tremendous progress. There’s advances in cancer treatment, there’s advances in treatment
of cardiovascular disease. These are all things that, traditionally, have limited the aging of
the population in the past and what I mean is, as we do a better job
at treating those things and our population is able
to age more successfully, that means we have more
and more older Americans. This is especially true
in the coming years as the Baby Boomers, I think
it’s estimated by 2030, that all the Baby Boomers
will be 65 and over. So, for the first time ever, there are gonna be more older Americans than there are young Americans,
than there are children. I think it’s estimated in the 2030s that there will be 78 Americans
above the age of 65. So, why is this a problem,
why is a relevant to dementia? Well, dementia tends
to be a disease of age. So, all of these people
are potentially at risk. And I’m certainly not saying
that everyone that is over 65 is at a risk for dementia, but certainly the risk
goes up as you get older. It goes up even further in
the 70s and 80s and 90s. So, thinking about what we can do about it is really important. So, let me define what I mean
by dementia, first of all, because I want to make sure we’re all on the same page for that. So, dementia in general is
defined as impairments in memory and at least one other cognitive function, that can be language, visuospatial
processing, attention. Memory and at least one other area and inability to function
in your regular activities of daily living. So, that means either you
can no longer do your job, you can no longer prepare meals, you can’t drive around
because you get lost, some way in which you can longer function in the way you could before. That’s dementia broadly. The leading cause of dementia
is Alzheimer’s disease. So, people often don’t fully
understand the difference. Dementia is the broad category
of this memory impairment that interferes with your functioning and Alzheimer’s is the
changes in the brain, by leading hypotheses, caused by buildup of what’s
called amyloid plaque. Alzheimer’s is the
leading type of dementia. Some of you may have seen in the news, there were a lot of
stories about a week ago about a new type of dementia
that has just been described in older people called TDP-43, which is just a name for another protein which appears to be another
important cause of dementia particularly over the age of 85. And that’s really a brand new pathology that’s been described, which I suspect there’s gonna
be a lot of research on. But to date, there’s
been a lot of interest, certainly, in Alzheimer’s disease. You may also be aware that
we have no current way to treat or prevent Alzheimer’s disease, and I’ve just said it’s the
leading cause of dementia. So, what I want to talk
to you about today is why there may still be opportunities to prevent dementia in general, including the possibility of Alzheimer’s. So, so, to finish up the definitions, mild cognitive impairment
is the other thing I’d like to define, or MCI. This is basically a similar
impairment in cognition, but not quite as severe, and it doesn’t cause inability
to do your daily things. So, this is the big difference between a diagnosis of MCI and dementia, people with MCI often can
still function pretty well, many people with MCI go
on to develop dementia, but not everyone does. So, it’s along the spectrum
of what we think about of normal cognition to dementia, it’s somewhere in the middle. So, now that we have those
definitions out of the way a little bit, I wanna tell you a little bit more about why I think we have a way to prevent this. So, dementia is something, if we look at all causes of dementia, it’s been estimated that one
in three cases of dementia is preventable, okay? That is not what most people think about when they hear about dementia and that’s why I want to
talk to you about this today. So, the Lancet Commission
put an official review of what we knew in dementia and they came up with the statistics that about a third of dementia
cases could be preventable. The National Academy of
Medicine had a panel of experts get together, they had
a systematic review, which means that they reviewed
all the existing literature in this area, they said
let’s look for evidence, and they’re looking for the
most convincing evidence which usually is in the form
of randomized clinical trials, but they reviewed everything, to say what do we know and what message can we give the public about how we can prevent dementia? And they recommended three areas where they thought was the most promise and the most potential from
the literature for prevention. One is control of hypertension, and I’m gonna tell you
much more about that, that’s an area where I
particularly do a lot of my work. Control of hypertension is one. Another is increasing physical activity. And the third is doing some
form of cognitive training. I’m gonna talk about the
cognitive training first because I have the least to say
about that mostly because there’s very little
guidance as to what form that cognitive training should take. So, everyone always asks,
what should I be doing if I’m doing cognitive training,
what form should it take? I would argue that going
to something like this is a form of cognitive training. It really depends on the person and even the few studies that
have successfully studied this tend to individualize
the cognitive therapy. So, that does not mean
that there is a single app or a single game or a single puzzle that you should be doing, it really depends on what works for you and what’s challenging for you, might not be challenging for
someone else and vice versa. So, we don’t know a whole lot
on what form it should take. The idea is to do something
where you’re using your brain to participate, and again, for some people it’s reading a book, for some it’s doing more
complicated puzzles, et cetera. So, what about hypertension? I wanna talk about that a bit. So, I said that Alzheimer’s was the
leading cause of dementia, but it turns out there’s a
tremendous amount of overlap between causes of dementia. So, even if you look at people given a clinical diagnosis
of Alzheimer’s disease, in autopsy studies, when they examine their
brains after they die, these were people who all were felt to have Alzheimer’s disease, there is a huge amount
of overlapping pathology when you actually look in their brains. So, some have pure
Alzheimer’s-type changes, actually relatively few, but most have some overlap. They might have a little
bit of vascular changes and some Alzheimer’s changes. They might have some Lewy body, which is another type of dementia, and Alzheimer’s, and vascular. Probably this TDP-43, I know based on seeing some of the data, is overlapping as well. And the reason that’s important is vascular changes in particular, which overlap a lot with
Alzheimer’s pathology, we know how to treat and
prevent vascular disease. We can’t do anything right now about the underlying Alzheimer’s pathology, although people are certainly working hard on advancing that field, but we’re very good at
treating high blood pressure, diabetes, telling people
not to smoke, et cetera. So, thinking about those
vascular risk factors is especially important because
there’s so much overlap. In addition, we know
there’s a lot of evidence, and this is where I do a lot of my work, I work with a large epidemiologic study, so this is a study of nearly 16,000 people from different places across the country who have now been followed
for 30 plus years, so these are people from
communities who come to visits, get phone calls every year, have been tremendous
participants in this research, but are people representative
of their communities, to allow us to study how
their vascular risk factors affect their cognition. And just to make sure we understand which vascular risk
factors I’m talking about, I’m talking about the same things that increase the risk for
heart disease and stroke. So, high blood pressure, diabetes, obesity, high cholesterol,
smoking are really big ones, and poor diet and
inactivity are also probably increasing evidence just showing that those are really important
as well in this question, in thinking about cognition and dementia. So, when we looked at
people in this large cohort, we found that people who
had high blood pressure particularly when they were middle aged, so if we looked at them
at the youngest time point when we saw them, so in this study, it was 40s to 60s, I have never given a talk
without somebody asking me how do you define middle age? So I’ll get it out of the way now. We think of about 40 to 60 as middle age, and then people can
quibble with the technical, multiplying things by two might
make that seem less likely, but in general, that’s what
we think about as middle age. But it looks like risk factor status, particularly for things like high blood pressure and
diabetes when you’re middle aged are especially important
for your subsequent risk of cognitive problems. That doesn’t mean that they
don’t matter when you’re older, but they’re really especially
important when you’re younger. And the theme is you need
to think about these things before you think you
need to think about them. What’s your blood pressure? Do you have diabetes? So, when we looked at people
who had high blood pressure, and the definitions of high blood pressure have changed recently,
when this study was done, it was sort of the old definitions, but if you looked at people
with elevated blood pressure, they had about a 40%
risk of having dementia at some point over the next 25 years. With similar increased
risk for people that had sort of pre-hypertension, which is now defined as hypertension. If you had diabetes when
you were middle aged, your risk went up by about
80% for having dementia over the next 25 years. And I’m glad that that
got the reaction it did because it does for us too. And to put it in context, the strongest known and most
frequent genetic risk factor for Alzheimer’s disease is the APOE gene, having the E4 allele. If you have one of these
copies of this gene, you have about a double
a risk of Alzheimer’s. We can’t do anything about that. Diabetes is pretty close, you know, we look at 1.8 versus two as our two hazard ratios which
are ways to look at risk, it’s very similar and we know how to treat and prevent diabetes much better than we can do anything about
these genetic risks. Similarly, people with
high blood pressure, and people with diabetes,
and people who smoke have steeper cognitive decline if we repeat testing over 20 years. Meaning that everyone, unfortunately, their cognitive performance
goes down a little bit as we age, and it goes down more steeply if you have high blood
pressure, if you have diabetes. And probably the combination
is especially bad. We can’t sort of see a clear pattern that’s a signal for this
combination of something we need to really worry about, but many of these co-occur. People that have obesity
might have high blood pressure and high cholesterol as well, et cetera. So, one thing that we’ve asked, and this is an area that I’m
particularly interested in, is that simply that if you have
these vascular risk factors, that your risk of other
things happening in the brain, stroke is one, or even changes that look like stroke but don’t cause symptoms, so what we call subclinical
or silent stroke, we know that people who
have these risk factors get these spots on the brain, is it simply that you
have high blood pressure, as an example, and that
changes things in the brain, and if you’re also having
these Alzheimer’s type changes, like more amyloid buildup, you’re more likely to be
given a diagnosis of dementia. That the combination
pushes you over the edge, is that what’s happening? Or is there a direct role
in the vascular risk factors in the development of Alzheimer’s
type changes in the brain? And the reason we think
about this, in general, most treatments for Alzheimer’s
to date have failed, partially because they
may just be focusing on one pathway which is this amyloid pathway, but also they’re probably being given too late in the disease. So, we know for Alzheimer’s disease, people start developing
cognitive problems here, but the amyloid buildup is happening here and probably things, and I guess I need to flip my (laughs) my imaginary graph, but the point is that things
take decades to occur. So, brains of people
with Alzheimer’s disease are abnormal before
they have any problems. And if you wait, and you can’t do a drug trial
on a treatment for Alzheimer’s until you know who to give it to. And so, those studies
have been ineffective probably because in some
ways the ship has sailed and it’s too late to stop
the course of the disease. There’s some exciting work being done in Colombia, in South America, Colombia with an O, where they’re looking at a familial form, there’s another genetic
risk for Alzheimer’s which causes disease at a much younger age and they’re aware of
families that carry this, so they can try the treatments. And this is a really good way to see what we call proof of concept if actually going after
amyloid at the right time is sufficient to stop the disease. But in general, if we think about the
time course treatments, we need to think about things
at an earlier time point. And it’s been hypothesized
that vascular changes could be one of those early
triggers for things like amyloid and tau is the other big
protein in Alzheimer’s, for those things to
accumulate in the brain. And because, as I’ve told you, the vascular relationships
with cognition are strongest when we look in middle age, it sort of fits this chronology. Vascular changes, vascular
exposure at a younger age leads to some of this buildup of Alzheimer’s specific proteins, ultimately leads to dementia. But we didn’t have clear evidence that there was a direct link
between vascular changes and vascular risk factors and amyloid until we did a study
where we looked at people, a group of people from this larger cohort, a smaller group underwent PET scans with a particular isotope, so this is a kind of technology where we can bind to something and see how it lights up in the brain, and there’s an isotope that
binds to amyloid in the brain. So, this is a way to study
Alzheimer’s in living people, and we did this in
people without dementia. And what we found is that people who had more vascular risk factors
when they were middle aged, so if we just did a tally, high blood pressure, diabetes, smoking, obesity, high cholesterol, the more of those you had, the more likely you were to
have amyloid in your brain later even without dementia. So, this suggests there might be a direct, possibly causative, we can’t show that it’s causative
in this kind of a study, but possibly causative link between vascular risk factors and the development of Alzheimer’s type changes. So, this is important because, again, we can do something
about these risk factors. I said that I would
mention that inflammation is highly relevant here as well. It turns out that in addition
to high blood pressure, diabetes, smoking, et cetera, that people who have high
levels of chronic inflammation in their bodies, and again, especially in that mid-life period, have a high risk of dementia,
worse cognitive performance, more brain volume loss in the
important regions of the brain that control memory, than to people who
don’t have inflammation. And that’s even if we eliminate the people with the really high levels from sort of underlying rheumatologic or even conditions like psoriasis, but even low levels but still elevated of chronic inflammation
can be bad for dementia. So, if my general theme is
that these things are bad and we can treat them, and therefore you can prevent dementia, where’s the evidence that
actually treating them, preventing them makes a difference? So, in the last few minutes, I just want to provide you
with some of that evidence. So, recently, an important study came out
called the Sprint Mind Trial. And this was a study, it was initially designed to look at aggressive blood pressure control and cardiovascular disease. It also had an arm where they measured cognitive performance. And so, what they found, unfortunately this study was stopped early because it was so positive
for cardiovascular disease, meaning they found that people who had better blood pressure control under an upper number of 120 systolic, as opposed to regular
blood pressure control, those people had less
cardiovascular disease, so the study was stopped early. So, we failed to show the
main cognitive outcome, we didn’t see a difference
in dementia rates, but what was found was that
mild cognitive impairment or a combination of MCI and dementia was less frequent in people who had more aggressive blood pressure control than those who didn’t. And this certainly goes along
with the general concept that blood pressure is bad for the brain, therefore, treating it should be good. My suspicion is if the
trial could be much longer, ideally, 30 years, it will never happen to
have a trial that long, but since I think
mid-life is so important, a longer study would
really potentially show us a benefit of treating that blood pressure for reducing dementia. What about anti-inflammatories? So, this came up previously in terms of the potential role of anti-inflammatories in psoriatic arthritis
associated cardiovascular events. There have been a number of
studies looking at aspirin and the role of aspirin in prevention of cardiovascular disease. I’m sure that all of you have heard the relatively recent guidelines that said aspirin is not good, after all, I wanna clarify this is
for primary prevention. So, people who have had a heart attack, people who have had stroke, who have heart disease, they probably still need to be on aspirin, obviously you need to
talk with your doctor. So, that’s a different population. Several studies, including
the Aspree trial, looked at aspirin in primary prevention, which meant people that
hadn’t had those things, to understand are we reducing the rate of cardiovascular
disease and importantly, for the relevance to my talk today, are we reducing dementia? This was a primary focus
of the Aspree trial. And what they found is that no, taking aspirin in people who didn’t have cardiovascular disease or stroke did not reduce the risk
of dementia down the road and this is sort of
something that we’ve seen for other smaller studies
of anti-inflammatories and dementia as well. So, we know that inflammation is bad but it’s not clear that a direct treatment of the inflammation is
gonna make things better. Probably it needs to
go a step further back and understand what
led to the inflammation in the first place, if we have a potential for prevention. And then finally, the last
trial that I wanna mention that’s been promising in this area is something called the finger trial. And this was a study in Finland and there’s a US version
called the US Pointer trial, there’s a finger theme here. And this is a study where they do a multi-modal intervention, so they take people with
early cognitive problems, the finger trial looked
at a combination of diet, exercise recommendations,
lifestyle recommendations, and vascular risk factor control, as well as cognitive training, and this is one where they did
an individualized approach, and they said if we do all of these things in half of our participants and the other half we
just sort of give them general generic guidance, are we able to see a difference
in cognitive decline? And they did. So, people who got that
multi-modal approach had less cognitive decline, we don’t know if it makes a difference in actual dementia cases yet, than to people who did not
get that multi-modal approach. And I suspect that this is gonna be an exciting area in the future. The dementia world very
much understands that that vascular stuff is important and we know how to treat it and really thinking about the
best way to prevent disease, prevent cardiovascular disease, but also prevent dementia is really something
that’s an exciting area where we’re going for it in the field. So, thank you very much for listening. I will happily take questions at the end. (applause)

Leave a Reply

Your email address will not be published. Required fields are marked *