What Clinicians Should Know About Alzheimer’s Treatment with Marc Agronin, MD

Journal of Clinical Psychiatry: psychiatrist.com/jcp/

Dr. Marc Agronin: https://www.marcagronin.com/

Figure referenced at 53:35 comes from Figure 1 in the paper “Alzheimer’s Disease Drug Development Pipeline: 2025.”: https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.70098

Ben Everett, PhD, is the creator and host of The JCP Podcast, a series that brings together leading voices in psychiatry to explore the latest research and its clinical implications. Everett earned his PhD in Biochemistry with an emphasis in Neuroscience from the University of Tennessee Health Science Center. Over a two-decade career spanning academia, publishing, and the pharmaceutical industry, he has helped launch more than a dozen new treatments across psychiatry, neurology, and cardiometabolic medicine. His current work focuses on translating complex scientific advances into accessible, evidence-based insights that inform clinical practice and foster meaningful dialogue among mental health professionals.

This transcript has been auto-generated and may contain errors. Please refer to the original recording for full accuracy.

00:00 – Meet Alzheimer’s Research Leader Dr. Marc Agronin

Dr. Ben Everett: Welcome to The JCP Podcast, where we explore the science and stories shaping mental health care today. I’m your host, Dr. Ben Everett, Senior Scientific Director with Physicians Postgraduate Press, publisher of the Journal of Clinical Psychiatry. On this podcast, we speak with clinicians, researchers, and thought leaders advancing the field of psychiatry with a focus on not just what’s new, but what’s meaningful for our listeners in their clinical practice.

My guest today is Dr. Marc Agronin, one of the nation’s leading geriatric psychiatrists and a pioneer in Alzheimer’s disease research. He serves as the Chief Medical Officer of the MIND Institute at Miami Jewish Health, where he leads one of the most active memory disorders and clinical trials programs in the region. Dr. Agronin completed his undergraduate studies at Harvard, earned his medical degree from Yale, and completed residency at MGH McLean, and subsequently did a fellowship in geriatric psychiatry at the VA Hospital in Minneapolis.

Over his career, he has authored numerous books and peer-reviewed articles on aging and dementia, and his writing has appeared in major outlets including The Wall Street Journal and The New York Times. A major focus of his work is advancing therapeutics for Alzheimer’s disease. He has served as a principal investigator on multiple cutting-edge trials, including recent phase 2 studies evaluating novel strategies for Alzheimer’s disease, including agitation and disease-modifying approaches. Beyond research, Dr. Agronin is known for his humanistic leadership in dementia care, including the development of the Empathy Care model at Miami Jewish Health, which emphasizes dignity, purpose, and person-centered treatment. 

It’s an honor to welcome you to the podcast today, Dr. Agronin.

Dr. Marc Agronin: Thank you so much. It’s an honor to be here.

01:45 – Why a Career in Geriatric Psychiatry and Dementia Care?

Dr. Ben Everett: So let’s kind of start at the beginning. In your undergrad, you focused on or majored and double majored in psychology and philosophy, which you can do a lot of different things from those two backgrounds. Did you know at that point in time that you wanted to go into medicine, or did that happen later on or sometime during your undergraduate studies?

Dr. Marc Agronin: I not only knew I wanted to go into medicine, I knew I wanted to go into psychiatry at that point, too. I think I decided on medicine in third or fourth grade. I grew up in a little town in Wisconsin, and my grandfather was the town doctor. That always inspired that role of a doctor, and I grew up seeing that very traditional role that a doctor can play, not just with a person or a family, but with a whole community.

As I got older, I knew I wanted to stay within medicine, but I had so many interests in different philosophers, in psychology, and a lot of the personalities in psychology. I got to meet some of them in college. So that pretty much brought both roads together. And psychiatry was really the only option at that point.

Dr. Ben Everett: Yeah, we talk to a lot of people. Like I said, we ask kind of the same questions. And psychiatry seems to come later for a lot of people. You may be the first that you knew pretty early on, but it’s a great story about how your grandfather played such a pivotal role in your life, but also just your community. I think that model of kind of the town doctor can be so powerful a driver for people going into medicine. And then your geriatrics – so you did a geriatric fellowship at the University of Minnesota VA following your residency. Did you know during residency that was something you wanted to do, or before that?

Dr. Marc Agronin: I always loved working with older people. I grew up surrounded by elders, and so, to me, I never looked at aging as representing decline or decrepitude. To me, aging was such a rich time. I always felt inspired by older individuals. I loved their wisdom, I loved their stories. So to me, it was also a very logical thing to go into.

Probably the first week in medical school, well, you could say happenstance, but I think there were certainly larger forces at play. I met a geriatric psychiatrist. I had never really heard of the term before, but we had such a nice bond, and I ended up doing some research with him and working with him. So that really cemented all roads now: philosophy, psychology, medicine, psychiatry, and now geriatrics all came together at that point, and I never really looked back.

What’s interesting to me today is even at this point, I’m doing all the same things. So if you were to look around me, you’d see me surrounded by books on philosophy and psychology and psychiatry and geriatrics, and all my loves brought together. And the hope is, in the coming years, is to put all that together into some new projects and to really develop or better develop a philosophy that honors our elders and provides the best care, but working within all the systems today and all the science that we have today.

Dr. Ben Everett: I think so many people don’t have that. It’s this confluence of all these different factors in your life and your upbringing kind of coming together, and you really feel like you’re doing everything that you love and enjoy, which I think always translates into that passion that I saw at least when you were on stage talking about this. So that’s awesome.

Speaking of seeing you on stage, we met right after you gave a presentation at Psych Congress a few months ago. It was called “Alzheimer’s Treatment in 2025 and Beyond: Emerging Therapies and Clinical Applications.” I did neurodegeneration as a graduate student. I haven’t really stayed on top of it as much in my career as I’ve gone into different things. And I knew there was a good bit going on in Alzheimer’s, but I had no idea the depth and breadth of the research that was going on right now.

And some of it is even disease modifying, which has been almost like just something so aspirational, it seems like in our lifetime. I didn’t know if we were going to get there. And to see that that research is going on now was really inspiring for me. And the other thing was just the way you laid everything out. I was like, man, I’ve got to get this guy on the podcast. Just the way you told everything and the way the story kind of developed over that 45 minutes or an hour your talk was. I was like, this is going to be great. And so here we are now.

So that said, before we really dig into the science, you’ve become a bit of a clinical trialist in this area. You’ve talked about geriatric psychiatry, psychiatry, philosophy, all these different influences. How did you pivot or get into clinical research on top of just doing clinical care for this patient population?

06:17 – Why Alzheimer’s Research Is Entering a Breakthrough Era

Dr. Marc Agronin: You’re right. There’s a lot going on now with Alzheimer’s disease. And I say, “Thank God,” because we’ve needed changes for a long time. When I started out at Miami Jewish Health in 1999, I would say a lot of what we were doing was not too different from what Dr. Alois Alzheimer was doing 100 years before. With that being said, we’ve had a lot of change since then. Five years ago, a study came out indicating that about 99% of all clinical trials in Alzheimer’s disease had failed. Finally, we’re starting to move the needle.

It wasn’t really a pivot for me to do this, because when you’re working with individuals who are aging, who have neurocognitive changes, who have psychiatric issues, you want to make sure you take a comprehensive approach. And that will involve comprehensive assessment. It will involve working with the family, getting to know them. It will involve all the latest in treatment, and by necessity, that will include clinical trials.

And at the time when I began putting together this memory disorder center, aside from clinical trials, there really wasn’t much else you could do for someone, at least in terms of therapeutics. It fit perfectly into what we do, and we make it a part of the treatment. There are certainly entities that exist where you go just for research. We are not one of those, because sometimes research makes sense for someone. It certainly makes sense always for the state of the science. But we always have to look at the person and what they need. And often research plays a pivotal role. So that’s why I’ve integrated it into what we do at our center, and we will continue to do that. But I will say it’s been different the last couple of years, and I know we’ll get into what’s different and where we’re heading. But it’s exciting, but we still have a ways to go.

08:07 – Why Alzheimer’s Disease Is Rising Worldwide

Dr. Ben Everett: You talk about the staggering rise in Alzheimer’s disease prevalence. What do you think is driving that? Is it just baby boomers aging, or is there something else going on, or any signal trends that people need to be looking for clinically, for early and appropriate screening and diagnosis?

Dr. Marc Agronin: We know Alzheimer’s disease has always existed. When Alois Alzheimer first looked at the brain of a patient of his after she passed away, what he found he didn’t really understand at the time, but he knew that these findings, these plaques scattered throughout the brain, these hair-like tangles that he saw within nerve cells, he knew that that had to play a role here. And in subsequent decades, individuals noticed a correlation or an association between more of these plaques and tangles and more neurocognitive impairment. It wasn’t until many years later, in the 80s and 90s, that we determined the stories of amyloid and tau being so pivotal here.

The other thing that changed is that not only did we start getting better at recognizing this, but our society continued to age. Alzheimer’s disease is largely a disease of old age. So the more people living healthily into their 80s and 90s, the more people you will see with Alzheimer’s disease. And the other difference is that when I say people are healthier as they get older, we see fewer other causes of neurocognitive disorders. So with better control of blood pressure and cholesterol and cardiovascular factors, we see better control of cerebral vascular factors, less stroke, less cerebrovascular brain damage.

That’s good news. People are living longer, they’re healthier, but now we see more Alzheimer’s disease. And so the prevalence of it has really exploded over the past 40 years, and it will continue to almost double within the next 25 to 30 years. So that’s the concerning trend, but it really speaks to the aging of our society, not just here in the US but everywhere in the world.

There’s one hopeful sign we’re seeing. If you look at the incidence of Alzheimer’s disease in younger cohorts, people now in their 50s and 60s, we’re beginning to see a little bit of a dip. And to me, this suggests that maybe the focus on healthier lifestyles is beginning to make a difference. And we hope to build on that. I’m sure we’ll talk about some of the recent studies that point to the role of a brain-healthy lifestyle. But the future is going to be a peaking of Alzheimer’s disease in the next 20 to 25 years. And then if we don’t have a cure by then, which I hope we will, but certainly we’re going to start seeing a decline even as our society is aging. And we will see brain health becoming a major force, just like heart health has been the past few decades.

11:04 – How to Explain Alzheimer’s Diagnosis to Patients and Families

Dr. Ben Everett: I’m here for that. That sounds wonderful. You mentioned a couple of things. You know, amyloid, tau, you talk about synaptic dysfunction in your talk. These can be pretty heady scientific topics to discuss with patients that might not have any medical or scientific background. You throw in some cognitive decline. How do you have these conversations with patients in a way that really empowers shared decision making?

Dr. Marc Agronin: This is a really important question. So many people come to me and no one has explained to them this disease and what’s going on. And if they don’t understand it, it’s more difficult for them to cope with it, to plan, to make decisions. And shared decision making absolutely depends on having that understanding, because then you have to make a level playing field in which you’re having a discussion with someone. So you’re not imposing a treatment on them, you’re explaining it, you’re giving them options, and you work together to make that decision.

So there’s a few things that have changed in the way I’ve talked to people about this disease, how I explain it, and my overall stance, and I want to start with that word I just used, stance. What I mean by that is that when you walk into the room with someone, already you’re making assumptions about them uncontrollably. We look at them and we see how old they are. We may have a sense for how well they can communicate, who’s with them, what we know about the diagnosis ahead of time. And unfortunately, these assumptions can get in the way because we may know how old they are, but the question is, what does that mean? We may know they have a diagnosis of Alzheimer’s, but is it accurate or not? We may see who they’re surrounded with or how they’re communicating with us, but is that truly who they are as a person?

I walk into the room with an open mind and with a sense of hope. Hope for building a relationship with them and for their future as a person. And that will be my guide. And I don’t want to underestimate this because it’s critically important. People know, they pick up on it, they sense it. And it also influences us, how we look at this disease. If you walk into the room thinking in your mind, well, this is a terminal disease, there’s nothing we can do or little we can do, that will influence the interaction, the relationship, everything downstream. That’s number one, the stance.

Number two is I no longer use the term dementia, or I try to avoid that. This is an ancient term. It comes from Latin. It was used in ancient Rome not only to describe people who were in dementia without a mind, but it was used, as you can imagine, as a political insult, as a put-down. If you and I were sitting in the Roman Senate here, we probably would not be surprised to hear a toga-clad senator get up and accuse one of his colleagues of being demented. Wisely, the American Psychiatric Association, going back ten plus years, said, we don’t want to use this term anymore. Now we will use the term neurocognitive disorder.

It’s a broader term. It may be unfamiliar to people, so my terminology is, I talk to them in terms of neurocognitive function, neurocognitive changes. So I’m not saying you are demented, you have dementia. I say you have neurocognitive changes. And I explain what those mean. I talk about at some point whether they may have a neurocognitive disorder. I emphasize at the same time that we’re working together here. This is not a race, it’s a marathon. So we may be working together for years and we’re going to keep you living as normal and happy a life as possible. At the same time, we’re going to get at this disease.

This process is enabled by a lot of the new developments. So we’re better at diagnosis. So it’s not such a mystery what’s going on. We now have a way to modify the disease itself so we can give people hope that we can actually slow it down. And for those who are beyond that point or who have really severe issues, it gets more complicated. But nonetheless, I’m still a firm believer that the stance we have, that we engender with others, that hope we bring into it, gets everyone involved. Because someone may walk in with more advanced disease and let’s say a really complicated neuropsychiatric symptom, apathy, agitation, things like that. And the caregiver is struggling and wrestling with this. The person is suffering because of this. We have to jump in with sleeves rolled up and do everything possible to move the needle to get things better.

And we can do that, but it’s very, very challenging. I think this is why very few people are going into geriatrics and geriatric psychiatry. Very, very few people, which is a problem. There aren’t enough people out there with this expertise. At the same time, you have this explosion of people with this disease state. So, yes, I’m very passionate about the fact that I think if people need the best care, we need to get them into the best hands. And those are individuals who are well trained. It doesn’t just have to be a doctor, but it’s the whole team. When I work with my team, I have about ten people, and I say, we need to wrap this person in all of us. Everyone here needs to understand the disease, understand how to work with people. So it’s not just one person who makes a difference. We all make a difference together.

16:11 – The Biggest Scientific Breakthroughs in Alzheimer’s Disease

Dr. Ben Everett: You kind of alluded to how much has been going on here the past couple of decades. Is there one thing in your mind that is the biggest shift in Alzheimer’s disease? No right or wrong answers, but I think a reasonable person could probably point to multiple different things. But I’m just curious, do you look at as being this was really the thing that turned the tide in where we are now?

Dr. Marc Agronin: Two different things. So one of them, I’ll tell you a story maybe going back 20 years. I remember a young researcher, a budding individual with pharmaceutical companies, came to me and said, “Hey, what do you think of this idea? We developed a dye that can stick to amyloid protein and we want to put together a study to show that what happens in the brain is what we’re seeing when we scan the brain of the PET scan.” And I thought, wow, that could be a game changer. And it went on to become a game changer. And now again, I had a very peripheral involvement with that. I was a member of the study. But in terms of the development of that, this is an amazing team that put this together.

But this is the change since 1905 when Alzheimer took a brain out, sliced it, and put a dye on the tissue and looked at it under a microscope. We literally had not changed in our ability to really make a certain diagnosis of Alzheimer’s disease. Taking a brain out or a piece of brain out is not a very efficient or welcome way to make a diagnosis. So now we have a new way to do that without taking the brain out. You put the dye into the body, it sticks to amyloid if it’s there, and you light it up on a PET scan. It’s like a virtual brain biopsy.

So this as a biomarker changed the whole landscape. Now, up to this point, we could, by doing MRIs and clinical testing and even other type PET scans with fluorodeoxyglucose looking at metabolism, we could get pretty close. But now this real-world biomarker, looking at an image of the brain and seeing the amount of beta amyloid, changed the whole landscape here. And now when you couple that with looking at either spinal fluid or now blood-based biomarkers, we can make a more accurate diagnosis, I would say in sometimes a more complex diagnosis, as it makes it clear it also obscures other things. But that development with biomarkers had changed the entire landscape because now we can identify people even before they’re symptomatic. That’s number one.

The second is for many, many years on this basis of a theory that amyloid and tau is so important, using immunotherapy to get rid of amyloid, with the theory being if amyloid is playing a role and you get rid of it, a person should, if not get better, at least not get worse at the same rate. And that was shown conclusively. We know with the immunotherapies now, we can slow the disease down. We don’t cure it, we don’t make people better, but we slow it down. So it tells us that even if at the end of the day, amyloid and tau aren’t the main issues, at least at this point in history, they are the main issues that we’re focusing on, that we’re moving the needle on and making a difference.

So consider how different it is, someone walking to my office in 2025 versus 2005. So they come in now, and with biomarkers, I can tell them, yes or no, you have Alzheimer’s disease. I couldn’t do that with certainty in 2005. And I also can say we can slow it down. So what you will be like from now in the next five plus years will be vastly different than 20 years ago. Because if you can slow it down 30 plus percent a year and you unfold this over time, it makes an enormous difference. This is the fundamental shift. Someone goes from thinking I have a terminal disease to I have a manageable disease and I’m going to continue to live and do things. Their whole mindset changes. That sword hanging over their head has suddenly been removed, or at least it’s been lessened. And they can have a sense of hope, a sense of normality.

It’s a game changer. And I would liken it to look in the world of cancer, what’s happened. You have many, many forms of cancer, which 20, 30 years ago, people looked at like a death sentence, now that are manageable, some curable, and that will continue to accelerate. I mean, it’s accelerating at a tremendous pace. So it changes the whole mindset of what this disease is like. You know, over our lifetimes we’ve seen that with other diseases. I mean, think about HIV and AIDS.

Dr. Ben Everett: Exactly what I was thinking a minute ago. Going from just the fear associated with the potential of an HIV diagnosis to now when we get PrEP. It’s amazing what we’ve done there.

Dr. Marc Agronin: It’s extraordinary. It’s due to just the absolutely ferocious efforts of so many scientists and advocates and others to get us to that point. We need to do the same with Alzheimer’s disease. I think there’s been a lot more funding and more advocacy lately. But far from what we need to do. Look, football players, others are running around wearing pink shoes for breast cancer awareness. People talk about cancer and cancer research and everything out in the open and promote it. And survivors running races. It’s great. We still don’t do enough of that for Alzheimer’s disease. And yet what’s ironic is that Alzheimer’s disease is the most expensive disease, more so than heart disease, more so than cancer, and exploding in prevalence.

A lot has to do with how we view aging and how we view older people. Which brings me back to my roots, that I spend as much time thinking, working, writing about aging and how we view it, because at the end of the day, how we view aging is how we’re going to view age-associated diseases. And if we have a negative view, it certainly will not translate into optimal care, research, all of that. This is also why for me, being passionate about is not just about helping patients and advancing research, but it’s also about changing our minds and how we look at the aging process. That stance we have is different because what’s remarkable, somewhat of an aside, is that we know having a more positive attitude towards aging influences your aging. People live longer, they do better, they have a lower risk for dementia with a more positive attitude towards aging. And when you realize that, you think, well, we better promote these positive views because that can make a difference.

I have to insert one story here because I just love how this illustrates that. I had a book called How We Age and then The End of Old Age, that came out in the last 10, 15 years, and I gave a talk once, and I made the point, as I said a minute ago, that if you have a more positive attitude towards aging, you live longer. There’s been a lot of data towards that. And someone who listened to the talk went home and they said they went to a talk on aging and their daughter at the time was maybe eight or nine, kind of poked fun at the parents and said, oh, you’re getting older and this and that. And they said, you know what I learned? If we have a more positive attitude to aging, I will live longer. Obviously, for a young kid, it just transformed their whole view and said, oh my God, I’m going to think of aging in a great way because I want you to live longer, Mommy. And I thought, wow, when you think about it, it’s very true. When we feel better, we’re happy, we’re more hopeful, we look at things in a good way, whether it’s aging or anything. It changes our performance, it changes how we feel, it changes our body chemistry, it enhances life. We are working now in some of the most difficult straits here with people with Alzheimer’s disease and other neurocognitive disorders. We have to have the right stance. We’ve got to get that right. We owe it to them, we owe it to ourselves. All of us are aging, all of us are heading to those waters. So what we’re doing and giving for them, we’re doing for ourselves as well.

Dr. Ben Everett: I just love the way that you approach this, the stance that you talk about, because it is empathetic. It is just talking to your patients with empathy. But the dignity, the grace that you’re extending to these people and like you said, just brings patients hope. And I think as clinicians, that’s just one of the best things that you guys can bring to people. That’s amazing. 

Let’s pivot a little bit and talk about where are guidelines now. So we’ve got the National Institute on Aging and Alzheimer’s Association, NIA-AA. So they’ve got new guidelines published last year. So 2024 and biomarkers made the guidelines for the first time. So you’ve talked about what a change that is, can you just speak a little bit about where we are with guidelines and biomarkers?

24:30 – How New Biomarker Guidelines Are Changing Alzheimer’s Diagnosis

Dr. Marc Agronin: Right now all of this is really hot off the press, this immense change in how we think about this disease and how we are going to follow it. So the difference now is that biomarkers help make a determination of whether you have Alzheimer’s disease or not. And you can stage people from having a positive biomarker and no symptoms, to positive biomarkers and very mild symptoms, to actually frank neurocognitive impairment with positive biomarkers. That’s where we started in the past. Now we have a whole track up to that.

It’s important with this staging because, number one, it’s accurate. In the past, it was a lot of guesswork and probably 20 to 25% of people diagnosed with Alzheimer’s disease never had it. And we know that to some extent because in some of the earlier immunotherapy trials, they began without having the requirement that you need an amyloid-based PET scan. And they added that later. And what they discovered is that a quarter of the subjects didn’t even have sufficient amyloid in their brain. So obviously you’re not going to get better from the treatment. So that’s probably accurate today. So the biomarkers give us better diagnostic and staging schemes. That’s really important.

At the same time, we also have a clinical staging scheme. You can have individuals on two different tracks. You’re looking at that one track which would be, do they have amyloid plaques and tau tangles in their brain and if so, to what extent? Let’s quantify that. How much is there, where it is in the brain, from people with just amyloid to those with amyloid and tau, to those who have tau, not just in the medial temporal cortex, but throughout the brain. And as you go along with more and more burden of amyloid and plaque, you tend to see more symptomatic disease. But you also can look at them clinically from mild, no symptoms, just the inklings of symptoms, mild cognitive impairment, and then moderate to severe.

When we put these two schemes together, you’re categorizing someone based on their biology and based on their clinical state. It gets complex. We still need a lot of work to do on this, but the scheme as it comes out allows us to track people in a more descriptive way. And over time, as we do a lot more research, it will probably help with prognostication as well. So if we know that at a certain point you have this biology, this is your clinical stage, this is the staging that you’re at based on the confluence of these two. Now we can better predict where you might be a year or two, or what treatments at this stage are going to be better. It’s just the beginning. We’re looking at this in a more descriptive, a more detailed way, and it certainly will have impact.

The other question it really raises now is what about people who have positive biomarkers but they’re not symptomatic and maybe they’re not even close to being symptomatic? We know that individuals with the apolipoprotein E4 allele, especially if they’re homozygous for it, have really a significantly increased risk, not only for Alzheimer’s disease, but just having amyloid pathology at a certain stage. I think one study looked at APOE4 homozygotes and found that by the age of 65, close to three-quarters of them already were lighting up with positive PET scans. Maybe they weren’t symptomatic. So what do you do? What do you tell someone like that?

This is really critical because in the past, if you had no treatment, why would you even want to know this in the first place? Now we’re motivated to know because we can give someone immunotherapy. The real question will be, when do you give it? What if someone has positive biomarkers but they’re not symptomatic? Do you give them the immunotherapy or not? Now we have anti-amyloid immunotherapy, we’re working on anti-tau, but still very experimental. There are still a lot of questions out there, but just the fact that we’re even talking about this and focusing on this tells us that we’re in a very different era. And this diagnostic scheme that we are talking about now is a way to put this together in a way that we can understand it better and begin to educate patients and caregivers about that as well.

Dr. Ben Everett: Yeah. The APOE4 story, I think, is very interesting. I’ve done a lot of cardiometabolic research in my career, and even 20 years ago, you look up APOB, APOC2, or APOC3, and it was all cardiometabolic, right. And you look at APOE and it was all neurocognitive and even trying to correlate APOE to cardiovascular disease. PubMed was just dominated by neurocognitive research. But if people get that APOE blood test done, you can make some dietary changes that we think will impact how you do this. And it’s one of these things. The earlier you can intervene, the better. I actually talked to my family practice physician about this in my annual. He was a fraternity brother of mine. We’d grown up together. We’d known each other a very long time. And he brought it up. He said, yeah, look, this APOE. He said, I’m having a lot of patients come in and request this now because they had a grandmother or an aunt or something like that, and they just want to know, hey, is there anything in their family history? So I thought, that’s good progress when you’ve got family practice specialists thinking about this and understanding that component to the pathophysiology. Yeah. So I think those are always good.

Your talk emphasized delayed assessment being one of the major obstacles to effective care. What are these common missed opportunities in early evaluation? And this kind of ties into the family practice or your generalist, your intern, whoever it is you’re thinking, is there something that primary care colleagues need to be doing before they refer to a specialist?

29:57 – Why Early Screening for Cognitive Decline Matters

Dr. Marc Agronin: As a specialist, I would always advocate for a specialist person with the most training and knowledge to do that. But realistically, that’s not going to happen. One, you don’t have enough specialists out there. Access is a major issue. So it leaves us with primary care settings being really in the trenches, and primary care physicians, whether you’re a doctor, PA, a nurse practitioner, any of these areas of social worker, you need to understand this well and be able to at least get people on the road to getting a good assessment.

So I divide it up into two different pathways here. So the first one in primary care would be get the story, know what’s going on with someone, be able to hear a story about potential neurocognitive change. Make sure you do your basic blood work and exams. If someone really has a concern or you have a concern, always in the office, have someone be able to do some sort of cognitive screen. We have all sorts of vital signs we check by routine. We need to have a cognitive vital sign that we check, and something like a Mini-Mental State Examination or Montreal Cognitive Assessment, something like that is practical to be done in primary care, should be done on an annual basis and used as a triage instrument, basically, not as a diagnostic guide. And if there’s concern, certainly primary care can do brain imaging just to rule out anything significant.

I think that’s the best point to go, because what I emphasize is that you never want to run a test that you can’t explain and interpret the results. I can do cardiograms in my office because we do them for research. But I’m not going to do that routinely because I can’t really explain to the person why I’m doing it, and I can’t interpret the results. And I certainly am not going to be working on treatment. I can’t close that loop. I’m going to leave someone in the lurch until I bring someone else in. And I don’t think that’s good. You never want to start doing all these biomarkers in a primary care without really being able to interpret them, because it’s complex.

Primary care needs to be able to recognize when there are cognitive changes and triage and get them into assessment. Once they get to a specialist, then what we can do is hear the nuances of the story. We can do more sophisticated neuropsychological testing and be able to interpret that. We can run a whole series of different biomarker studies, and then we put that all together, we present it to the patient, we explain it, and it’s important to explain it in the right way, and then we look into treatment. So we work in partnership with primary care to do that.

To me, that’s really important because otherwise people get misdiagnosed or they get treated inappropriately or they miss out on treatment. So that early detection, that accurate detection is really, really important. And to focus on the basic science, too many people come in and they’ve been listening to Dr. Instagram and Dr. Google and all these sources that have a lot of information, a lot of extraneous information, a lot of people out there just to sell you on some blood test or some pill or potion. That maybe sounds good in terms of what someone is describing, but at the end of the day, doesn’t really do anything.

Right now, that’s where the memory disorder center or a specialist comes in, and it’s typically going to be either a neurologist or a geriatrician or a geriatric psychiatrist. I always advocate for my own field, geriatric psychiatry, because so many people come with neuropsychiatric symptoms. So I can not only treat the cognitive issues, but also if there’s depression or agitation or apathy or psychosis or anything like that. But realistically, what I do is unfortunately not common, not people really going into it. So we really need to cast a wide net in terms of specialists who can do this.

Dr. Ben Everett: Have you seen a change in referral patterns or anything with primary care becoming more aware of doing some of these tests and whatnot? And sometimes insurance is just going to dictate. Okay, well, you’ve got to use your primary care doctor as your quarterback. They have to start here and then do the referral. Medicare may be a little bit different anyway. Any changes in referral patterns that you’ve noticed recently with biomarkers or you just having a better idea of where the patient is when they show up?

Dr. Marc Agronin: I’m seeing more primary care offices doing cognitive screens and making referrals. I haven’t seen them doing actual biomarker studies yet, which makes sense, but I think that will continue. I think some sort of cognitive screening will become a more routine part of primary care for aging individuals. But we need to improve what happens afterwards, because that’s what I’m finding is that a lot of times the office doesn’t know how to interpret it or what to do about it. And if they don’t get a person to a specialist, then not a lot happens.

But by the same token, a lot of people come to our center who they’ve already been down the road with a specialist. And now I’m a second or third opinion, not so much because there’s more testing that needs to be done. But no one’s really explained to them the process and gone into the details. And I understand it’s a practical issue. It takes time. Look, we know in medicine today time is money. Medicare is not going to pay you to sit and explain things for a long time. It’s based on volume procedures. So there’s a lot of pressure not to do those things.

So that’s what, at least in our center, I’ve tried to carve out the time and the space for people. It’s hard to do that in settings where you don’t have external funding or research or things like that. So it’s a big issue. It’s a big issue of access. The crazy thing now is we have so much science going on and we have these amazing immunotherapies, but very few people who could be getting it are actually getting it because of issues of accessibility. And once you get out of the US, it’s even a worse situation. So I work in Miami, so we have people coming in from all over South America, Central America, and other places because they want access to treatments that they’re struggling to get outside of the U.S.

Just imagine if you had a chemotherapy that treats a cancer, but people can’t get it. They can’t afford it. You’ve got to jump through ten hoops to get it. I think there would be a lot of outrage. We just don’t see that with Alzheimer’s disease because there’s not the same degree of advocacy and focus on it. And I think that comes down to views on aging. There’s still a lot of stigma about aging. And when you mix aging and neurocognitive disease and psychiatric illness together, you’ve got a double or triple stigma. Unfortunately, people then don’t get the degree of care that they really need to get.

36:13 – Brain Health Habits That May Reduce Alzheimer’s Risk

Dr. Ben Everett: It’s really a lot to think through there. I think I understand your passion for philosophy too because there’s really so much that we could pack in there before we really tackle or dive into the pharmacological interventions. Now let’s talk about what are things that patients can be doing on a non pharmacological side right now. Behavioral, environmental interventions. They don’t get the spotlight. Maybe they’re not seen as sexy, but there are things that can be helpful. What do you like to recommend or talk to people about options on the non pharmacological side where cost and access might not be as big an issue.

Dr. Marc Agronin: So this comes down to brain health. Brain health is a new exciting trend. It will continue. I was at a wonderful conference this past summer sponsored by the American Heart Association. Obviously they’ve always been about heart health, but they very wisely recognize that heart health and brain health are in some ways one and the same. What we’re seeing from lots of accumulating research, particularly the FINGER study out of Finland and now it’s somewhat of a replication of the U.S. POINTER study with the data just came out, is that if you’re intentional about your brain health, it helps cognition, it can reduce the risk for Alzheimer’s disease.

Every several years the British medical journal The Lancet has this wonderful article compendium update of risk factors for Alzheimer’s disease. Now they’re up to 14 official risk factors, but certainly there are others that can be considered and it all comes down to a brain-healthy lifestyle. So what does this involve? Number one is making sure that anything that contributes to brain damage or reduces brain health needs to be addressed and mitigated. That can be substance use, medications with anticholinergic effects, and many others. I would reference the Beers Criteria by the American Geriatric Society is a really good reference for that.

Individuals who have really sedentary lifestyle risk factors like diabetes, high blood pressure, elevated cholesterol, hearing loss, visual loss that are not being attended to and mitigated, all those factors can reduce brain function. So we need to address those. Then there are positive things. Exercise, a healthy diet, similar to a Mediterranean diet, as we’ve been seeing. Keeping your brain and spirit stimulated through social activities, spiritual activities, cognitive activities, doing things you love, so you keep on doing them. Computer games.

Put this together with physical exercise, which I would emphasize really makes a difference. And as I alluded to this before, having a positive attitude, having a sense of purpose, these things make a difference. We put together a scheme in our office for an Alzheimer’s prevention program in which we go through all these risk factors. We score someone low, medium, or high risk, and we give them a color, green, yellow, or red. So to make it really obvious to them whether their risk is high or low. And then we talk about what they can do to address those things and reverse them.

And very simple things. So we know that dental health is important. The bacteria in your mouth is very close to your brain. And some research has even shown a correlation between the amount of bad bacteria in your mouth, which is largely due to poor dental care, and the amount of amyloid in the brain. We need to understand this connection better. We ask people, how often do you see your dentist? What kind of dental care do you get? One person in the study said, I haven’t been in a year. So we said, go to your dentist. And she was happy to report to me next time she had two cavities that got repaired. We probably saved her a root canal, based on our Alzheimer’s prevention program. But that’s brain health. It’s not just oral health, it’s also brain health.

We do hearing tests. We make sure if someone has hearing loss, they get that corrected. Because the growing evidence is showing that using hearing aids or mitigating that hearing loss can reduce the risk. Who would have thought that hearing loss is such a big risk factor for Alzheimer’s disease? Now we know it is. Many different factors like this. We teach people, we encourage them, we educate them, and we’re seeing from data now that when people are more involved physically, mentally, socially, spiritually, in different activities, they feel better, they cope better, they adjust better, and it reduces their risk for Alzheimer’s disease. It improves cognition. I think we’re going to see over and over and over again how well this works.

The one thing I would add is that a lot of people want to just shortcut all this and just take a pill or potion. That’s going to make a difference. And I would just say nothing has been shown to really make a difference with that. Now people are going to tell you it makes a difference because they want to sell you something and it’s usually very expensive. But the bottom line is that that data has not caught up with the claims. In fact, I direct people to the Cognitive Vitality Reports. You can find the web put out by the Alzheimer’s Drug Discovery Foundation in New York. Neuroscientists put together these amazing reports on just about every pill, potion, lotion, purported treatment for Alzheimer’s disease and really tell you the lowdown on them. And you’ll discover that many of them, despite their wild claims, don’t even make it out of the stomach. So they certainly won’t make it to your brain. It comes down to just every day engaging in a brain-healthy lifestyle. That makes a difference. It’s helping your brain, but it’ll also make you feel better. We are really encouraging, pushing that, developing structures for that is part of what we do at our memory disorder center. And that’s something primary care should be doing as well.

Dr. Ben Everett: I like so much what you just talked into there. Sometimes we say, oh, it’s a heart-healthy lifestyle. Oh, it’s maybe a brain-healthy lifestyle. It’s just a healthy lifestyle. Like, we just need to take care of ourselves. I have yet to see any area of research where exercise started as maybe a crazy hypothesis. And they really look into it and it’s like, wow, we’re really moving the needle. Like with schizophrenia and functional improvement, Parkinson’s disease. It’s really pretty amazing what we’re doing there. I mean, who doesn’t like doing a puzzle or reading a book, these types of things?

Dr. Marc Agronin: That’s right.

Dr. Ben Everett: The hearing loss research was kind of new to me, but I feel like I can’t hear at all. Certainly, as my wife and kids tell me, that may be a different type of hearing, definitely on the left side. But I referred myself, I’m 50. I referred myself to an ENT, had my hearing checked. I thought for sure I was going to leave with hearing aids. It’s like you gotta have a baseline, right? You can’t manage what you don’t measure. And so now I’ve got a baseline and high frequency. You’ve got some issues, you know, take care of your ears, protect your ears, but you’re not ready for hearing aids yet. But we’ve got to have that baseline on all these different areas so that we can track how we do over time.

All right, well, let’s move into pharmacology. What’s in the toolbox right now that you can do. Maybe we can start with the easier or the lower hanging fruit and then get into more of the immunotherapy and whatnot.

42:50 – Current Alzheimer’s Medications and How They Help Cognition

Dr. Marc Agronin: There’s two different approaches. There’s cognitive enhancement and there’s disease modification. So cognitive enhancement. There are currently four FDA-approved medications. Three of them are in the same category. They’re acetylcholinesterase inhibitors. That’s your donepezil, rivastigmine, and galantamine. They all do the same thing. So you just need to be on one of those at an optimized dose. We know that acetylcholine is the key neurotransmitter in the brain involved in learning and memory. The cells that produce it are being damaged and dying off. And so your levels of acetylcholine and the cholinergic function of the brain is declining.

So we can bolster that by interfering with the enzyme acetylcholinesterase that breaks down acetylcholine by inhibiting it. With one of these medications taken on a daily basis, we improve modestly cholinergic function and we can see a modest benefit in terms of cognition and function for individuals. It’s not always that noticeable, especially in early stages. You have a bit of a ceiling effect, so you’re already doing so well. So it’s not pushing you up so much that you sometimes can notice it. But we know that from mild through advanced disease, people on one of these tend to do better than not on it. It’s the best we have. Now. They’re all FDA approved based on lots of good studies. That’s our base cognitive enhancement. Paying attention to GI side effects and vivid dreams. Those are the two most common issues.

In addition, when people get into moderate to advanced stages, we can add on to that the fourth FDA-approved medication, memantine. It is an NMDA or glutamate receptor antagonist. We recognize, or we’ve seen over time that excess glutamate activity in the brain can be damaging to cells. It appears to be in many different neurodegenerative conditions you get this excess glutamate activity. Memantine turns down the volume. As I put it, it to some extent reduces, mitigates this glutamate activity also associated with a modest cognitive enhancement. And we know that, at least in some studies, over time the combination therapy tends to give the best results.

And I tell people it’s modest. You might not notice anything. You may or may not, but we know that the data is pretty clear enough to guard our FDA approval that these agents and we know in combination, people do better. So that’s our baseline. I’d love to have better agents, but I will tell you everything out there that you can throw at me. Ginkgo and vitamin E and lots of other things. Nothing has the same amount of data on Alzheimer’s that it makes a difference. So a lot of claims, a lot of people want to sell these to you, but that’s why nothing else is FDA approved. And there’s certainly in clinical trials, lots of things they’re testing, but it’s a high bar. Just claiming something works doesn’t mean it really works. And something like ginkgo is a perfect example because it’s been used for thousands of years in medicine. But when you really do rigorous studies, it doesn’t really bear out the benefit. And so for a lot of people, these agents are more of a placebo effect than anything else.

45:45 – New Anti-Amyloid Treatments That Slow Alzheimer’s Progression

Dr. Marc Agronin: And now we have ways to slow the disease process itself, because these cognitive enhancers don’t appear to affect the actual disease process more the effects of the process. With the new anti-amyloid immunotherapy, basically, we give people antibodies that stick to different forms of beta amyloid in the brain. Your immunologic process in the brain, your immune cells, your macrophages in the brain, your microglial cells literally chew up and dissolve the amyloid. You can watch sequential PET scans and see amyloid plaque literally melting away. It doesn’t make people better. It’s not a cure. But if you track them over time, as the studies did, the pivotal studies for both lecanemab and donanemab, which are monoclonal antibodies directed towards different forms of beta amyloid, we see over the 18 months of the studies that the rate of decline in terms of both cognition and function is on average about 30% slower. And then we know that after 18 months, it’s a very slow rate of reaccumulation. And now you can do maintenance and keep it from reaccumulating.

It slows the disease process down. I give the analogy it’s like putting out a fire after a good part of the house is burned down. You can’t restore the house, you can’t repair it or take a long time. Cause you’re dealing with the brain, but you slow the fire down. Now we still have the damage done, which is why people are not cured. We still have tau, which is another form of fire in the brain, hopefully attenuated to some extent with less amyloid. But it slows it down. And right now that’s been a game changer in terms of how we work with people, certainly over time.

In fact, clinical trials are trying to find ways to clear the plaque quicker, more efficiently, with less side effects more effectively. We’re working on anti-tau immunotherapies. I can imagine a combination therapy that if at the earliest stages, when you find people have amyloid and tau before they’re symptomatic, if you can clear both from the brain, you could imagine it’s close to a cure as you’re going to get. I think that’s the hope, that’s the theory. We will see if that occurs. You think about that with HIV and AIDS. Suddenly the page turned and now it wasn’t for the vast majority of people, terminal illness anymore. You controlled it. That could happen with Alzheimer’s disease one of these days, if we find the right other immunotherapy, we find the right combination, we suddenly could be dealing with a disease now we can pretty much stop or slow in its tracks and either prevent people from getting in the first place or at least slowing it down so it’s manageable for the remainder of their lifetime.

Dr. Ben Everett: I tell you, for whatever reason, if you’re going to have these plaques build up in these beta amyloid and tau tangles and whatnot, if we can’t prevent them from showing up in the first place, certainly being able to clear them efficiently and effectively is definitely a game changer and that’s great. So that you mentioned a 30% slowing, what’s the timeframe over which that occurred? Is that a one year study or, you know, one year study with like three, four, five years of follow up?

Dr. Marc Agronin: All of the pivotal trials were 18 months. Now they do have data now going out three, four years thereafter showing persistent benefit. But that 18 months now is the focus. I think over time we’ll refine this. The other thing is there’s an agent being studied now which appears to do this a lot quicker. And if that bears out, and maybe that you don’t need 18 months to clear this out, you can do it sooner. But the other thing is with biomarkers now, especially knowing some people more or less at risk, maybe because they’re homozygous or APOE4, we can imagine giving a treatment and eliminating these toxic proteins years before they even get symptoms. And then you have to decide do you need your annual maintenance or how we do that. I envision that will be standard of care within the next five to 10 years. And we’ll have a deeper understanding of how long you need to do it, and we’ll have better agents as well. Now, it’s not going to address other forms of neurocognitive disorders like frontotemporal dementia, Lewy Body disease and others, which may exist alone or in combination with Alzheimer’s disease, but certainly having a significant impact on Alzheimer’s or knocking it out, will address the vast majority of people. The 60 to 80% of all individuals with neurocognitive disorders after the age of 65, it’s Alzheimer’s disease. So that will truly be a game changer.

Dr. Ben Everett: All right, so you had some slides on amyloid-related imaging abnormalities or ARIA. I really enjoyed that part of your talk. Can you kind of explain this ARIA detection methodology and some of the learning curves that have been associated with that?

50:01 – Understanding ARIA Side Effects in Alzheimer’s Immunotherapy

Dr. Marc Agronin: When you infuse someone with antibodies directed against amyloid, you see that you activate the immune system in the brain. You slowly dissolve it. We know that amyloid is embedded in brain tissue. It’s embedded in the vasculature of the brain. And so the theory is that for some people, as you mobilize and get rid of this, you can get some leakiness in small blood vessels, which may lead to what we call microbleed or microhemorrhage. You can get some leakiness of fluid causing spots of edema.

In the clinical trials, most of the time, when people had microhemorrhages or edema or evidence of bleeds and called superficial siderosis, it was asymptomatic in most people, not always. We also know that if you’re on an anticoagulant or if you’re APOE4 positive, you have a higher risk of having these symptoms. Because it was typically seen on an MRI, they refer to as amyloid-related imaging abnormalities, or ARIA.

We see ARIA in anywhere between 20 to 30, 35% of individuals on treatment, typically in the first six months, usually, but not always asymptomatic. And they’ve developed a whole protocol to how you deal with it, depending on what you’re seeing, the extent of it, whether it’s symptomatic or not. Do you simply hold treatment and then re-challenge? Do you stop treatment and not re-challenge? These are all these questions that were, there’s a whole scheme for that. I think sometimes it scares people unnecessarily because if someone says, well, this treatment is causing a brain bleed, well, no one wants that. That’s frightening to use that.

Technically, it’s true. The treatment can cause a brain bleed, but a microhemorrhage is very different from a macro hemorrhage. So the terminology is very important and understand it, and this is not to minimize it in any way, shape or form, but just to realize that we need to describe this in ways that is accurate and we educate people about that and we manage it. I’ve had many patients and research subjects I treated who have had ARIA, vast majority asymptomatic. And those who did have it, we managed it successfully. The cases, the things were more catastrophic are few and far between. But obviously we never want to ignore that or minimize anything like that.

And we’re hoping over time that newer agents and others may be eliminated ARIA or make it allow more people to be able to have this. Because the real question is when someone is on an anticoagulant or they have APOE4, how safe is it in other safer agents? I have a patient now, it’s a dilemma because he had been on treatment with one of the immunotherapies for a year and doing very well. Very, very, very early stage disease, barely symptomatic, and then developed the DVT with a pulmonary embolism had to go on an anticoagulant. And technically now she would not qualify or be a contraindication to continuing with his immunotherapy. So this is the question, what do we do? Is it safe to go off of that, the anticoagulant? Obviously that’d be a concern. So these are the type of questions we have now we need to address with the treatment with respect to what we call ARIA.

Dr. Ben Everett: Anticoagulant use, or at least dual antiplatelet, which might not be the same in terms of a risk factor here, but very common, common.

Dr. Marc Agronin: Those tend to be okay. Anybody with atrial fibrillation needs to be on an anticoagulant and most common rhythm disorder. So it’s clearly something people need to be aware of and just be on the lookout for.

Dr. Ben Everett: We’re kind of coming towards the end of our time together. I just want to kind of, in terms of giving people an idea of how much research is going on, you had this one figure and it was sort of like concentric, almost like a target. And you had like your phase one, phase two, phase three research. But the amount of programs that are going on right now, I just found staggering, honestly. And we’ll try and put that figure in the show notes. Assuming copyright and all that sort of stuff. Can you just give us an idea of sort of what else is going on. You’ve talked about anti-amyloid, hopefully anti-tau is coming on. Anything else that we should be on the lookout for? Or is it just more and more agents in kind of in these same classes, which can be very helpful also because no one medicine tends to work for everybody.

54:09 – Emerging Alzheimer’s Treatments and Future Research Directions

Dr. Marc Agronin: I would divide the research into two categories. One focusing on the disease itself, on slowing or stopping Alzheimer’s disease. A lot of the other research focusing on neuropsychiatric symptoms. So there’s a lot of studies out now on agitation, some looking at psychosis. We definitely need more studies on apathy. That’s a separate area of research.

In terms of Alzheimer’s disease itself, there’s certainly a lot of focus on newer agents, better approaches to anti-amyloid immunotherapy. There’s one agent which they developed a unique way of getting it into the brain, what they call kind of a brain shuttle. So you can get more of it into the brain quicker and appear to be able to degrade and eliminate the beta amyloid quicker. So we’ll see how that turns out. There is a big focus on finding an anti-tau immunotherapy. So far, there’s different points of tau that you need to try to hook onto to mobilize it from the brain. I give the analogy of you’re trying to grab a fish out of a barrel. Do you grab the tail or the head? Which is more effective to get that fish out? So that we need to find an anti-tau immunotherapy.

Certainly some focus has been on brain metabolism. And so, for instance, there’s this theory of what we call type 3 diabetes. We know that just as in type 1 and type 2 diabetes, the basic problem is that your somatic cells are not uptaking or utilizing glucose as efficiently as they need to, either because there’s something at the cellular level or you don’t have insulin. We know that in the brain you see cerebral hypometabolism leading up to clinical symptoms of Alzheimer’s and certainly throughout. And so the theory is, well, maybe the brain cells are not taking up and utilizing glucose as much. How do you, can you improve that? Can you mitigate that? So that’s been an area there’s been focus on so far, not as successful. There’s a semaglutide study that just had negative results recently, looking at neuroprotective agents, looking at other ways to slow down the buildup of amyloid and tau.

So much focuses on this theory of amyloid and tau being central to Alzheimer’s disease. And other people have argued that maybe they’re not central, they’re byproducts of something else. So they’re looking at, can we find ways to get at the other cellular mechanisms that may be producing this disease in the first place? Lots of different ideas and theories. It’s slow going because it’s enormously expensive to do a trial like this. You really need to have results above and beyond what you can already do. So a good example is that we’ve done studies on other cognitive enhancing agents and they really haven’t done much more than you’re going to get from your acetylcholinesterase inhibitor, for instance. So the question is, what are they really going to offer you if you’re not doing better than what’s out there already? Is the time and expense and effort to develop these going to be worth it in the end? Many, many, many studies out there, many of which either are or may fail. So the yield would be low.

I would say there’s one final issue which we’re really wrestling with now is that it used to be in terms of clinical trials, there was really no other game in town because we had no way to slow the disease down. Now we do have immunotherapies, and when people have early stage disease, that should be the focus. So how do you tell someone, hey, wait on the immunotherapy, let’s do this other trial for a couple years. You may advance and be out of the window and not even qualify for it. There’s less incentive for people to do that and get into clinical trials. So we need to have more trials that do combination therapy that allow you to be on immunotherapy and you add something on top of it. But obviously that raises more methodologic issues with the research.

Dr. Ben Everett: So certainly IRB, informed consent, those extremely important parts, letting people make those decisions. But yeah, it does get complicated and you kind of get to be, well, if this is considered standard of care, then maybe we ought to look at standard of care plus something new versus placebo. It’s certainly more ethical to do it that way.

Dr. Marc Agronin: Exactly.

Dr. Ben Everett: But like you say, then your power calculations change, you need more patients, research becomes more costly. These are the challenges that we face in trying to run these types of studies. All these different categories you just talked through, is there, based on your knowledge, what you’re finding, is there anything that really excites you? And I don’t know if you’re a betting man, but it’s just one of these things that you’re like oh yeah, my money’s on this technology or this idea. Not anything specific brand or company wise.

Dr. Marc Agronin: Nothing that exists right now. I’ve learned to be very, very cautious and conservative with any of these trials because the yields are generally modest even with existing treatments. But I will say what I’m excited about is I’d love to see a combination of anti-amyloid and anti-tau therapies and to see what that, if that makes a difference. The other thing is I’m interested to see and I know there’s efforts underway is in the past studies that were done using anti-amyloid therapy with individuals who were at high risk of developing Alzheimer’s disease were not effective agents. So now that we have more effective immunotherapies, I’d like to see if we can do that and actually see the amyloid plaque dissolve in someone’s brain who’s not symptomatic. Is that going to really head off symptoms or what’s going to happen with that? It’s kind of a redo of the same approach.

To me those are going to be the most interesting, exciting coming down the pike. I know there’s other agents that are being looked at. I think there’s exciting data. I don’t know that it will be such a game changer in the next five years other than what’s going in the immunotherapy. So those are really the main, the hottest games in town and we’ll see what unfolds with that. But nonetheless we just need to focus on better earlier diagnosis, refining biomarkers, making sure we’re accurate on what we do. And it’d be ideal if we can do a blood test rather than an expensive PET scan or spinal tap to really be able to be accurate. But the blood-based biomarkers are not yet the gold standards.

Dr. Ben Everett: Beyond pharmacotherapy, exercise, anything that you’ve seen from like a digital tool, wearable tech, these things that seems to be a lot of research going into these. Anything you’ve seen there that seems to be helpful or potential for being helpful?

Dr. Marc Agronin: Well it raises the question of what’s AI going to do? Putting aside what it may do for research, what will AI do for a person? And you see now I just saw an ad for an article on developing these robots in Japan that can actually care for someone and spend time with them, interact with them. I think we’ll see a lot more of that. It’d be interesting to think if someone has short-term memory impairment, could you have some device they wear that kind of feeds into their head, reminders, cueing, things like that. A type of virtual reality where, or enhanced reality where they look at an environment and cues can pop up. I can envision more of that.

But two things. Keep in mind that if someone is already struggling with neurocognitive issues, adding in prompts and cues and all this sometimes can be more confusing for someone or frightening or whatnot. So we have to think about that. And at the end of the day, the human touch makes a difference. You can develop a really brilliant robot, but robots don’t have empathy and they can’t feel what you’re feeling. They can’t sense that. And I don’t think that even the most gentle soft robot touch is ever going to approximate what humans can do. So medicine needs to be very careful and cautious here that we don’t lose that human element. Because AI can be spectacular, but it’s not human and it’s only as good as the humans who develop it. And at the end of the day you need that human touch and humanity and empathy. Without that, nothing will be truly effective.

Dr. Ben Everett: Yeah, I think there’s already been numerous case reports about AI being used as therapy and actually being very dangerous. You need to have a human who understands, is appropriately trained to do these things. So you’ve really been a leader in this person-centered dementia care. How do clinical trial advances and compassionate care models coexist? I think you’ve talked so much about this. I’ve certainly gotten a feel for how you approach this, but I don’t know, can you, you really started with this at the beginning. Let’s kind of tie it all together.

1:02:09 – The Role of Empathy and Person-Centered Dementia Care

Dr. Marc Agronin: Well, the concept of person-centered care really says that instead of having the person accommodate to the care, you have the care accommodate to the person. We get to know what does this person need, what do they want, what’s good for them? And model the care around that rather than conforming to the schedules, the needs of the staff or the environment or whatnot. It goes deeper than that, in my opinion, and we need more to develop it more. So I just make two comments about that.

This largely comes from the work of a really amazing British geriatrician by the name of Thomas Kitwood. In the 90s he wrote just a small little volume which to me should be required reading for everyone going into the field about, he spoke about dementia reconsidering dementia. And essentially he was saying that if you speak to the person, if you engage with the person, there’s a lot of philosophy involved in this, which taps into my interest. Not only do you accord them the right dignity, you optimize the interaction, but he was convinced that you alter the course of the disease itself, that people do better when you have the best interaction with them. Then that’s really where person-centered care jumped off from that. I agree with that.

But the more I researched that, what I thought to myself is that makes perfect sense. But in order to do that, you need to know the person, you need to understand the person. How do you best understand what someone is thinking, feeling, going through? We use empathy. Now empathy is a tool that can be used, it can be overused. Empathy allows us to imagine what someone is thinking or feeling. It doesn’t tell us what they’re thinking or feeling. So you imagine it and then you test it out. So you may see someone crying and you may feel sad, but that doesn’t mean they’re sad. It means that there’s an emotion and you need to find out, is there tears of sadness? Are these tears of happiness? But empathy is that perfect tool, that humane way of doing it.

So we’ve been working at my institute at Miami Jewish Health on what we call empathic care. It’s a way of teaching people to recognize what empathy is, how they empathize, and to use it in an effective way. It’s a work in progress, but you can see it brings together philosophy and psychology and psychiatry and aging and all this together and just to find a way to care for people better. And to be frank with you, even though I’ve spent my career doing this, I always marvel when a loved one comes in with a spouse. They’ve been together decades, or a daughter or a son, and they just, they love the person, they care for them. It’s just a natural empathy. And that’s always the best care. And I learn from them, they teach me what’s the best way, the best approach here. That’s the essence of shared decision making. It’s the essence of good person-centered care. At the end of the day, if we can adopt a stance which recognizes that, which engages in that, we’ll find the best way for the patient. Because even the super specialist can be completely off base sometimes. Happens to me all the time. But I have good people to teach me and that’s the patients I work with and their loved ones, their caregivers, they’re the best teachers.

Dr. Ben Everett: I read a couple of years ago. Empathy is compassion in action. That stuck with me. I like that definition.

Dr. Marc Agronin: I like that term a lot.

Dr. Ben Everett: Well, look, this has been absolutely wonderful. I just want to thank you for joining us today on The JCP Podcast for sharing your experiences, your expertise in Alzheimer’s disease, this empathic care model that you’ve embraced, and that you’re training all these young clinicians in as well. It’s been a real pleasure today. It’s really been a joy for me talking through all this stuff and just spending this last hour plus with you so.

Dr. Marc Agronin: Well, Ben, I want to thank you just for this opportunity and to talk about this, and so many good, good people are working so hard on proving how we address this. There’s so many caregivers who are working their hearts out to help people and people living with this and we need to do better for them. So thank you for this opportunity. I’m really honored and hope that this will be helpful for those listening. Yeah.

Dr. Ben Everett: I want to thank you again for your time today. This has been The JCP Podcast, Insightful, evidence based, human centered. Thanks for joining us. Until next time, stay curious, stay informed, and take care.