Catching Cognitive Decline Early with Gary W. Small, MD

Journal of Clinical Psychiatry: https://www.psychiatrist.com/jcp/

Dr. Gary W. Small: https://www.hmhn.org/find-a-provider

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 – Introducing Dr. Gary W. Small

Dr. Ben Everett: Hello and welcome to the JCP Podcast, where we explore the science and stories shaping mental healthcare today. I’m your host, Ben Everett. 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.

Dr. Ben Everett: Today my guest is Gary Small, a world-renowned psychiatrist and one of the leading voices in geriatric psychiatry, with a career dedicated to understanding brain aging, memory, and the early detection and treatment of cognitive decline. He currently serves as Director of Behavioral Health Breakthrough Therapies at Hackensack Meridian Health in New Jersey, and is Professor of Psychiatry and Behavioral Health at the Hackensack Meridian School of Medicine.

Dr. Ben Everett: Prior to this, Dr. Small spent decades at UCLA, where he was Professor of Psychiatry and Biobehavioral Health Sciences and founding director of the UCLA Longevity Center, helping to pioneer research and clinical programs focused on healthy brain aging and dementia prevention.

Dr. Ben Everett: Dr. Small’s contributions to the field are extensive. He has led major efforts in neuroimaging and biomarker research for Alzheimer’s disease, including work focused on early detection using PET imaging and other advanced technologies.

Dr. Ben Everett: He has served as the President of the American Association for Geriatric Psychiatry, contributed to national advisory panels with the FDA and NIH, and has been consistently recognized as one of the top investigators in Alzheimer’s disease research.

Dr. Ben Everett: In addition to his research in clinical leadership, Dr. Small is a prolific educator and communicator. He has authored numerous scientific publications and bestselling books on memory and brain health, and has spent his career translating complex neuroscience into practical strategies for clinicians and patients alike. Importantly for our audience, Dr. Small also serves as Section Head for Geriatric Psychiatry at The Journal of Clinical Psychiatry, where he continues to shape how we think about aging, cognition, and mental health later in life.

Dr. Ben Everett: Today we’re going to focus on a topic that’s increasingly relevant across all of medicine: the early detection in treatment of age-related cognitive decline, and how advances in biomarkers, imaging, and intervention strategies are changing the way we approach brain health across the lifespan. Dr. Small, welcome to the podcast.

Dr. Gary W. Small: Thank you, Ben. Thank you for that wonderful introduction.

02:20 – From Math to Metaphysics to Medicine

Dr. Ben Everett: Now, look, it’s a real pleasure to have you on today. We start each episode with a couple of icebreaker questions just to try and get our audience to know you a little bit more as a person and try and just make this a little bit more personal. So, let’s start at the beginning.

Dr. Ben Everett: You majored in biology as an undergrad. That’s certainly not an uncommon major for someone planning a career in medicine. But did you know going into college that you planned on going into medicine, or was it something that happened a little bit later for you?

Dr. Gary W. Small: Well, I thought of a number of career choices. I even considered becoming a classical pianist. And, in fact, when I started in college, I was a math major, and soon realized that math was a little more challenging, so I switched to philosophy, and then I decided to go pre-med.

Dr. Gary W. Small: There was one quarter where I was taking physics for pre-med and metaphysics in philosophy. I figured I covered everything there with physics and metaphysics, but it eventually drifted towards biology, which I’ve found just fascinating over the years. So I’m delighted that I had the opportunity at UCLA to explore all these different topics.

03:30 – Finding a Path into Psychiatry

Dr. Ben Everett: I tell you, that resonates with me. I loved math and I was gonna minor in math until I took Calc 2 in college, and that cured me of wanting to minor in math. You ended up in medical school; at what point in time did you decide, you know, psychiatry is really where I want to focus my career?

Dr. Gary W. Small: It was after medical school. I went to San Francisco and did a year of internal medicine, and was really struck by the fact that my patients had a lot of mental issues, and that was really what was driving a lot of their disease states. So I felt maybe I could get into that more and help people more if I straighten out their minds to help straighten out their bodies.

04:20 – The Road to Geriatric Psychiatry and the Case for Early Detection

Dr. Ben Everett: That’s certainly not something that’s uncommon for me to hear on this podcast. Even just interacting with general practitioners, emergency room people, mental health is very key. So, in your career, you’ve really focused on age-related cognitive decline and geriatric psychiatry. What drew you into this area of research and practice?

Dr. Gary W. Small: So, I was a fellow in geriatric psychiatry at UCLA, and the main geriatric psychiatry professor was Lissy Jarvik. That was her area of work: dementia and Alzheimer’s disease. And so she had me helping her with her NIH grants, seeing patients. And one thing that struck me was that for most of these people, it was a very gradual progression of decline. And I just thought maybe getting ahead of the game, helping people earlier on, would have a bigger impact. And that’s always been a theme of my work—early detection and prevention—because I think it’s easier to protect a healthy brain rather than try to repair damage once it becomes extensive.

Dr. Ben Everett: I tell you what, I agree completely. I think it really extends to all areas of health, right? You think of heart health, it’s like, why would you wait until you have a heart attack to be aggressive with lipid lowering and hypertension and those types of things.

Dr. Ben Everett: This is a topic that really feels like it’s evolving in real time, with all the advances in biomarkers and scanning and whatnot. It seems like not too long ago, cognitive decline was something that we really reacted to. It was like, you’re at a point in time where we’re gonna try and slow decline, or, or, or something like that.

Dr. Ben Everett: But now, it’s like you say, we’re, we’re talking about identifying risk earlier, intervening sooner, before patients ever even meet a specialist. Hopefully this is happening more in, you know, with their, with their internal medicine or their family practice doctor. And I think it’d, it’d really be helpful today to start by grounding ourselves in how we define this space.

06:10 – Defining the Continuum: Normal Aging, MCI, and Dementia

Dr. Ben Everett: When you think about age-related cognitive decline in 2026, and—maybe if, if we conceptualize this as a continuum—how are you thinking about that continuum of age-related cognitive decline now, as opposed to maybe a, you know, a decade ago?

Dr. Gary W. Small: It hasn’t changed that much in a decade. I mean, certainly the technology’s improved and we have better biomarkers, but I think the concepts remain, and we have the brain gradually getting worse for most people. Certainly some people have strokes, and that happens quite quickly, but for the average person, there’s a gradual decline, and what we do is we come up with categories of degree of decline. So there’s three major categories. You have normal aging—the kind of mental slips that we all joke about. Where did I put my keys? Just walked into the kitchen. I can’t remember why I came into the kitchen. Of course, it gives me an opportunity to get a snack—hopefully a healthy snack—to protect my brain. So you have that. But at a certain point it gets worse, and that’s where we call it Mild Cognitive Impairment, which is a term that was introduced decades ago, and it is really a more challenging state of cognitive decline, but the person is still able to compensate for those memory slips, so they’re able to live independently. When that compensation breaks down, then we call it dementia. And a simple definition of dementia would be memory or other cognitive decline that interferes with the person’s ability to remain independent. So it’s defined by their functional status. So we have these three major levels of cognitive deficiency. And then from there, we need to tease out what we can do to help people. And, and there really are issues. You know, we’re talking about early detection and prevention, and we’re coming up with new drugs, and the question that arises with many patients and families: well, should I try this? I just had a positive biomarker test, but I’m concerned that I’m going to be having to label my cabinets in a couple months, so should I get started on this drug, which has a lot of side effects and is very expensive? And, and that raises concerns, because we don’t have data on how this particular drug performs in healthy people who may have an ugly test.

09:00 – Interpreting Cognitive Complaints and the Weight of Information

Dr. Ben Everett: Yeah. So, you know, how should clinicians in psychiatry, and those in general practice maybe who, who aren’t quite as in tune—they, you know, they haven’t done a fellowship in geriatric psychiatry—how should they interpret these subjective cognitive complaints? You know, when does it go from “I walked into the room, you know, I can’t remember why I came into the kitchen, I know I came in here for a reason,” versus, you know, when it really does become something more than just age-related cognitive decline?

Dr. Gary W. Small: I think it’s quite challenging, because we have new studies all the time and they’re hard to interpret. They’re even hard for experts to interpret. So I think it’s challenging. A lot of what I do as a clinician is education, trying to put all the information in perspective so that the patients and families can understand that and make an informed decision about what to do. So a lot of times it comes to preferences, and there’s, you know, the biomarker tests can have a negative effect on the person’s psychology. Some of the early studies with Apolipoprotein E4, APOE4, found that someone who has just normal aging—that forgetfulness we joke about—if they have a positive genetic risk, an APOE4 test that shows they’re a carrier of that allele, if they’re informed of it, they actually perform worse on cognitive tests than if they’re uninformed and carry that genetic risk. Another interesting study I just looked at the other day was, they informed people about their positive PET scan or biomarker test, and most people responded that, yes, I’m gonna change my lifestyle and protect my brain more. But then they looked at, did they actually do that? Didn’t make a difference.

Dr. Ben Everett: That’s unfortunate. Yeah, it, it’s always an interesting, you know, double-edged sword. I think when we, you know—like, I’ve done 23andMe, and I’m, you know, I’m a scientist, I believe in research. There, I’m always saying, yeah, you can use my stuff for whatever research, but anytime there’s a new allele or a new association, you have to opt in to get the results, which I think is obviously good and probably legal—they have to do it that way—but a lot of people just don’t want to know. They’re like, well, you know, is it really gonna impact the way I live my life? And we would hope it would, but I guess, at least in this one study, the data are maybe not necessarily.

Dr. Gary W. Small: Information is very powerful, and it can have both positive and negative effects. And I remember there was a family member who had a family history of Huntington’s disease, which is a very genetically driven disease where either you have the gene or you don’t. And if you have the gene, it’s not a good prognosis. And there was this young man who finally decided to get tested. There was a strong history of Huntington’s in his family. He tested negative for the gene, but got depressed, because he was really living a very reckless life. Before, he assumed he was gonna get Huntington’s—I might as well enjoy myself. Now he felt guilt. Now he felt, oh my God, I’ve gotta do something with my life. So there can be surprising psychological reactions to information.

12:30 – The Biology of Cognitive Decline and the Role of Inflammation

Dr. Ben Everett: That’s really interesting. Well, let’s kind of transition a little bit into the underlying biology of cognitive decline. What have we learned about the underlying biology? Has there been a lot of movement in that area, or is it sort of, we know that hasn’t changed that much, but maybe the way that we are trying to address these problems—we have better technologies for detection, we have better drugs for, for treatment now? So, as, as you think about the underlying biology of cognitive decline, where do you think we are now?

Dr. Gary W. Small: Moving forward, we’re getting more information. Back in 1906, when Alois Alzheimer first defined the disease, he unveiled to the medical community there’s an accumulation of abnormal protein deposits in the brain, in areas that control thinking and memory. So these amyloid plaques and tau tangles have driven a lot of the research over the years, and that’s led to drug development, particularly in the area of reducing amyloid in the brain. But we’ve also learned about some of the neurotransmitter systems that are affected, particularly the cholinergic system, which led to the first symptomatic drug treatments—the cholinesterase inhibitors—that were introduced decades ago and have helped people to some extent with their symptoms. There have been other neurotransmitter systems that have led to drug discovery. But another area that I think has gotten more traction over the years, and one that’s fascinated me and driven a lot of my research, is the impact of heightened inflammation in the brain that drives not only cognitive decline, but also mood changes. And some of the research I got into in the middle of my career, earlier on, was to see whether anti-inflammatory interventions, before there’s extensive cognitive decline, whether they have an impact on cognition. And it looks like they do, depending on the timing of the intervention. But it’s complicated, because—you know, we did a study a number of years ago, an NIH study, where we put people on celecoxib, or Celebrex, a Cox-2 inhibitor that reduces inflammation in the brain, and these were people who did not have dementia. They had either normal aging or mild cognitive impairment. And we found that after 18 months, cognition was better when you compared it to placebo, and we even saw effects on their PET scans, where there was an effect on glucose metabolism, and that was quite interesting. The problem is, these drugs have a lot of side effects, and you don’t want to put everyone on them, especially older adults who are having cognitive struggles. And also, previous studies found that if you treat patients who already have dementia from Alzheimer’s disease, it doesn’t help, or it can even make them worse. So there’s a tipping point when introducing a medicine like that may help or hinder the brain.

16:00 – What Is Lost When We Wait, and the Curcumin Story

Dr. Ben Everett: Well, with respect to timing, you know, when we talk about waiting until symptoms are more obvious, right? When, when it goes from, “Boy, I, I can’t remember where I left my keys,” to where it’s, “I don’t know where the plates are”—you know, you mentioned labeling your kitchen cabinets earlier. So, what is actually lost in terms of brain function when we wait too long to treat these symptoms?

Dr. Gary W. Small: You know, I think function is an important word. I even brought that in with the definition of dementia, and I think that’s an issue going on in the brain. Initially, there’s functional loss of these neuronal connections, so the synapses are affected. A buildup of these abnormal protein deposits are toxic to the brain. It’s unclear whether amyloid is causing all the problem, or it’s a result of other dysfunctions. If you stain those amyloid plaques in the brain with certain stains, you see elements of inflammation. I talked about heightened inflammation. There’s activated microglia. There’s complement. So one hypothesis is that the hyperinflammatory response is destroying brain tissue, and these are just the gravestones of those effects. But I suspect it’s not just one mechanistic explanation. There’s a lot going on. So, I think one summary of this discussion is, we don’t understand it completely. We’re trying to develop drugs to intervene with the process, and we’re seeing some benefits from these interventions. But also, what we’re seeing—and another area of interest for me—is that lifestyle changes can have a protective effect. The mechanism also may involve reducing inflammation. So people who engage in aerobic exercise have less inflammation in their body. If you get a good night’s sleep, it cuts down on inflammation. Also probably helps with accumulation of amyloid. If you consume Omega-3 fats from nuts, that reduces inflammation. So there’s a theme with these different lifestyle interventions that have a similar effect to the drug intervention. If I can just also follow up on that initial study we did with the anti-inflammatory drug: the next one, which was designed very similarly—an 18-month study, people with mild memory complaints—we decided, let’s try something that is less toxic to the brain. And along with David Heber, who at the time was the head of the Human Nutrition Center at UCLA, we raised some money and we did a study where, instead of giving people an anti-inflammatory drug, we gave them curcumin, or a bioavailable form of it. Curcumin is derived from turmeric. Found that people in India, where they consume a lot of spicy foods, have a lower rate of Alzheimer’s disease, and in the laboratory, curcumin is anti-inflammatory. It’s also antioxidant, and seems to be anti-tau and anti-plaque. So all your ducks are lined up if you want to have an anti-brain-aging spice. And so we gave the bioavailable curcumin to these people, compared it to placebo, and it was a pretty significant effect. And that line of research is, is continuing. There’s a, a pathologist in Taiwan that got very excited about the curcumin study that we published, and he flew out to UCLA. And he had all these ideas about it.

20:20 – The PCP’s Role in Early Intervention and Lifestyle Counseling

Dr. Gary W. Small: In fact, that led to a synthetic form of curcumin that he’s developing, and now there’s an international trial that I’m involved in to try to see if this is, is gonna be something that will help a lot of people.

Dr. Ben Everett: That’s really exciting right there. Alright, so, you know, we, we’ve talked about early is better. You know, if we wait until symptoms are more obvious—if we think about our general practice colleagues, do they have a better opportunity to intervene early, just because they’re seeing the patients maybe more often? Or, you know, a lot of times a patient might not even have a psychiatrist or a neurologist. Is there something that those primary care clinicians can be doing, and, and at what point in time should they start?

Dr. Gary W. Small: I think that it would be helpful to start sooner rather than later. And even later is good, because we find that these approaches can help people who are in their seventies, eighties, and beyond, and even starting to have cognitive difficulties. But I think it would be helpful if lifestyle were part of the regular medical evaluation that primary care practitioners are involved in. Challenge, of course—the whole reimbursement model of our health system—and there’s very little time to do that. And so there’s not a financial incentive to have these doctors really delve into those issues. So I think this is something that has to go to policymakers, so we have a better system, so we can encourage doctors to find out about exercise and diet and stress levels and sleep. I think sleep they do get into more, because it’s seen as a so-called medical problem rather than a mental problem.

22:10 – Biomarkers and Imaging: From Research Tool to Clinical Reality

Dr. Ben Everett: Yeah. I agree. We had a sleep doc on a month or so back, and, we talked a good bit about the influence of sleep on, you know, mental health, specifically for our podcast. But yeah, it bleeds into so many different other areas of our healthcare. So. Alright, so you’ve been at the forefront of, you know, biomarker development, and as well as imaging research.

Dr. Ben Everett: How much of this has changed in terms of how many of these tools have come just from research to now they’re widely available to clinicians everywhere, whether it be primary care or specialist? And I’ll tell you, you know, when I was in for my primary last year with my doctor—he knows what I do, we grew up together, we were fraternity brothers together—and he actually brought up APOE4 to me, and he said, yeah, I’ve gotten to where I’m doing a lot of APOE4 screening on people when they know they have a family history. You know, they say to me at 40 or 50, “Hey, I’m a little bit, you know, concerned about this. Is there anything you can do?” He said, well, the easy thing I can do is just do an APOE4, and we’ll at least know if you’re genetically at risk for this. But, you know, maybe other than APOE4, where are we with, with biomarkers? I know there’s been a lot of development in the Alzheimer’s space, blood-based biomarkers. How many of these tools have, have gone from the research side to the, to the ready-for-clinic side?

Dr. Gary W. Small: The pace of innovation is fast and furious, and before we truly understand these biomarkers, they’re out there, and people are getting them, and, and this has been going on for years. I remember when the first amyloid PET scans were coming of age, and there was still a research tool, and people would come to me, and they’d say, “Well, doc, I was just misplacing my keys last month, and now I’ve got Alzheimer’s in my brain. What do I do?” As someone who’s been involved in the development of these tools, I’m very conservative in using them, because you don’t treat a blood test; you treat a person. You don’t treat a scan. I mean, you know, the old joke was, the good news with some of these early anti-amyloid drugs, the brain scan looks great. The bad news is, you’re going to forget this conversation. So we were able to clear the amyloid out of the brain, but the drug didn’t work with the disease. So I think that that’s, you know, I see that a lot in my practice, where people are very confused by all the information they’re getting. “I got this tau blood test, and what do I do?” And it has to be put into context. You have to look at how bad the symptoms are, what’s the risk versus benefit of doing intervention A or doing nothing. And, and that’s really the challenge, and it’s not a simple cookbook that helps us sort this out. It takes some time and mental focus to really understand it.

25:00 – Biomarker vs. Surrogate Marke r

Dr. Ben Everett: I think that’s really important, and, and some of these things seem to continue to evolve. It’s, if this is causal and we clear it out, then why aren’t we, you know, why aren’t we seeing an effect? It can be confounding to try and think through. In terms of, like, routine screening, you know, you said you’re pretty conservative with these things. Do you think any of this is really ready for prime time? Like, everybody at age 50 should start getting this, like we do with a number of other different blood tests for different things? Or should it really just be, you know, based on symptoms, or family-history driven?

Dr. Gary W. Small: First of all, there’s a difference between a biomarker and a surrogate marker, and I think people confuse this. So, a biomarker would be something that seems to correlate with the disease state, and when I say disease state here, we’re really talking about cognitive impairment. A surrogate marker is really, is something that if you treat someone, you know, that surrogate marker shows positivity for the disease, and you treat that, quote, surrogate marker, you see improvements. So, good examples of surrogate markers would be blood pressure or cholesterol level. So if you have high cholesterol and you take a statin drug, we know from the data that your risk of a stroke or heart attack will be reduced in the future. But what happens is, people jump ahead, they take a biomarker, and they—well, let’s treat that biomarker. And we don’t know what the result will be. We don’t know whether they’ll have a, a good effect on the disease in the future.

Dr. Gary W. Small: So it’s always—and it’s whether it’s a, a biomarker, or even spending time with a patient and family and applying a screening tool or a test—we don’t want to waste people’s time. We don’t want to send them down a road, a confusing road. So, before, if they’re asking about a test, or if I think there’s a test or scan that may inform them, I go over the positives and negatives of getting that test.

Dr. Gary W. Small: So, you know, if you are a person who is serious about having amyloid levels reduced in your brain, depending on the level of your cognitive impairment, I can review what’s the pro—that might be a reason to get an amyloid scan, because it’s not gonna work if you don’t have amyloid in your brain.

27:20 – Differential Diagnosis and the Brain as a Rheostat

Dr. Gary W. Small: So, I think you’ve got to be very systematic, and stick to the science and what it shows us.

Dr. Ben Everett: In terms of differential diagnosis, if you’ve got a patient—like you say, you’re, you’re treating the patient in front of you—the patient comes in, and they’ve, they’ve got some complaints about, you know, okay, I am, you know, can’t remember my keys. I think that’s gonna be our go-to for this one.

Dr. Ben Everett: Is—but are there, you know, common pitfalls with that? I shouldn’t—maybe not even common pitfalls—but is there, sometimes it might look like a horse, but it’s actually a zebra? Is there anything in the differential diagnosis that people should be wary of, or people should be looking out for in cognitive decline, but maybe it’s actually something different?

Dr. Gary W. Small: So, if somebody has dementia, the chances are two out of three times they’re gonna have Alzheimer’s disease in their brain. But there are a lot of other causes of dementia, and I mentioned stroke earlier. It can be thyroid imbalance. Rarely, it’s normal-pressure hydrocephalus. So I, you know, this is something—when I, when I started with Lissy Jarvik, that’s pretty much what we did, was try to rule out other causes. It could be depression. So oftentimes a geriatric psychiatrist has to sort out how much of this is from an underlying organic or Alzheimer’s disease state, and how much is from depression? Sometimes it’s mixed. So I think it’s very important to go through the differential diagnosis to rule out these other causes. I think where it gets a bit tricky is when you come to the biomarker test. Well, should I get a tau blood test? Should I get an amyloid or tau scan? I mean, what will that tell you? Just have to look at the data and see what it tells you, in terms of your particular level of cognitive decline. It’s going to be different if it’s just normal aging, or mild cognitive impairment, or dementia. Let me also say, going back to our earlier discussion, the brain doesn’t work like a light switch, where it goes on and off. It’s more like a rheostat. You get into these gray zones. This person, you say, has mild cognitive impairment, but he’s the CEO of a major company. He’s got handlers who give him a list of items. Without those handlers, you’d probably—he has dementia.

29:30 – Pharmacologic Treatment: Symptomatic vs. Disease-Modifying Drugs

Dr. Ben Everett: Yeah, that’s a good point. Alright, so let, let’s move a little bit more into pharmacologic treatment, and then, you know, we’ll talk about other types of treatment like, you know, anti-inflammatories, exercise, those types of things. But where are we right now in terms of interventions that have the strongest evidence for slowing or modifying cognitive decline?

Dr. Ben Everett: You know, you mentioned cholinesterase inhibitors earlier. Is that kind of class 1A for first line before you get to other things? How do you think about sequencing treatment for your patients?

Dr. Gary W. Small: I would start with: we have two types of drugs right now. We’ve got symptomatic drugs, and we’ve got what we think are disease-modifying drugs. So, the symptomatic drug would be defined as a medicine that doesn’t alter the disease state but improves the symptoms. So, if you had pneumonia and I gave you aspirin, that would be a symptomatic treatment. You’d feel a little better, but you have to keep taking that. The disease-modifying treatment would be an antibiotic that gets to the disease state, and you take it for a while, and that cures you of the pneumonia. So, the symptomatic drugs would be the cholinesterase inhibitors, NMDA, and those you have to take every day. They have, you know, modest effect sizes, but they make a difference. And the way I describe it to people, and that’s where I start—I start with a cholinesterase inhibitor, and then add NMDA after they’re stable. And I, I say that we have a lot of studies showing that if you take this medicine, you’ll be at a higher level of cognitive function, say, in a year from now. You may not see any improvement in your memory, but the studies show it’s, it’s gonna help you. And I think that’s important to tell people, because a lot of people don’t see improvement. They expect it, and then they stop the drug. It’s a very common scenario. So, that would be a first line of treatment. The next question is, well, what about an anti-amyloid drug? And there, I, you know, I have a conversation with the family. Here’s the pros and cons. You’re gonna have to get an amyloid scan. The effect size, which is pretty much defined of how the drug works compared to a placebo—it’s also pretty modest. It’s comparable to what you get from a cholinesterase inhibitor, but it’s also more expensive. You have to come in to an infusion center to get infused, and there are potential side effects where you may get bleeding in the brain, edema, and so you have to get MRI scans periodically.

32:40 – Lifestyle Modification and the Evidence for Aerobic Exercise

Dr. Gary W. Small: Now, all those potential side effects can be managed, but it’s a little bit more challenging than just taking a single pill, and, in fact, that’s where the APOE test may be relevant, because we know if you’re an APOE4 carrier, the risks of these kinds of side effects are greater. So, I think there’s not a set algorithm that everybody uses, but, based on the data, that would be the approach I would take.

Dr. Ben Everett: Yeah. And then we talked about exercise earlier, and I’ll just put this as lifestyle modification. Eating a healthier diet, getting more natural anti-inflammatories in your diet, Mediterranean diet, get your Omega-3 fatty acids. I’d spent half my career working on Omega-3 fatty acids, so I’m pretty passionate about those too. The intake of fat can definitely be confounded by your APOE status, and maybe that’s a whole other podcast for, like, what people need and, and don’t need, and how they metabolize those different things. But let’s just back this up to lifestyle intervention.

Dr. Ben Everett: I don’t think I’ve ever seen any part of medicine where aerobic exercise does not have an impact, whether it’s schizophrenia, obviously heart disease, cardiac rehab, orthopedic rehab, all these different types of things.

Dr. Ben Everett: And from what you indicated earlier, it seems like maybe there’s a benefit for cognitive function as well.

Dr. Gary W. Small: When I was at UCLA, we found that people who exercise more had less amyloid and tau in their brain. So we did PET scans of FDD using FDDNP, the probe that Jorge Barrio and I and several other investigators introduced, and there was a definite effect. We found that people who consumed a healthier diet had the same kind of effect, or had lower BMI levels, had less Alzheimer’s, if you will, in their brain. So it’s really important. The challenge, though, as a PCP: you just can’t write a prescription and think people are gonna follow it. It’s not so easy. Now, when I went to New Jersey, and I was looking for a doctor, I asked the head of cardiology, who would you recommend?

35:40 – Train, Don’t Strain: Exercising the Mind Socially

Dr. Gary W. Small: Oh, I’m gonna recommend this doctor, because he’s really into—I know you’re into prevention. So I started seeing this guy, and he would shame me into exercising more. And it had an impact. I mean, something about your doctor is an authority figure, and you want to perform well, and he really motivated me to do more. And so I think a doctor can have an important effect. But, what can our doctors do, whether they’re psychiatrists, PCPs, specialists? You’ve got to embrace or develop some kind of a program to motivate people. When I was at UCLA, we had a number of programs. We had memory trainers. I had physical trainers I would send people to. So you can develop your own little team to make an impact on people’s lives, but you just can’t hand them a brochure and say, well, here, exercise more. You’ve got to help them get motivated.

Dr. Ben Everett: Yeah, there’s different ways. I think about a coach. I used to do a lot of youth coaching, and, and you can’t coach every, every kid the same way. I imagine in healthcare it’s the same way. You can’t necessarily have the same conversation with every patient and, and expect it has the same impact. You’ve gotta understand who you’re talking to, and a lot of that is just the, the therapeutic relationship I think you develop with the patient. So, alright, well, what about exercise for the mind? We see so much of this. I hate the app store, then. It’s these, oh, you know, neuroscientists say play this game 10 minutes a day. I was like, I don’t think any neuroscientist ever said that, but certainly I think exercise for the brain can be important. I read sometimes about—as soon as people retire and really they don’t have that, that academic challenge of just thinking through work, or thinking through problems, you know, maybe you’re becoming more socially isolated. There’s all these different things that come with retirement for people who just go, okay, I’m just gonna go sit in a recliner all day.

Dr. Ben Everett: So, when you think about exercise for the mind, what do you think about that? Where’s the data? And was there anything you kind of recommend for patients?

Dr. Gary W. Small: The data are pretty strong for exercising your mind, and the key is to train and not strain your brain. Do something that’s interesting and engaging. I remember a friend of mine years ago said, I’m really mad at you, Small. You told me to learn a language, and I hated it. First of all, I didn’t tell him to learn a language; I was just reporting the news that people who are polylingual have a lower risk for dementia. So the key is to find something that engages you, that has meaning, that is interesting to you. You want to, you know, for example, if you do crossword puzzles—and there are some data showing that doing crossword puzzles protects your cognitive health—if you do the ones in the newspaper every day of the week, it gets harder. So I tend to be a Tuesday, Wednesday puzzler. I mean, Monday is too easy. Thursday I can do, but Friday and Saturday’s a killer. But I really enjoy Sunday, because Sunday they have these cute themes, and it really is fun and humorous. And, and so I think the, the key is to find something that you really like doing, and do that.

37:50 – Knowing When to Refer and Building Specialist Relationships

Dr. Gary W. Small: And you mentioned social isolation. Do that socially. I mean, we have—I have different groups of people I play word games with. You know, we compete against each other, we share our scores, and it can be a lot of fun.

Dr. Ben Everett: That’s fun. At some point, clinicians have to decide when to bring in someone with some additional expertise. You know, is this kind of beyond what I have time or expertise to do? And this can be a gray area in clinical practice. It can also be constrained by where you live, if you’re in a rural area versus a more urban area, where, where you have good referral centers. If you’re talking to a group of general practitioners, how do you help them understand when is the right time to refer to a geriatric psychiatrist or maybe a neurologist who has a better grip on cognitive decline?

Dr. Gary W. Small: Depends on the comfort level of the primary care provider. Not just cognitive impairment, but just look at depression. There’s too much of this going around for specialists to take care of. So clearly our PCPs are taking on a lot of these problems, and they develop a comfort level on it. I always encourage them to connect with a specialist, or, if they can, several specialists, who they feel comfortable working with, and they can even ask them, well, gee, should I send this to you? Would this be better? I’m, I’m kind of scratching my head here. And with time, if they have that relationship with the specialist, they’re going to learn more, and they’re going to feel comfortable taking on some of these more complicated cases. So I think the key is having a good relationship with the specialists, where you have a comfort level, and you understand each other.

Dr. Ben Everett: That’s really good advice right there. So let’s say that when they do go to make the referral, is there anything in the workup—and I suppose this is part of just having the relationship, you already know, alright, I know what Dr. Small wants when, when I send a patient to him—but is there anything they need to be thinking through before they send it to him? Like, before you go see your neurosurgeon, you’re gonna have your MRI done to make sure, okay, yeah, this is, this is definitely a neurosurgical type of consult. Is there anything that they need to do beforehand in, in the workup, or is there anything you need to see in a referral note that makes it better or more efficient for you, or maybe a, a more effective, you know, first visit that you have with that patient?

41:00 – Comorbid Conditions and the Whole-Person Approach

Dr. Gary W. Small: I think a standard workup for cognitive impairment is helpful. It speeds it up. So, you know, the standard approach would be, do a good medical workup to look for other medical illnesses that might be causing cognitive impairment, screen laboratory tests to follow that up. What’s recommended in these consensus guidelines is some kind of a structural imaging study to rule out a space-occupying lesion. So I think that is important and helpful. Now, a lot of the PCPs will be going ahead and getting biomarker tests, and that’s sometimes where it gets confusing. How do you interpret those tests, or what to do next? I mean, that can be up to the PCP, whether they want to get that or not. You know, in my mind, it might be helpful to hold off on that until the specialist has a chance to discuss the pros and cons of each of these tests, what they’re going to get from it.

Dr. Ben Everett: Yeah, that, that’s good. That’s good. Alright, so as we kind of move maybe from the middle of our conversation to kind of starting to close things out. When you think of psychiatry, you mentioned depression, a number of other things that, that might, you know, mimic cognitive decline or cognitive impairment—when you think of common comorbid psychiatric conditions, depression, anxiety, sleep disorders, how do those influence or predispose to cognitive impairment?

Dr. Gary W. Small: They definitely do. I mean, people who don’t get restful sleep, it increases your risk for cognitive decline. I just wrote something on adult ADHD. A lot of times it’s unrecognized, and can look very much like primary cognitive decline in older peoples, very similar mechanisms. So I think, we’ve got to treat the whole person. We’ve got to uncover anything that may be contributing to the problem.

42:40 – Looking Ahead: The Next 5–10 Years

Dr. Gary W. Small: What really scares people are, without our memory, we have no past. We can’t really appreciate the future or plan for it, and we can’t appreciate the present. So it’s really scary to people, and they focus on that, and they may forget that—may go to the doctor worrying about their memory, and, well, gee, you’re not sleeping at night, you’ve lost some weight, you’re complaining about your pain issues, your energy level is down, and, you know, it ticks all the boxes for major depression. And that could be the dementia treatment that cures you.

Dr. Ben Everett: Interesting. Alright. So, if you pull out your crystal ball, or maybe your magic eight ball, and you shake it up and you, you look at it, you know, where do you think we’ll be in another five to 10 years? Is there any research that’s maybe preliminary right now that you’re really excited about, or is it just, science is kind of, it’s all baby steps and we’ll know when we know?

Dr. Gary W. Small: It’s so difficult to predict. I, you know, I would say the crystal ball, the eight ball would say, you know, because we just don’t know the direction things are going to go. I’m hoping that we will refine our understanding of all these mechanisms, whether it’s inflammation, neurotransmitter dysfunction, abnormal protein accumulation, or, or other issues that we’re—we haven’t had a chance to talk about—that are affecting the brain. So I, I expect that we’ll refine that. We’ll—I hope that we’ll have a better understanding of how lifestyle contributes, and maybe more public policy that helps people to live a healthier life. And it will not only lower their risk for cognitive decline, but it will strengthen their heart. It will reduce the risk for diabetes. I mean, there’s tremendous overlap of these chronic age-related diseases.

Dr. Ben Everett: I think that’s so important. I also just think of, of overall quality of life. We are getting older as a society. Maybe we can all live to 95 now, or whatever it is, but if you don’t feel good and your body is just not in very good shape, your overall quality of life is just not that great.

44:20 – The Single Best Recommendation: Physical Exercise

Dr. Ben Everett: So that’s where I think about lifestyle intervention, eating that healthy diet, trying to get some good movement, have some good social networking as well, so you can exercise your brain in, in positive ways. This is really all about the quality of life part that I think that we should really be focused on.

Dr. Ben Everett: So, hey, well, let’s kind of bring this full circle, and just think of, of, regardless of, of where a clinician is, what type of practice they have, if there’s one thing they were gonna tell patients they should start doing to improve their brain health, if it’s one thing that you would recommend people do, what would it be?

Dr. Gary W. Small: Physical exercise.

Dr. Ben Everett: Physical exercise.

[45:30 – Closing Thoughts]

Dr. Gary W. Small: There’s no question about it. We have the strongest data on it. For some people it’s addictive, because it gets your endorphins up, which lifts your mood. It helps with your pain levels. It lowers inflammation, which further helps with pain, and it makes you more alert, sharper, and happier, and more fulfilled. So, if it’s one thing, they’d say in New Jersey, the crossword puzzle, forget about it. Get on the treadmill, or even better, get outside and take a brisk walk or jog.

Dr. Ben Everett: Get a little vitamin D. We seem to be pretty deficient as a society as well. Well, Dr. Small, this has been a lot of fun. I’ve really enjoyed having you on the podcast today, and sharing your experience and expertise with us. Yeah, I think one of the big takeaways here is that, you know, cognitive decline is really not something that begins at diagnosis. It’s a process. It unfolds over time. I think regardless of where our listeners are in clinical practice, they can definitely help their patients improve their potential for preserving cognition. Well, look, I appreciate you taking the time to share your expertise and perspective with us today.

Dr. Ben Everett: For our listeners, I always want to thank you for joining us on the JCP Podcast. If you found this discussion helpful, I’d say be sure to subscribe. We’ll include links in the show notes, so, additional resources. Just recently, we had Dr. Marc Agronin on, where we really delved deep into the pharmacological development of different treatments.

Dr. Ben Everett: So if you really want to get into the nitty-gritty on some of these different treatments, I’d, you know, recommend people go and listen to that conversation we had with Dr. Agronin. Until then, this has been the JCP Podcast. Insightful, evidence-based, human-centered.