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We’ve had multiple GeriPal episodes about treatments for dementia, including aducanumab (here, here, and here) and lecanemab (here).  As today’s guest, Kristine Yaffe notes, part of the reason for that emphasis is that in the US we prioritize treatment, whereas other countries are ahead of us in prioritizing prevention.  Deb Barnes and Kristine Yaffe published a landmark paper in Lancet Neurology finding that up to half of dementia risk is due to modifiable factors.  If we focused on prevention, from a public health standpoint, we would achieve far more than spending millions billions on treatment.

Today we talk about steps we can and should take to reduce the risk of dementia, including:

  • Education and cognitive games (I reveal my embarrassingly poor average time on the NYT mini cross word)
  • Physical activity
  • Sleep
  • Depression
  • Smoking
  • Social isolation
  • Blood pressure control (listen also to our podcast on Sprint Mind with Jeff Williamson)

We also delve into an exciting new trial Kristine led with others on the impact of risk factor reduction on cognition – here’s a link to press about the trial from a fall meeting presentation – article forthcoming.  

And because we can’t resist, we dip into aducanumab and lecanemab at the end.



Eric: Welcome to the GeriPal Podcast. This is Eric Widera.

Alex: This is Alex Smith.

Eric: And Alex, who do we have with us today?

Alex: Today, we have a true luminary in the field of dementia research. We have Kristine Yaffe, who is the school endowed chair and vice chair and professor of psychiatry, neurology, and epidemiology at UCSF, and is also one of the leading figures in the Clin-Star program and the Beeson program and a friend of the podcast. I can’t believe this has taken us this long to have her on. Welcome to the GeriPal Podcast, Kristine.

Kristine: Thank you. I’m really happy to finally be here.

Eric: We’re going to be talking about the prevention of dementia, Alzheimer’s disease. But before we do, we always start off a song request. Kristine, do you have a song request for Alex?

Kristine: Well, I did have a song, but I was negligent at giving it to him. So, he tried to read my mind…

Eric: What was your song?

Kristine: I was going to do David Bowie Changes for a variety of reasons, but it was sort of somewhat around the topic. But then what we decided to do was sort of reminisce about the Beeson sing-alongs and another sort of relevant song. So, Alex is going to do In My Life by the Beatles.

Alex: Great, thank you. We’ll do Changes next time we have you on, for sure.

Kristine: Okay.

Alex: (singing)

Eric: That was wonderful. I was going to ask you…

Kristine: Woo-hoo! Woo-hoo!

Eric: … Alex, why’d you pick that song…

Kristine: It’s pretty perfect.

Alex: Well, It’s got the places I remember.

Kristine: Yeah, yeah, yeah.

Alex: Recollection. They’re lovers and friends I still can recall. Loss of memory. Yeah.

Eric: And for our listeners, what’s the Beeson meeting? Is that for beekeepers, sons of beekeepers? [laughter]

Alex: Beeson meeting is a terrific meeting of aging research scientists who have an award called a K76 award. The beautiful thing about this meeting is that K76 is… Kristine, please add to whatever I’m saying here. K76 is a terrific award. The beautiful thing about it, it’s more than just having a career development award; it’s a community of aging researchers. Unlike some other programs, they invite you back to the meeting in perpetuity. That’s thanks to a grant that Kristine Yaffe and Tom Gill were awarded from the NIH to make sure that this meeting continues to happen. It’s a terrific meeting. Kristine, what else do you want to say about Beeson?

Kristine: I would say, just to clarify for the listeners, that it’s an NIH career development award, but it’s really specifically for the future aging leaders in research. So, it’s a little more selective maybe, and there’s some different aspects to it, which is great.

I agree with you. One of the highlights really is the networking and the community that it fosters and highlighted, in some ways, by the meeting, which of course you often lead the sing along at. It’s just another example of, I think, that there’s a little extra special sauce there in the Beeson program.

Eric: Kristine, before we jump into the topic of prevention of dementia, you’ve had an incredible career that’s focused on this issue. How did you get interested in this as an issue and a career focus?

Kristine: Sure. Let me stretch those cobwebs here. But I think there were two things that really paved the way for me to be wanting to focus on Alzheimer’s and related dementia, which I may refer to as ADRD, the recent parlance here.

The first is that when I was an undergraduate, even, I was always really interested in sort of psychology, but the biology behind the psychology. I was a psychobiology major, surprise, surprise, one of the first at Yale. Then I went to medical school and I thought, “Well, should I go into psych? Should I do neuro? Should do medicine?” Because I loved internal medicine. But something with behavior.

Anyway, long story short, I did a neurology residency, which I learned an incredible amount, but there was some things that were missing for me in terms of going beyond the localizing the lesion, talking more about behavioral aspects and thinking more a little bit about the person and what they were going through.

So then, I did a second residency in psychiatry, which didn’t get me any political clout, but I did learn an awful lot. There I was, extremely overly trained with brain stuff, and I wanted to learn how to do clinical research. I thought, well, where do these things come together, the brain and behavior? And really, they come together primarily at, I think, in pediatrics when people are young; or in later life, delirium, dementia, all kinds of things. So, I decided I was going to really focus more on the later life. In particular, I was really interested in Alzheimer’s because at that point, it’s very common, but there was so much we didn’t know about it, and the treatments were really quite rudimentary. One might argue they still are. I just thought there was so much we could learn and offer from every sense, from the clinical point of view, from the family point of view, from prevention, from treatment, epidemiology, et cetera. So, that’s how I ended up there.

The other thing about it, which was really interesting, when I started the… I’d say the methodology was still pretty old-school, so it was still kind of case control. There weren’t a lot of prospective studies. There was this idea that somehow you magically had dementia. There was very little sense of the whole preclinical phase or continuum. That’s really what I started focusing on, in a lot of ways. What is that early phase? What can you do about it? Why do some people progress and some people don’t? Who gets this? Et cetera.

Eric: Well, what do we know about that right now? What do we know about what are some of the risk factors for progressing to dementia?

Kristine: I think we know a fair amount. When I think back on the last, I guess, 20-25 years, we’ve learned a lot. I think that one can argue about the strength and the evidence a little bit, but I’d say they’re probably now certainly a handful, maybe a dozen things that really look like they have been well-studied risk factors for ADRD. Often, we can talk a little bit about that there used to be this dichotomy in sort of vascular dementia and Alzheimer’s. That’s really falling apart. A lot of these are more vascular risk factors: hypertension, certainly; diabetes; obesity. Certainly education, quality of education is extremely important. Physical activity is a big one. Sleep has become a really interesting area and has shown us a lot about the mechanisms behind sleep and the connections with dementia. Traumatic brain injury, that’s another big one. Those are some of the ones that I think are best studied. They’re not a lot of randomized clinical trials. So, if you’re looking for RCTs as your gold standard, that’s still an area that we don’t have a lot of.

Eric: I guess there’s the difference between what is a risk factor and does modifying that risk factor decrease the incidents of ADRD?

Kristine: You bet. Yeah. That’s the rub. Yeah.

Alex: The reason there aren’t many randomized trials is because many of these risk factors develop in midlife, and the outcomes you’re looking at are like 20-30 years later in late life when people are at greatest risk for cognitive impairment and dementia. Is that the reason there are so few randomized trials in this space?

Kristine: That’s one reason, I think. As you know… Gosh, where do I begin? Randomized control trials are very expensive and they take a long time. I think in this country… I mean, this is sort of opening up a can of worms here. But in this country, I don’t think people have been as interested in risk reduction for dementia that they are in other countries. Really, Europe, Australia, Canada maybe, even, have led some of these studies, much more so than the US. The US, as we know, is much more often focused on pharma and I think biotech, et cetera. So, while this is increasingly appreciated and certainly in the last 10 years, much, much more so than before, I still think there’s this sense that this is somehow soft science and it’s not going to really get to the answer. I think as a result, the NIH… It just hasn’t been on the forefront. I think that’s starting to change somewhat.

Eric: I guess the question is, we have these risk factors. Some of them, like education, definitely social determinants of health. What’s your sense of how much of a bang for the buck would you get by changing these things? And how does it actually work? Like, education, is it that it prevents you from getting Alzheimer’s disease, or does it just give you more reserve so Alzheimer’s peeks out later?

Kristine: All of these questions, each of these is an hour discussion. But I would say that in terms of education, it’s really complicated because it’s so confounded by socioeconomic status and so many social determinants of health. So, that’s one thing. But there is this theory that education and using your brain, whether it’s your occupation or your leisure activities, that somehow using your brain gives you sort of a buffer, I would say. There are some really interesting studies often using biomarkers that show that if you’re more highly educated than another group, or if you’re being cognitively active, that despite having, say, the same amyloid burden, you have less decline in your cognition or less symptoms. That tells us it’s either acting as a buffer… The idea behind cognitive reserve is that despite having equal amounts of neuropathology, that having that education or proxy, other cognitive reserve, gives you a buffer.

What the mechanism might be, we don’t really understand. I explain it to people and I say, well, it also could be reverse causality. You’re born with a bigger brain, so to speak, or more efficient brain, you go farther in school, and maybe that’s the buffer, too. Or maybe it’s later in life that it’s the buffering. It’s probably both, but we don’t really know for sure.

Eric: Well, what if I start doing daily crossword puzzles from the New York Times?

Alex: We do the mini every day.

Eric: We’re doing the mini. I’m not sure the mini counts.

Alex: Just for our listeners, so they have benchmark here. Eric, what do you think your average is for the mini?

Eric: A minute-and-a-half.

Alex: Minute-and-a-half. Yeah. Ann Kelly, who’s been on the podcast many times, social worker on palliative care, she’s always under a minute. 30 seconds is probably her average. My average is probably like eight minutes.

Kristine: And I don’t even do them. So, there you go.

Eric: Think about this, Alex. It could mean that you’re at high-risk for dementia, or it could mean that you are actively using your brain for seven-and-a-half minutes longer than us. [laughter]

Alex: I’m getting more exercise than you are. I’m getting a lot of cognitive exercises. I’ve stumped on The New York Times mini crossword puzzle.

Eric: Where does that fall in? Can we modify, not just by going to school, but maybe doing some cognitive training, whether it be simple stuff, or they market these cognitive training things, apps?

Kristine: Yep.

Eric: Does that play in?

Kristine: Yeah. We’re getting down this rabbit hole here of cognitive training. I think we probably want to keep it a little broader. But I will just say that in terms of cognitive training, it’s not an area that I’m particularly expert at, but most of the studies, there have been some RCTs; there have. In particular, there was something called the active trial a number of years ago, and they actually trained people. It was an RCT. They trained people on certain domains, like speed or executive function or memory. What they found, which I actually think is quite important, is that you can train people on these things. They will get better at these things. The question, I think, really, that’s not clear and hasn’t been answered, is does this generalize to other things, and can it protect you against developing dementia? So, we know you can get better at certain things, but does it actually have some sort of… And I don’t think we know the answer. I think despite all the aggressive marketing and computer games or whatever, I don’t think we know that.

Eric: Yeah.

Alex: Yeah. Can I ask if you… Okay, so moving off of… Unless, do you have another question about cognitive training here?

Eric: No, go ahead.

Alex: Moving off of cognitive training. If you could put your nickel down and say… I’m going to ask the magic wand question way earlier here.

If you could wave a magic wand to change one thing: sleep, blood pressure control, eradicate diabetes, get everybody exercising, what do you think would have the most bang for the buck in terms of dementia reduction?

Kristine: Can I say age? No. I like to tease.

Eric: That’s the biggest risk factor, right?

Alex: Is age.

Kristine: I like to tease my geriatric friends about age. All right. No. I would say… Ironically, we’re trying to get off of this topic, but I’d have to say education. I’d have to say socioeconomic status/education. But that’s really so easy to fix that if I had to think of other things… Getting back to one of Eric’s questions that I think I didn’t quite answer, which was if we could really… There are certain risk factors, like age and genetics that we really can’t do much about. But there are some things that we really think we can modify: the vascular risk factors, sleep, physical activity, maybe cognitive activity, and what kind of bang for the buck could we get?

Deb Barnes and I, a number of years ago… I was asked to do this review and then we’re like, “Ah, we don’t want to do another review. We want to do something more interesting.” So, we did this sort of an exercise where we said, “Okay, let’s look at how common these risk factors are. Let’s take sort of our best evidence for how much, what the effect sizes are for these, and let’s calculate the population attributable risk, and let’s then even account for the co-linearity of these things,” because obviously diabetes and hypertension and obesity would pretty colinear, as an example. What we found was that we thought these risk factors account for 30-40% of the variants of ADRD. Now, that doesn’t mean it’s a one-to-one, and this is very hard as we see it with our patients who have done all these things. But in general, we thought it really did account for a lot of the variants, and that if you could modify these things, not even 100%, but 20%, 30%, you could actually have a big downstream effect, and it would have a very big public health impact.

Eric: Going to some specifics, let’s go into vascular risk factors like hypertension. Sprint mind comes to my mind when I think about whether or not treating hypertension changes, risk factors for dementia. What are your thoughts on Sprint mind? Let me ask you that.

Alex: Didn’t you write the editorial for that?

Kristine: I did.

Alex: And Jeff?

Kristine: I did. Yeah, I did. I think we were talking before about it. They’re not a lot of RCTs. So, I was thrilled that this was an RCT and it was well done. You can quibble about… There was a relatively small but I think clear benefit to more aggressive systolic blood pressure lowering in older adults with hypertension vis-a-vis developing MCI and dementia. The dementia was not statistically significant alone; they were underpowered. But when you looked at MCI or MCI and dementia, it was statistically significant. I think that the concerns I have, obviously, and I’m sure you would share, are in some people, an aggressive systolic blood pressure lowering to 120 might make good sense and be really helpful, but in other people, the harms might outweigh the risks.

Eric: Mm-hmm. I guess it was a goal of 120, actually, most people didn’t reach 120.

Kristine: No, it was more like 130, I think.

Eric: Yeah.

Alex: And we’ll link to our prior podcast with Jeff Williamson, who was the first author on that study.

Kristine: Yeah, yeah.

Eric: What about just giving everybody a statin instead?

Kristine: The statin literature, these things come and go. But the statin stuff never really bore out. When you look at lipids as a actual risk factor independent of some of the other things, the lipids haven’t… They don’t seem to be a big risk factor in and of themselves. For a while, statins looked like they were going to help with everything, and then there was some concern that statins might be harmful. I don’t think the data’s super strong either way.

Eric: Mm-hmm. Any other, from a vascular risk factor modification, hypertension, smoking?

Alex: [inaudible 00:21:37] diabetes, any comments on those?

Kristine: Diabetes is a very important one. Smoking is a whole other story. But certainly you shouldn’t smoke for all kinds of reasons. There’s not that much information on smoking and cognition. For a long time, people thought it might be protective because of this nicotinic thing. But I think that it probably did not bear out, and it turned out a lot of that was actually supported by Big Tobacco, some of those studies.

I think clearly most of the vascular researchers are, I think, very important. We can talk a little bit about it used to be that people thought, oh, that was vascular dementia and it didn’t have a role in Alzheimer’s. Turns out that a lot of the traditional vascular risk factors actually have a very important role for Alzheimer’s as well. They seem to be very involved in amyloid metabolism and clearance. It’s really, I think, a fascinating area.

I love biology. I use biomarkers. So, I think one of the really cool things about this field is that it’s taught us a lot about the mechanisms of Alzheimer’s. A lot of these, whether it’s physical activity or whether it’s sleep or vascular, there are some really interesting underlying mechanisms that point to actually amyloid and tau and, of course, vascular changes. So, I think it’s really exciting, and sleep is probably one of the best examples.

Eric: Well, before we get into sleep, because I want to talk about sleep, how much of this is also is that is we often think of it separate diseases, but there’s a whole lot of overlap with people with Alzheimer’s pathology and vascular issues going on…

Kristine: Yes, there is. Yes.

Eric: … in the brain, and it certainly doesn’t help in either regard.

Kristine: Sure. Yeah. They tend to go… It’s one thing if you get Alzheimer’s when you’re 60. But if you get Alzheimer’s when you’re 85, there’s going to probably be a lot of vascular changes and other neuropathologic changes. We know from the oldest old field, when you look at the pathology, it’s really heterogeneous and there’s just a lot of different pathologies. So, it makes sense, frankly. I mean, if you’re thinking about… You want to find some risk factors that might operate on these different pathways simultaneously.

Alex: Yeah. Mm-hmm.

Eric: Okay. Let’s talk about sleep. Issues with sleep, like insomnia, does it lead towards a diagnosis of dementia, increase your risk, or is it that people with cognitive impairment, an early-on symptom is sleep disturbances and it’s more of a sign or symptom of early cognitive issues?

Kristine: Yeah. That’s a good question. I’d say that you could ask the same thing with depression, for example.

Is it a prodrome? Is it a prodrome of early changes, maybe even before cognitive changes, or we can’t detect the cognitive changes, or is it actually a risk factor? It’s hard if you’re doing certainly a cross-sectional study or even a prospective study later in life; it can be very difficult to tease those things out. I think the life-course perspective comes in here and is very, very important, and I think has really helped the field.

We and others have done some studies where we actually looking in midlife or even early adulthood and are showing that depression and sleep remain, as best we can say, real risk factors because it’s been 40 years till they got cognitive changes in later life. So, I think that both are true.

I think certainly sleep, particularly in certain types of dementias like Lewy Body, et cetera, you can have a lot of sleep disorders and REM sleep changes, REM behavioral sleep disorders, and with depression as well. But it seems like they’re probably also risk factors.

Alex: Mm-hmm. I wonder if disturbed sleep is the mechanism by which some of these factors operate. I’m thinking of chronic pain, for example, and individuals with chronic pain often have disturbed sleep or other conditions. People who exercise probably sleep more on average.

Kristine: Yeah, it’s funny. It’s funny. I’ve brought this up to people because people tend to look at one thing or the other and they don’t… But I think that’s a really good example with physical activity. If you’re physically active, you’re probably going to sleep better and your vascular stuff is better. So, yes, they do.

But getting back to sleep, I think for a long time we haven’t really understood why we spend a third of our life in sleep. Some of the work in the last 10 years has really been just fascinating. It does seem like it’s a time when the brain is quiescent and that actually there’s sort of a clearing out of a lot of these proteins. Certainly, that applies to amyloid and tau. Some of the animal models, including fly models and rodent models, really do show that if you don’t let the animal sleep, they do get greater buildup of these proteins. So, I think it’s pretty convincing.

Again, we don’t have a lot of RCTs, getting back to our question. If you improve sleep or you prevent sleep apnea or you treat sleep, can you then prevent dementia? And we don’t know.

I do want to make sure we have a little bit of time to talk about this trial that we did that we just finished.

Alex: Please.

Eric: Please.

Kristine: I’ve been in this space for a long time, trying to understand who’s at risk for dementia, early cognitive changes in particular, looking at modifiable [inaudible] – things theoretically we should be able to do something about. Like we talked about, some on the RCTs are suggestive, some have been negative, some are conflicting. So, we decided a number of years ago to try and do a what I call multi-domain lifestyle risk reduction trial.

You might have heard of this trial. There’s something called the FINGER trial, which was done in Finland. F for Finland. What they did was they randomized a group of older adults who were, because of their age, and I can’t remember exactly the inclusion criteria, but because of their age, and I think they had sort of low normal cognition, they were randomized to the intervention group. The intervention group got physical activity; they got diet strategies; vascular attention with certain parameters; and cognitive stimulation. Then the control group just had usual care.

After the end of two years, they found that the intervention group actually did better on most of the cognitive tests. It wasn’t a huge difference. But they did improve. This was a big deal because it was one of the first times that we actually thought, oh, if you actually do some of these things, you actually can get some benefit cognitively.

So, we decided we wanted to do something like that. There was nothing in the US like this. In the US, there have been single domain or maybe one or two. But what I decided to do at the time was I thought, “Ah, well, let’s just do this and let’s try and make it personalized.” It was my chance to poke fun a little bit of personalized medicine.

Eric: Precision medicine right there.

Kristine: Precision medicine. The idea was that we were going to basically enroll people who… They had to have at least two risk factors. So, we had to have some ability to intervene, and we were going to have people decide what they wanted to work on because, of course, changing behavior is difficult. But this is a trial we put together with colleagues at Group Health in Seattle; it then became Kaiser and some colleagues from UCSF.

We wrote to the NIH; we got the funding, and we implemented this trial. Just as we were going to finish enrollment, COVID came, so it was a disaster. We had to curtail our enrollment somewhat because, of course, don’t forget, Seattle was the first place to shut down. Of course, naturally. So, everything had to switch to phone assessments because these were older people. They didn’t all have access to computers. I thought, “Oh, my gosh.” It was really challenging. But we did the intervention. The control group got educational materials and they had regular assessments. The intervention group, basically people could pick what they wanted to work on. They were given what their risk factors were and they could pick what they want to work on, how they wanted to work on it. Did they want to do classes; did they want to do an app? And they would set goals. This was done in a traditional motivational coaching, health coaching. We also worked a little bit with the primary care team certain of the risk factors.

Then it was two years, like FINGER. At the end of two years, which just ended over the summer, we then looked at the data, blah, blah, blah. I presented this at the big clinical trials meeting in November in San Francisco. Lo and behold, we found that the intervention group did much better than the control group despite these very insensitive phone assessments, et cetera. So, we were able to show that we could improve the risk factors. The risk factors were reduced in the intervention group, and their cognition was, compared to the control group, much better. Of a magnitude, much, much stronger than the FINGER trial or even a lot of drug trials.

Eric: And if I remember the FINGER trial, the outcome was mainly a neuropsych battery.

Kristine: Yes.

Eric: Similar to the cognitive training issues, it’s not like how things are working in real life or…

Kristine: Well, yes.

Eric: Because it’s a short trial, right? Two years.

Kristine: Yeah. That is sort of the nature of the beast, often. Yes.

Eric: Yeah. Same thing here, looking at these cognitive batteries, or smaller, probably, cognitive batteries, because if it’s on the phone for some of these folks.

Kristine: Yes. Time, it was a cognitive battery. That was our primary outcome. Yes. We did look at quality of life and that was better. We had a bunch of other outcomes that we had planned, but they were all in-person, and so we couldn’t…

Eric: Were there themes that most people chose? Or was it kind of all across the board?

Kristine: Yeah. Most people wanted to work on physical activity. A lot of people wanted to work on sleep, and it was across the board, but the biggies were physical activity and sleep.

Eric: And let’s say they want to work on sleep. Is it like a CBT app that they did for sleep?

Kristine: Correct.

Eric: I’m guessing you didn’t give everybody Ambien?

Kristine: No. We didn’t give them drugs. A lot of it was CBTI or even just some sleep hygiene: don’t drink coffee after a certain point of time. It was a variety of things. Or maybe you need to talk to your doctor about getting a sleep assessment, et cetera.

Eric: And for exercise, what was it like?

Kristine: Same. We actually had people use sort of a Fitbit if they wanted to, or they could do classes. Again, it was sort of personalized to what they wanted to do, how they thought they would be able to change their behavior the most.

Alex: Yeah. Yeah.

Eric: Let me ask you, for diet, did it include… I know Mediterranean diet has been… Ah! It feels like a lot of people don’t talk about it as much anymore. Is that part of what people want to do around diet? What were the recommendations if they wanted to focus on diet?

Kristine: Diet wasn’t one of the risk factors that we included in the… We had eight things that could get you into the trial because I don’t think the evidence with diet is as strong, frankly. I think it’s very likely confounded by a lot of things, but I think the jury’s still out.

Alex: Yeah. So, not completely convinced by the eating fish and the Omega-3 and the…

Kristine: Well, I think the Mediterranean diet probably has the best evidence of things. But again, I don’t feel that that’s as solidly understood or investigated.

Alex: Yeah.

Eric: Well, let me ask you another thing. One of the hot topics in the last couple of years has been the focus of social isolation potentially as a risk factor for dementia, too. Does that play a role as you think about kind of advice?

Kristine: That was one of the things we looked at in our trial, by the way, social. Don’t forget, this was COVID. So, a lot of the risk factors…

Eric: We were all socially isolated.

Kristine: … got worse and they got worse, particularly that first six months. There was a lot of social isolation and just physical inactivity. But they got less worse in the intervention group during that COVID bump.

I think social isolation’s, again, very, very interesting. I find it a little hard to disentangle from some of these other things. I don’t know how it operates. Is it really a risk factor? Is it sort of the company it keeps? Is it more the depression leading to the socially… I’m not really sure, but I think it’s a very important area for sure.

Alex: Right. I just want to clarify, when we’re talking about major outcome, which is this cognitive battery, is it that their cognition in the intervention group actually improved or did it decline less than the control group?

Kristine: Good question. They both improved, which sometimes we see in healthy… They weren’t cognitively impaired… healthy adults. We often do see whether that’s a little practice effect or something. So, both groups got better, but the intervention group got 80% more better than the control group.

Eric: Do you remember the eight different risk factors that you could choose from?

Kristine: Let me try.

Eric: This is like a cognitive battery for you, huh?

Kristine: Let me try. Yeah, hold on…

Alex: I’m counting on my fingers as we go.

Kristine: Thank you.

Alex: I’m putting up eight figures, and I’ll bring down one finger for each one, Kristine.

Kristine: Thank you very much. Okay. We had diabetes, hypertension, risky medications. So, medications that… Like sort of Bier’s criterium.

Eric: Anticholinergics, benzos, those.

Kristine: Yeah, exactly. Then we had physical activity; we had sleep; we had social isolation; depression. And where are we?

Alex: One more.

Kristine: One more.

Eric: Did we do exercise already?

Alex: We did. Physical activity.

Kristine: Smoking. We had smoking.

Alex: Smoking. Yeah.

Kristine: Smoking, which, by the way, didn’t move. I wouldn’t do smoking again because…

… by the time you’re 75 or 80 and you’re still smoking, I think you’ve decided you’re going to still smoke. So, there were very few people who smoked and it was hard to move those people.

Alex: Yeah.

Eric: Do you think it’s worthwhile, based on this, is like if you have somebody who’s concerned about their risk for dementia, to assess for those seven risk factors and maybe throw in smoking too, still, and see which ones they feel like…

Kristine: By the say, some of the reason we picked those is because… I didn’t get into the detail of this trial, but we were using EHR to be able to… We were trying to make it a little pragmatic. So, we wee using EH R to assess. If you were to ask me what are the eight risk factors, I’m not sure I would’ve picked exactly those eight. Theoretically, this was somewhat practical.

But here’s what I think. This is a very exciting time in the Alzheimer’s field. We finally, after 20 years, have some new drug development, which obviously is quite controversial, but nonetheless, there are a lot of excitement and exciting aspects to it. The biomarker discovery is tremendous, and I think truly will change the entire way ADRD is diagnosed and conceptualized in some ways. So, it’s a very exciting time.

I do think that these modifiable risk factors are extremely important as well. I do think that they should be part of what we ask and what we measure and what we advise people to do. Absolutely. My prediction, my hope is that in 10 years, Alzheimer’s is going to be more like cardiovascular disease, where we have a drug for tau; we have a drug for amyloid, but the early steps or maybe the adjunct are these risk reduction strategies.

I don’t think it should be black and white. I don’t think it should be, are you more a drug person or are you more a risk reduction person? I think you have to do what’s right for the person, and they’re all grounded in biology and they all seem to be beneficial.

Eric: Yeah. In some ways, I mean, I guess the question is with these new drugs, these amyloid antibody drugs, lecanemab, aducanumab, having them does not negate the importance of these other potentially preventative interventions.

Kristine: Well, that’s my belief, yes. Sure.

Alex: Well, we should get into that a little bit more. We’ve talked about this with many other folks, Jason Carlowish and Aaron Kesselheim, and many others about aducanumab and lecanemab, these anti-dementia drugs. Interested in your thoughts on these. As you said, it is an exciting time. How excited should we be about these drugs?

Kristine: All right. Tongue in cheek, cautiously optimistic. Look. For 20-30 years, people have been saying it was the amyloid cascade hypothesis, and that if you could just get rid of the amyloid or slow the amyloid deposition or increase the clearance. All these drugs over the years either didn’t work or caused a lot of harm. The whole field had really kind of been devastated and many drug companies weren’t really pursuing Alzheimer’s as a focus anymore, et cetera.

So, in many ways, this came at a very important time for the field because I think there was a lot of frustration, billions of dollars, et cetera. So, I think, in some ways, it was reassuring to all of those decades of research that, oh, yes, the amyloid really is important, and moving amyloid, reducing amyloid, and binding amyloid, which is clearly seen, really is a strategy that has some benefit. So, in that sense, I think it was very exciting and hopeful.

Personally, I think that certainly aducanumab, the negatives to me outweigh the positives. The trials are mixed; the side effects are very real. Even if sometimes asymptomatic, often they are symptomatic, the expense, having to have infusions, et cetera. So, for me, I don’t think it’s something I would advocate for patients.

Lecanemab, I think we’re still learning more about. But it seems like the efficacy was a bit more clear. The side effects were a little less. So, I think we’re still learning a lot about it. I think lecanemab may turn out to be something that is helpful for people, but I think we still don’t know a lot. The effect size was small. There was a 27% difference. But I tease everybody, 27% of what, right? That’s the thing people don’t understand. I said that and people said, “Oh, 27%, that’s a lot.” I’m like, “Well, 27% of what?” It wasn’t a big effect. But I think, again, it’s a step in the right direction. I don’t know for sure, but I think lecanemab will be something that’s going to be used a fair amount. I think in the next few years we’re going to know a lot more.

Alex: Eric, I know you’ve pushed on this issue before, that lecanemab did a great job of removing amyloid, and yet the result was a 0.5 difference in cognitive decline on an 18-point scale. So, it clearly seems to indicate that while, as you say, removing amyloid does have potential and it does seem to do something, it sure means that there’s like a lot of dark matter out there. There’s something else going on that we need to work on because if we just focus exclusively on amyloid, we are not going to make big major public health changes in this department.

Kristine: To be fair, I think there’s just so many things we don’t know. Is it that there are other things that weren’t happening, and that’s why despite lowering the amyloid, it only worked a little? Is it because it has to happen 10 years before? I don’t know.

Eric: It also kind of feels like we’re rehashing similar arguments we had with Aracep 20 years ago on something that’s statistically beneficial, but marginally clinically. Again, we don’t know if the benefit’s going to accrue over time. Is it going to be the same? Or is it going to get worse because they’re now having these complications from lecanemab?

Kristine: Exactly.

Eric: All right. Since Alex stole my magic wand question, I got another question for you. This is my last question. I’m 48 years old. What should I do in my life right now to help… And again, I know we don’t have RCTs of Eric Widera doing prevention trials, but what’s the best guess? What should I be focusing on? A, I don’t smoke.

Kristine: Right. I get asked this question all the time. I would say take care of your heart. Right now, maybe you’re heart healthy, but obviously try and maintain that. If you end up getting high blood pressure, like most people, make sure you pay attention to it and treat it as well as you can. Same with diabetes. So vascular health, heart health, for sure. I put that up top. Then I’d say be active, mentally active, physically active. Wear a helmet. Try not to get a traumatic brain injury. Wear a bike helmet, et cetera. And try and get a good night’s sleep.

Eric: That was excellent. I love that advice. Alex is a big biker. So, Alex, make sure you’re wearing your helmet.

Alex: I do wear a helmet.

Eric: Yep. Just stop falling so much, for God’s sakes. [laughter]

Kristine: There you go.

Eric: That was wonderful, Kristine. But before we end, maybe we can end with a little bit more of the Beatles.

Alex: Beatles. (singing)

Kristine: Woo-hoo!

Eric: Kristine, thanks for joining us on the podcast. It was really wonderful. I learned a lot.

Kristine: Good to be here, you guys. Have a great weekend.

Eric: And thanks to all of our listeners for continued support.

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