Podcast: Helping Older Adults Manage Alzheimer’s and Other Dementias

Jeff talks to Dr. Brent Forester about dementia and other cognitive disorders that are often found in older populations. They discuss the basics of Alzheimer’s disease and other dementias, how to navigate treatment and support a loved one living with these conditions, and some of the current research going into the future of dementia care.

Brent Forester, MD, MSc, has served as the chief of the Division of Geriatric Psychiatry at McLean Hospital and medical director for Dementia Care and Behavioral & Mental Health Population Health Management for Mass General Brigham. His research has focused on novel treatment approaches to manage the disabling behavioral complications of dementia, such as agitation and aggression.

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Episode Transcript

Jenn: Welcome to Mindful Things.

The Mindful Things podcast is brought to you by the Deconstructing Stigma team at McLean Hospital. You can help us change attitudes about mental health by visiting deconstructingstigma.org. Now on to the show.

Jeff: Hi there, and welcome. My name is Jeff Bell, and on behalf of McLean Hospital, I’d like to say thank you.

We’re so glad that you’ve joined us for this episode of our educational webinar series. Our focus today, helping older adults manage Alzheimer’s and other dementias, it is a topic that impacts so many of our lives, and the broader subject of aging brains impacts all of us, right?

Our brains change as we grow older. It’s natural to notice some subtle differences in the way that they work, for example, some of us might notice that we misplace our keys a lot more than we did when we were younger, but for far too many people, brain changes can lead to serious conditions such as dementia or other cognitive disorders.

Over the next hour, we’re going to do our best to share with you what you should know about all of this, and we’re going to get some help. A lot of help actually, from a leading expert in this field.

Dr. Brent Forester is the chief of the division of geriatric psychiatry at McLean Hospital, also medical director for dementia care and behavioral and mental health population health management for Mass General Brigham.

He specializes in the treatment of older adults with depression, bipolar disorder, and behavioral complications of Alzheimer’s disease and related dementias.

Brent, thank you so much for being with us today.

Brent: Thank you so much for having me here, it’s a pleasure.

Jeff: Well, I want to share with you and our audience at the onset that this is a deeply personal topic for me. My mother and her father both developed dementia in their later years. I know firsthand how dementia can impact families.

So please know how much I appreciate the critical work that you are doing in this field. We certainly need that, and we need so much more. And I know you’re going to provide some hope for us today on that front as well.

Brent: Yes, indeed. Well, first of all, it’s a pleasure to meet all of you, and thanks for being here today. It’s a topic that’s been near and dear to my heart for my entire career. As mentioned, I’m a geriatric psychiatrist. I’ve been caring for older adults with mental health concerns and Alzheimer’s disease and related dementias for the past quarter of a century or so.

And the reason why I think it’s so imperative that we all educate ourselves about the importance of early recognition and assessment and treatment of people with dementia is because of the vastly rapidly growing population of older adults in our country, led by the baby boomer population.

We’re seeing a dramatic increase in the number of people with Alzheimer’s disease, predominantly because we’re all aging. Age is indeed the number one risk factor for dementia.

And as a psychiatrist, the part of this illness that I think impacts individuals with the disease, and especially their families the most, are the emotional and behavioral complications of dementia.

It’s one thing to have a loved one have trouble with their memories, you were saying before, misplacing their keys or forgetting where they put things or even forgetting names. But when they start to become anxious or agitated or paranoid or not sleeping, or really becoming irritable and moody, this is often when families become really overwhelmed.

And I agree. There is a message of hope here. There’s a lot that we can do.

Jeff: I’m sorry, before we dive in on the dementia front, I want to ask you to talk a little bit about natural brain aging. I’m going to use my little prop here.

This is my McLean-issued, portable brain that I keep with me here on my desk. How does this thing change over time naturally, Dr. Forester?

Brent: Well, as we all get older, there are a couple things that change in terms of our cognitive functioning and cognition. There are many domains of cognition, attention, organization and planning, memory, language, et cetera. But what normally happens with aging is it takes us longer to do things, our processing speed slows down a bit.

And so you may notice that it takes longer to come up with a word or a name or a film that you saw a while ago, but it eventually comes back to you. It may take a hint, a reminder, or a cue, but it often comes back. So there’s the processing speed, there’s some of this delayed recall that requires some more prompting.

Those things tend to occur normally with aging. But as we start to learn more now about the biology of what’s going on with the aging brain, we’re starting to try to understand what’s going on in the brain that’s causing normal aging versus what’s going on in the brain that’s causing something more serious, like a clinical condition we call dementia.

And I think it’s really important, maybe we’ll get to this in a minute, but just the terminology and the definition, so we’re all on the same page. I think that’s really critical that we’re talking from the same language.

Jeff: Let’s start there. I think that’s always so important to get the vernacular right, get the vocabulary consistent with our conversation today.

So talk about cognitive decline, talk about dementias, talk about Alzheimer’s in terms of the vocabulary that we’re going to use today.

Brent: So I’ll break it down into three buckets that are relatively simple to understand. There’s normal age-related memory decline, or this aging phenomenon we just talked about in terms of slower processing speed, and sometimes needing help with reminders and cues and things like that.

We’ll call that normal age-related memory decline, okay? The second bucket is called mild cognitive impairment. And the third bucket is called dementia, okay? We just talked about normal aging.

Mild cognitive impairment is a syndrome that’s caused by a whole host of diseases in the brain, and it’s characterized by some decline in someone’s cognitive functioning from their previous baseline. But their day-to-day functioning in daily life is completely normal.

They’re paying their bills, they’re driving, they’re working, they’re having relationships with other people. You wouldn’t know it having a casual conversation that they’re experiencing this cognitive decline from baseline. The only way to really know is to do an objective assessment, which we’ll get to.

So if you think about it simply, mild cognitive impairment is cognitive decline with normal functioning. And dementia is cognitive decline with abnormal day-to-day functioning.

So in other words, when someone tips the scale from mild cognitive impairment to the dementia syndrome, then we’re talking about someone’s having difficulty with paying their bills, or maybe they’re not able to be as productive as they once were at work because of the cognitive decline, not because of something else.

Or they’re having trouble with things that become more obvious, like driving or dressing themselves or bathing themselves and things like that. So when you have functional decline plus cognitive decline, that equals dementia.

When it’s cognitive decline alone, that’s mild cognitive impairment. Now, what’s really important to know is that these are descriptors. These are just descriptions of syndromes that have many causes.

Like in psychiatry for example, we talk about depression like we know what that is biologically, we don’t really know what depression is biologically. It’s many things. It’s a final common pathway of many changes that are going on in the brain.

Dementia also is a final common pathway of various pathological processes in the brain. It just so happens that the most common cause of dementia is the one that we often use to describe dementia, which is Alzheimer’s disease.

But Alzheimer’s disease refers to a very specific brain pathology, which we can get into in a moment. And there are a whole host of causes of both mild cognitive impairment and dementia, the most common of which is Alzheimer’s disease.

But it’s helpful to understand that when we talk about dementia, we’re talking about a series of symptoms and a syndrome that does not necessarily tell us what’s causing the problem.

Jeff: So we’re going to zero in on Alzheimer’s in just a moment here. But can you quickly give us a look at the landscape of dementia’s overall, perhaps naming by name some of the other dementias that are commonly treated as part of this work that you do.

Brent: So if you were to look at the diagnostic manual, or DSM, we call it the DSM-V now. There are probably, there are dozens and dozens of dementias, but the top four or five, I would say, based on prevalence include, number one, is Alzheimer’s disease.

And this was a diagnosis that was first coined by Dr. Alzheimer himself back in the early 1900s when he came across a woman in her fifties who had cognitive decline, confusion and paranoia that her husband was being unfaithful. And she passed away at a relatively young age in her mid-fifties.

And when he looked at her brain under a microscope, he saw what today is defined as Alzheimer’s disease, which are these amyloid sticky plaques, protein deposits in the brain outside of brain cells.

And these within brain cell tangles made out of the protein tau, neurofibrillary tau. Those two hallmarks of plaque, amyloid plaque and tau tangles are the two pathological hallmarks of Alzheimer’s disease.

Now, Alzheimer’s disease begins really, really gradually. It occurs probably insidiously over a period of years. So it’s often hard to pinpoint when you ask a family member, even the person with the illness, when did you start having problems with your memory?

They may not be able to point to a single event. There may have been a single medical event that uncovered an underlying problem. But most of the time it’s gradual and it’s insidious.

The hallmark cognitive decline you see with Alzheimer’s disease is inability to learn new information. So you give somebody a word list, like five words to remember, and after five minutes, they have no idea what those words were. And you can give them all the hints and reminders in the world. And if they get it, it’s only a guess.

It’s a deficit in the ability to store new information. So the first part of the brain that becomes affected by Alzheimer’s disease is the memory storage part of the brain called the hippocampus.

So that’s the most common cause of dementia, probably about two thirds of all dementias. The other top three or four include vascular dementia, okay? This is a dementia that’s caused by strokes in the brain, either a lack of blood supply because of a bleed or a lack of blood supply because of a clot.

And they can be large strokes, or they can be small or what we call mini strokes. Sometimes these mini strokes accumulate over years as well. And it’s often a very subtle process. But the cognitive problems that somebody with a stroke type of dementia we call vascular dementia, is different than Alzheimer’s disease.

People with the stroke dementia, we call vascular dementia, have what we call delayed recall problems. In other words, they may not remember those five words after five minutes, but when you give them a reminder, like say it was a type of like, say the word was apple, and we say a type of fruit, they’ll often get it.

Or if you give them a multiple choice, they’ll get it. We call that a delayed recall problem that improves with cues or prompts or reminders. So that’s a very different type of memory problem than Alzheimer’s where they can’t store the information in the first place.

The other problem that people with vascular dementia often get is what we call executive dysfunction, or an inability to organize and plan, to make decisions, to multitask, to shift from one thing to the next easily. Those two things often go hand in hand with a vascular type of dementia.

The third common dementia is what we call Lewy Body dementia, L-E-W-Y body dementia. It’s a Parkinsonian like dementia because it often looks a lot like Parkinson’s disease.

People have three cardinal symptoms with Lewy Body dementia. They have Parkinsonism, so they have tremor, shuffling when they walk. Sometimes they’re stoop posture, sometimes they’re affect, their facial expressions are flat, so they have Parkinsonian symptoms.

The other hallmark is a really interesting finding, which are visual hallucinations, seeing things that aren’t there. And these are often formed visual hallucinations like people or animals.

And the person with the illness may describe them matter of factly without even any emotion attached to them. Like, “Isn’t that interesting that I just saw a couple of lions outside the window?” Or, “I see about 35 babies sitting on that couch over there, but they’re not making any noise.”

So visual hallucinations, Parkinsonism, and then the cognitive problems, which often are problems of attention and focus and concentration.

The other type of the fourth category, I’ll just say of common dementias, that’s maybe five to 7% of all dementias is called frontotemporal dementia, this is a large category. It includes many subsets of dementias, one of which is called Pick’s Disease.

This illness often strikes when people are relatively younger, like in their fifties and sixties. And it often presents not with memory problems, but with changes in personality or demeanor or mood. Often it’s behavioral changes or behavioral changes before you see the memory problems.

And many times, certain variants of frontotemporal dementia will present first with a language problem, like with an inability to express oneself that then progresses into a more formal frontotemporal dementia.

So there are many other kinds. HIV can cause dementia. Parkinson’s disease itself can cause dementia, alcohol can cause dementia, and the list goes on and on. But those are the big ones.

Jeff: So under this umbrella of dementias, how difficult is it to tease out what’s what from a diagnostic standpoint? I mean, do you have to be a well-trained expert such as yourself, or can a general practitioner determine what’s what?

Brent: So I would ask the question first. How do you assess dementia in the first place? Maybe we should start there.

Jeff: Let’s do that.

Brent: I think before we get into how do you tease out Alzheimer’s versus vascular versus Lewy Body? Let’s just figure out the person has dementia. You would think that would be relatively straightforward, but it’s not.

And in the United States today, let’s say there are 6.2 million Americans with dementia, half of those people aren’t even diagnosed.

Jeff: Wow.

Brent: And the people that are diagnosed are not diagnosed until it’s so obvious that they can’t drive a car anymore, pay their bills, that there’s a problem going on. The delay in diagnosis in this illness is a huge barrier to effective treatment.

It’s a huge barrier to prevention of bad outcomes, including safety concerns and even someone’s quality of life and how long they live. So the first thing we need to do is figure out a way to have systematic screening for cognitive impairment and assessment for “Do they have dementia, or something else causing the memory problem.”

That is, to me, is the fundamental problem that we have right now, not only in this country, but around the world. And there are many reasons why there’s this delay in diagnosis. There’s the stigma issue. You know, nowadays in 2023, even people treat dementia like they treated cancer 50 years ago.

Like doctors don’t even want to make the diagnosis because they don’t feel comfortable making the diagnosis. They don’t have the tools to make the diagnosis. And then they don’t know how to tell somebody they have the diagnosis because they don’t feel confident in themselves in making the diagnosis.

And they certainly don’t feel confident in saying, “Okay, this is what we now need to do.” They don’t even feel confident in saying, “This is the roadmap we now need to follow in helping you with your care plan.”

So I think for us to, this is like a, maybe a conversation we can have a little later on, but the policy implications here and like what do we do to incentivize earlier diagnosis?

You know, once we have a definitive treatment, which we may have soon enough on the market that we think actually treats the underlying illness, which we’ll get into, I think there’ll be more support and motivation and incentives frankly, for this diagnosis to happen earlier and earlier.

But right now, that is the number one problem. But in order to make the diagnosis, the answer to your question is absolutely, a primary care physician, a general practitioner, a family practice clinician should be able to make this diagnosis in their own clinical practice. And so the first thing to do is to get a really good history.

We have a lot of fancy tests we can do, but the number one thing to do is to find out the story. The story will often give the answer. Is this person experiencing a decline in their memory or their thinking or their judgment or what are you noticing that’s different about mom or dad or your sibling or your spouse?

And how long has that been going on? And was it all of a sudden, like in a stroke, it’s an all of a sudden problem. Whereas in Alzheimer’s it’s been over years and I never really noticed when it started, but I started to notice X, Y, and Z.

So that’s how you start to differentiate the types of dementias. Get the story right. When did it start? How long has it been going on? Did it start all of a sudden, has it been gradual? So that’s one thing is getting the story right.

The second thing is doing a basic medical workup. Are there any blood test abnormalities that may indicate a medical problem that could be masquerading as a memory problem? Do they have sodium deficiency or is their blood sugar through the roof or is their blood pressure all over the place?

You know, do they have an underlying medical problem that’s not being adequately managed? Like they have a lung disease, emphysema, and their oxygen status is low and so they’re not getting appropriate oxygenation to the brain. I mean, it could be a million medical problems.

So we have to make sure there’s none of that going on. It could be vitamin deficiencies. We often will screen for vitamin D or B12 or folate deficiency. It could be a thyroid abnormality. Underactive thyroid conditions can cause depression. It can also cause a cognitive problem that is treatable.

So we need to look for these medically reversible causes of cognitive impairment. We also need to look very carefully at medications. What medicines are they being given by their doctor? Or what medicines might a person be taking over the counter that could be causing some of the memory problems and cognitive issues that we’re seeing in front of us.

Some of the common mistakes that doctors make is they prescribe medicines for condition A, which causes side effects that look like a new condition B, but they’re really just medication side effects.

So for example, you give somebody a pain medication like an opiate for pain because they’re post-operative surgical patient and they’re on oxycodone and they look terribly cognitively impaired because it’s a side effect of that medication.

Or they’re given certain psychiatric medicines for anxiety like benzodiazepines, like Ativan, Lorazepam or Klonopin. Clonazepam for sleep or for anxiety. And those can cause cognitive problems. And so you need to go through the whole laundry list of medications that could be causing this.

Over the counter medicines, there are numerous, but the ones that I often will alert people to be careful about are things like anything that will help you fall asleep that has Benadryl in it, like Tylenol PM has Benadryl in it.

Benadryl diphenhydramine blocks a chemical in the brain that we need for normal attention and memory. We’re actually exacerbating or causing what looks like a clinical syndrome of a cognitive problem by taking too much of this on a regular basis over the counter.

So we look for the medical problems, we look for the medication side effects, both the prescribed and the over the counter. And then we do some basic testing. Okay, and this gets at your question about how do we tell the difference?

There are some simple tools that can be used in general medical settings for cognitive assessment. One widely used tool is called the Montreal Cognitive Assessment or the MoCA. This assesses eight domains of cognition.

It can be administered by a professional in under 10 minutes, and it can give you a tremendous amount of information about someone’s executive functioning and their language and their memory and their orientation and their attention.

That’s not a diagnostic tool, it doesn’t give you a diagnosis, but it gives you a lot of clues and it starts to show you where someone’s strengths and weaknesses are.

Now, a couple caveats. If you have someone who is a PhD in biochemistry from MIT and they run their own company, they’re really smart.

In other words, their cognitive reserve is really high, they may have mild cognitive impairment and get a 30 out of 30, a perfect score because you didn’t challenge their brain enough. You didn’t do enough of a stress test on that really cognitively well intact at baseline brain.

You may have somebody with an eighth grade education where English is a second language and they score a 24 and that’s completely normal out of 30 because they have a different level of education or they may have a different language.

Now luckily the MoCA comes in many, many languages. So language should not be a reason that you can’t get adequate data. But baseline education, baseline cognitive functioning makes a huge difference.

So all you’re doing when you do a MoCA, a Montreal Cognitive Assessment or any other cognitive screening tool is getting a point in time cross-sectional assessment of someone’s brain function at that moment.

Doesn’t tell you how they’ll do in a week or how they were doing a month ago, it’s just today. But it’s a good baseline of something and that you can go with. So if you do a good history and a good medical workup, including an exam like physical and neurological functioning, and you do a cognitive assessment, you’re getting close to everything you need.

The last thing you might want to do if you’ve never done this before is get at least one brain imaging study. Because there are many causes of cognitive problems that are identifiable through imaging. Alzheimer’s disease is not visible through an MRI.

You can’t see plaques entangles with an MRI, but you can see brain shrinking. You can see atrophy, which we call brain shrinking in certain parts of the brain. And this is again where we get it, is it Alzheimer’s or something else?

If it’s Alzheimer’s disease, the part of the brain that shrinks first is the hippocampus. If it’s frontotemporal dementia, it’s the frontal lobes of the brain. So you can see things with imaging that may point you with all the other information I just said towards one or the other.

So the American Academy of Neurology recommends that we do imaging at least once as part of our workup, not to make the diagnosis, but to rule out other causes. For example, you might see a stroke, or you might see a tumor, or you might see fluid in the brain called hydrocephalus, which could be causing a whole host of symptoms including cognitive decline.

That’s why we do MRI scans, not to make the diagnosis, but to look for treatable and reversible causes of cognitive decline. Once you’ve done everything that I’ve said, you’re almost all the way there.

There may be certain people because they’re really high baseline cognitive functioning or because there seems to be a problem with a MoCA, but you can’t tell is it due to something else where you might want to do more detailed testing.

That’s where we would think about referring somebody to a neuropsychologist to do more extensive cognitive assessment, we call neuropsychological testing. Not everyone needs this and not every neuropsychological exam has to be six hours or four hours. It could be two hours, but it needs to be done by a trained neuropsychologist to provide input.

And that’s where you can really learn strengths and weaknesses in a much more specific and refined way. And then you can really start to hone in more on this diagnosis, is it Alzheimer’s? Is it frontotemporal? Is it Lewy Body? Is it something else?

And I haven’t even talked about a lumbar puncture to get cerebrospinal fluid. I haven’t talked about a PET scan to look at metabolic functioning of the brain or looking at amyloid and tau in the brain or genetics. You don’t really need to do that in clinical practice to make this diagnosis.

Most of what I just said is almost exclusively now in research, will be moving more into the clinic, I think over time. But almost every primary care clinician can do everything that I said. It just takes time and education and frankly, some support, because it takes time.

That was a very long-winded answer, but I thought it was important to go through all those different steps.

Jeff: Yeah, no, I appreciate that and that really gives us the background we need for the context to understand what’s going on with these different labels.

One more question about these labels. We hear dementia and Alzheimer’s used interchangeably, oftentimes at the layperson level. Is that a concern of yours?

Are the distinctions specific enough that we shouldn’t refer to dementia defined as Alzheimer’s, for example? Does it impact the treatment?

Brent: It’s a great question and whenever I give presentations to public audiences, it’s the first question I get asked. And I’ve had individuals for example, say to me, “Well, I know you just told me I have dementia. Thank God it’s not Alzheimer’s.”

Okay, so let me just clarify this because it’s a really important question. Dementia is a generic term, okay? It’s a syndrome defined by a loss of cognition and a loss of daily functioning. It’s caused by a whole variety of diseases.

The most common disease in the brain that causes dementia is Alzheimer’s. It’s one form of dementia. Just like a Volvo is one type of car, right? Or a Chevy Suburban is one type of car. Alzheimer’s is one type of dementia.

And it’s important because the treatments that are now starting to be approved by the FDA that attack the underlying biology of these amyloid plaques will only help in people with amyloid plaques in their brain.

And that’s again, the biological hallmark of Alzheimer’s disease. So becoming specific about Alzheimer’s becomes even more important as we have what we call targeted therapies.

You know, not unlike, again, I used the cancer analogy before, but it’s very much like this. You know, 50 years ago, 40 years ago, the chemotherapies that we used in cancer were very non-specific for the biology of the cancer.

We knew they could kill cancers by doing general destruction to cells. Now we have cancer therapeutics that are targeting genetic markers that are expressed on cells. So they’re very specific for the cancer.

And that’s where we’re headed with Alzheimer’s disease. We’re just decades behind because there’s never been adequate investment or funding and frankly because the brain is so complicated. But anyway, that’s the simple answer to the question of Alzheimer’s versus dementia.

Let me say one other thing. The younger you are when you first have symptoms of dementia, the more likely it is that there’s one type of problem causing the dementia. Like someone in their sixties who can’t remember five words and it has a story and everything else adds up to Alzheimer’s disease.

If you happen to look at their brain when they pass away under a microscope, you’d probably see Alzheimer’s disease alone. If they’re 85 and they’ve got dementia and they pass away and you look at their brain, you’re probably looking at more than one different type of pathology.

You’re looking at Alzheimer’s plaques and you’re looking at many strokes, for example. That makes it very confusing when you think about treatment that’s targeted at certain biologies because the older you are, the more likely it is it’s not just one thing that’s driving the cognitive problems, it’s likely many, many processes.

Jeff: What do we know about the role of genetics when it comes to dementia?

Brent: So the number one risk factor for developing dementia is age, as I said, okay, beyond genetics, it’s age. But genetics plays a really important role, and we know the genetics of Alzheimer’s as well as any other types of dementia.

So I’ll just keep it to that since it’s so common. I like to think of two different types of genetic risks for Alzheimer’s disease, okay? There’s a singular gene called the APOE4 gene. If you inherit one or more copies from each parent, you can inherit one or two copies.

You’re more likely to develop Alzheimer’s disease than anyone at the same age than you are now who does not have one copy of that gene. We call that a risk gene. It doesn’t determine you get the syndrome of dementia. It puts you at higher risk of getting it, maybe two to three-fold that of the general population.

Then there are determinant genes which are inherited in a very different way.

It’s an autosomal dominant transmission, which means that if your parents, say, had Alzheimer’s disease at a relatively young age in their fifties, and you get genetically tested for one of these determinant genes or autosomal dominant genes, there are four major categories of those, there’re many of them probably, but there are four major ones or three major ones.

If you have one of those genes, you get the syndrome, period. It’s like Huntington’s disease. You get the gene, you get Huntington’s, you get one of those autosomal dominant Alzheimer’s genes, you get Alzheimer’s disease.

Luckily these are rare, these are really rare. And they run in family cohorts, and they often will present very young, some people as young as their twenties and thirties. These are very rare, like I said.

There’s a famous family in Columbia, South America. Originally came from Spain to South America and this cohort of a family, there are about 5,000 plus members of this family. They have this gene in the family and it’s an autosomal dominant gene. And people develop the illness in their thirties and forties.

And that family has been participating—the reason we know about them is they’ve been participating in landmark research around the genetics of Alzheimer’s and treatments for Alzheimer’s for the past couple decades—it’s called the Colombian cohort.

They’ve been, you know, there’s a great story on 60 minutes about them a few years ago, but these are rare family, in family genes, but it’s not the only genes that cause Alzheimer’s. There’s the risk gene that I mentioned.

There are many others as well. But I think what I like to focus on is, again, my whole attitude about Alzheimer’s is don’t focus on what you can’t do, we can’t fix our genetics, right? But we can change the way we live our life, and we’ll get to lifestyle interventions a little bit later on. But genetics are part of the story, but they’re not the only story.

And if you went to go see a regular doctor or even a specialist like me, a geriatric psychiatrist or a neurologist. For the most part, unless you were involved in a study, research study, you’re not going to get your genetics tested because it’s not going to tell us whether you’re going to get Alzheimer’s or not.

That’s going to be less important than all sorts of other risk factors. But it’s really important when it comes to research, because it’s going to be the research which will guide us.

If you have that risk gene I told you about, APOE4, not only you’re more likely to get Alzheimer’s, but if you have Alzheimer’s and the gene and you get one of these new treatments, you might be more likely to have side effects from the treatment and the dose may have to change.

So the genetics are going to start guiding treatment soon, but not quite yet. It’s going to happen very soon, but not today.

Jeff: What should we know about how gender factors into dementia?

Brent: This is a question which I don’t know the answer to because there’s a lot of debate about it.

But basically, more women than men develop Alzheimer’s disease and women live longer than men for all sorts of other reasons, which means that there are more women than men with dementia, but it might be because they live longer or it might be because of other biological factors, including the genetics of, you know, gender.

We just really don’t know the answer to that. But I think a lot of it is driven by age and other factors related to age. I’m sorry, just one other thing I’ll just say about gender is the estrogen effect. There’s a lot of controversy in our field in the medical profession, about estrogen.

Do you use estrogen to prevent dementia? Does the use of estrogen cause dementia? Does going through menopause increase your risk of getting dementia?

There’s a lot of debate on this issue, you know, the Women’s Health Initiative came out with their landmark findings two decades ago that essentially has stopped regular use of hormonal therapies, postmenopausally chronically.

We used to, when I was in my training, we used to put people on estrogens to help prevent Alzheimer’s disease and then we stopped doing that because of cancer risk. So this is a really interesting, complex, complicated question, but I raised it only because you brought up the gender issue, it just is always questions that people have.

Jeff: You touched on treatment briefly. Let’s circle back to that and talk a little bit more in depth about how Alzheimer’s, for example, is treated. Medical approaches, non-medical approaches. What should we know?

Brent: So let me talk about the medical approaches first, because they’re frankly way more straightforward and the non-medical approaches are way more important as of today, I would say.

But the medical approaches include the following. There are two types of medications, now there are three. There are three types of medications approved by the FDA for the treatment of Alzheimer’s type dementia, okay?

We’re talking specifically about Alzheimer’s disease. Now some of them may have beneficial effects in Lewy body dementia, et cetera. We can talk more about that. But let’s think about Alzheimer’s type dementia here.

The first are these drugs called cholinesterase inhibitors. They basically block an enzyme in the brain that breaks down this chemical we need for normal attention and memory called acetylcholine.

There are three on the market now, there are four that are on existence, but three on the market. The first of which was approved in 1996. So we have a lot of experience. The first one was tacrine in ‘93, 30 years ago, but that’s off the market.

So Aricept or Donepezil was the first of the class of drugs on the market with widespread use in 1996. It blocks the breakdown of acetylcholine in the brain, so there’s more acetylcholine around to help with attention and memory.

The second is called rivastigmine or Exelon. The third one is called galantamine or Razadyne. All three drugs were studied in trials of six months duration. They compared drug to placebo over six months and they used a 70 point measure of cognition called the ADAS-Cog.

And after six months there was about a four point difference between drug and placebo. Almost every study showed the same findings. Kind of amazing. These are in people with Alzheimer’s type dementia.

So these drugs for the most part have been approved for mild, moderate, and pretty much now severe dementia. So it’s never too late to start. But the earlier you start, the better. Because if you wait, what happens after six months is if you put the placebo patients on drug after six months, they never quite catch up.

So the earlier the better. However, these are only symptomatic therapies. What that means is if you stop the drug after six months, that four point difference, you lose it very quickly. The lines converge within a few months.

In fact, some people on these medicines who are on them for years and the family says, “you know, mom’s not doing much better, let’s just stop the drug.” They have a rapid decline in cognition and the rapid decline may be withdrawal from coming off the drug too quickly.

Or it could be because it’s only symptomatic and helping to kind of boost the acetylcholine levels. Once you remove that symptomatic, you know, effect of the drug, then the benefit is gone and they sort of, they fall back to placebo pretty quick.

So one of the questions that comes up with this class of medication particularly is how long do we treat people? So I usually say start as early as possible, once the diagnosis has been made. And then unless they’re having side effects which we can talk about, then I would treat them until there’s no function that’s worth preserving.

Now what does that mean? Well, it could mean the person’s able to ambulate and feed themselves, but they can’t communicate. There’s a lot of function that’s still preserved when someone can ambulate on their own and feed themselves even though they can’t communicate.

But if someone is bedbound and they can’t talk and they can’t feed themselves, then it may be time to try to stop. But again, this is an individual decision, and this is important to talk about with families and with patients when they’re able to make informed decisions.

The second class is one drug. It works on the glutamate system of the brain. It’s called memantine or Namenda. This drug came out in 2003, 20 years ago and until July of 2021 it was the last drug of its kind to come out on the market.

This drug modulates a chemical in the brain called glutamate, too much glutamate, toxic for the brain, too little glutamate, not enough attention in memory. So it basically tries to keep it at a steady state, if you will. It blocks over excitement of neurons with glutamate.

So it basically reduces glutamate but not too much. Studies have shown now repeatedly over the last 20 years that if you combine the first class like Donepezil or Aricept, get them on that for a couple months, add the second class which blocks glutamate, Namenda or memantine, that combination’s better than either drug alone and that’s our standard of care in 2023.

Okay, that’s the medical therapies. Now in 2021, a whole new class of medications started to come on the market. These medications are not symptomatic therapies. Their effects don’t necessarily go away when you remove the drug because what they’re doing is they’re removing, they’re addressing the underlying biology of the disease.

They’re removing the amyloid plaques, and these are antibodies that are targeted against the amyloid plaque. And they’re given through an intravenous infusion.

They’re not given orally like a pill like the other drugs, they’re given through once a month, over an hour. An intravenous infusion of an antibody that goes up into the brain, essentially removes the amyloid by dissolving it in the brain.

The first drug that got approved was Aducanumab or Aduhelm in June of 2021. We can talk about the controversy associated with its approval, but it was approved not based on its ability to improve symptoms.

It was approved through a mechanism in the FDA which we call accelerated approval because it can remove amyloid from the brain. There is no controversy in our field about whether Aducanumab removes amyloid. It definitively does.

If you look at an amyloid PET scan before, there’s amyloid riddled in the brain and you look at one after and it’s gone, it’s pretty amazing. It goes away, the question is, does it matter? Does getting rid of amyloid change the course of illness? Does it change the symptoms?

And unfortunately the two studies that Biogen did for Aducanumab were equivocal, one study showed a clinical benefit. The other study did not show a clinical benefit. You need two studies to show a clinical benefit in order to get approved.

And, both studies were stopped early for a whole variety of reasons we don’t have to get into. So there was a lot of controversy when the FDA made their decision to put it on the market, but they did not put it on the market with what was called full clinical approval. They went through this accelerated approval process based on its ability to remove amyloid.

So because of that, Medicare doesn’t pay for it. Because of that and the high cost associated with the drugs, about $20,000 a year, it’s pretty much not being used today.

Now there’s a second drug, this is the promising drug. This drug is called Lecanemab or Leqembi. It came out, it was approved by the FDA just, you know, just earlier this year, January 6th it was approved.

Now it was also approved on its ability to remove amyloid. However, at the same day that it was approved, there was an article published in the New England Journal of Medicine that showed it not only has an ability to remove amyloid, but it has a clinical effect as well.

After 18 months, which is how long these studies were, there was a difference between drug and placebo of about a 27% difference in decline. So the slope of decline, there was a decline in both groups, but the slope was more steep in the group that was on placebo versus the group on the drug.

I think it’s going to be the first week of July, I think it’s going to be the first week of July. The FDA is going to make a decision based on the full review of all the data, whether they give it full clinical approval. And if they do, which we believe they will, based on the data we’ve seen published, the FDA will give it full clinical approval.

Medicare, CMS will have to make a decision about covering the drug, which they may likely do and then it will likely be available on the market. But right now there is no medical infrastructure to deliver this drug in the United States, in rare exceptions. It requires an infusion center.

It requires careful monitoring, it requires MRI scans multiple times over the course of a few years to make sure you’re not getting the most common side effects, which are swelling in the brain and bleeding in the brain. They’re unlikely to occur and they’re unlikely to have symptoms when they do occur. But if they do occur and they have symptoms, it’s problematic.

But all of that is going to have to be built into a whole new healthcare system of, you know, has to be, you know, orchestrated. We’re doing that right now in our system. Figure out how are we going to deliver the drug? How are we going to find the people who need the drug?

There are a couple things to know about this drug. Unlike with the Aricepts of the world, it will only work if we get people early in the disease course. This drug will only work if you remove amyloid at the very earliest stages of mild cognitive impairment and very early dementia.

If we wait too long and by too long, I mean once someone is unable to drive or pay their bills, it’s too late. It probably won’t work because they’re already in the moderate stages. In fact there was a decade of research starting these drugs too late and they just don’t work.

But if you get people early enough, people stabilize and they have a meaningful stability in their illness, they will decline over time. But their quality of life and functioning over time will be better. That’s at least what we’re hoping for. And that’s where we think this is all going to change.

We’re really on the verge of a dramatic change in the landscape of biological dementia care within the next few months. Medicare will likely cover it, it will likely be very expensive. Some people won’t have access because of that. That provides a massive equity issue that this needs to be addressed and we can talk more about that, but this will change the landscape of care.

The good news is there are other treatments down the pipeline as well, not just Leqembi, which is coming out hopefully this summer, but there will be others addressing both amyloid and tau in the brain.

And then we didn’t even get into the other biological mechanisms, but there are about 28 drugs right now that are in the final stages of drug development that are trying to address the underlying disease process.

So we’re going to be seeing a whole change in the landscape of available therapies over the next couple years with Lecanemab Likely the first later this year.

Jeff: Well that all sounds very promising. I want to work in a couple of questions that have come in from the audience and this is one I know you’re going to want to answer because I know this is important to you. What can a person do to prevent dementia?

Brent: Yes, prevention is key. There have been a lot of studies that the federal government and the Alzheimer’s Association and others have been funding over the past few years that are finally bearing fruit.

And basically what we’ve learned is that there are four factors that we have control over that will impact how our brains age. One factor is exercise. We know that aerobic exercise, and this doesn’t have to be training for a marathon or an Ironman, it can be 30 minutes of aerobic exercise, getting your heart rate up, you know, three times a week.

You know, that could be a stationary bike, it could be a brisk walk, it could be a jog, it could be strength training. But aerobic exercise has a hugely beneficial effect on brain aging. And there have been animal studies and human studies and of all the powerful things we do with medications, this is as powerful, if not more powerful.

So one is exercise. And you’ll notice by the way that these four things I’m going to tell you do not come in a pill. They require behavior change and behavior modification. Doctors can prescribe go exercise three times a week, but it requires like a social mold, you and somebody, you know, holding you accountable.

So let’s just throw that out there because that’s a big part of this is the behavior change. So exercise is one. The second is nutrition or diet. There have been a lot of studies on this and if you boil it all down, dietary interventions that basically are antioxidant in nature can be really helpful for brain aging.

So for example, the Mediterranean diet and diets that are rich in omega-3, fatty acids and green leafy vegetables and fruits and really low in saturated fats can be extremely potent in terms of healthy brain aging. And the mechanism is by preserving the energy part of the brain cell called the mitochondria.

It’s like preserving brain energy function and reducing the effects of oxidative stress on the brain. So there’s true biological pathways and rationale for nutrition interventions. Exercise, nutrition.

Number three, social engagement. We’re now starting to see the adverse effects in older people in particular of loneliness and lack of social engagement. Social interaction, social connection matters not just for how we feel emotionally, but how, believe it or not our brain ages.

And again, it requires behavior change, but this is a huge powerful predictor of successful aging and brain aging in particular. And then the fourth thing is exercising our brains. So it’s one thing to, like, for me to give the same talk over and over again. I mean that’s a good thing to do, but I need to challenge myself with new things as I get older.

And it may be as complicated as learning a foreign language or doing a crossword puzzle, but doing something or learning a new musical instrument but doing something new that is challenging your brain.

There’s a lot of money in these cognitive brain games that are out there, some of which have been shown to help and some seem to help on paper like pre-post. But does it really translate into your daily life? Like you may do better on a game, but then well do you do better in life? You know what I mean?

So I think there’s a lot of questions about what’s, you know, what is the one brain game or brain exercise I recommend, I can’t really tell you. But I do think exercising your brain with cognitive stimulation is really critical.

Those are the four things. Exercise, nutrition, social engagement, and cognitive stimulation. All of those things are important to prevent the onset of dementia, to delay the onset of dementia and even to treat cognitive impairment once you already have cognitive decline.

Jeff: Okay, we could do a whole hour on this next topic and hopefully we will down the road, but give us the most important things that we should know about aging brains and psychiatric impacts. And I know that this is an area that you specialize in.

Brent: Yes, this could be an hour plus. Couple principles. Number one, there are many risk factors for dementia. We talked about age, we talked about genetics, we talked about all the risk factors for heart disease and stroke can cause dementia. That’s why nutrition and exercise is so important.

But the one thing we didn’t talk about is depression. And it’s probably not just depression, but it’s probably any chronic psychiatric illness, anxiety, depression. But we know for sure with depression that if you had depression earlier in life, it’s a risk factor for getting Alzheimer’s disease in later life.

The second thing is once you have dementia, even if you never had depression before, you’re at a very high risk of getting depression. And it’s not just because you’re realizing you’re losing your memory.

It’s because the biological brain changes that the dementia itself is causing, neurotransmitter changes, structural brain changes, connection between brain regions, circuitry changes in the brain, all of that you can only imagine how much must go awry in the brain of somebody with dementia biologically.

So there’s the risk factor that depression has for dementia. There’s the risk of getting depression once you have dementia. And it’s not just depression. People with Alzheimer’s disease and other forms of dementia develop psychiatric complications almost all of the time.

Almost a hundred percent of people with Alzheimer’s disease develop apathy, which is lack of motivation or interest, or anxiety or depression or paranoia or hallucinations or agitation. Some one or more combination of these various psychiatric symptoms or syndromes are commonly complicating dementia.

And the reason why it matters is it impacts the quality of life of the person with the illness. It dramatically impacts the quality of life of the caregiver and it predicts someone’s course of illness.

People with these symptoms that are not treated will have a more rapid decline and they may actually have more likelihood of winding up in a more, like a care environment, like a long-term care facility sooner rather than later. And the good news is there’s a lot we can do to treat those symptoms.

There are medications we can use, there are behavioral interventions we can use. There are ways to prevent those types of syndromes. The problem is they often don’t get addressed until there’s a crisis.

But if we intervened early on with some of the treatments, the prevention strategies and finding those symptoms of agitation and anxiety when they’re mild to prevent them from getting severe, there’s a lot of opportunity for risk reduction there.

Jeff: Let me work in one more audience question here. Is it normal for an older adult to demonstrate confusion and or difficulties with cognitive functioning after surgery or certain medical procedures?

Brent: Very, very common. And oftentimes it’s because there’s already an underlying biological process going on in the brain. So imagine, you’ve had one thing I didn’t say in the whole diagnosis of Alzheimer’s, but it addresses this question.

We now know that if you are diagnosed at the age of say 70 with Alzheimer’s disease and you had the magic wand of looking back in time to when you were 50, the beginning of the amyloid plaque deposition probably began in your fifties, okay?

And you didn’t have symptoms until you were like in your late sixties or until you were 70. So there’s like decades, probably two decades of brain pathology before symptoms occur, okay? That’s because it takes a while for there to be enough loss of brain cells.

So now you have somebody with a vulnerable brain of a disease who goes in for surgery, you think they’re fine, right? Because they don’t have a lot of symptoms, but they got the brain pathology, now you give them anesthesia.

Now you may deprive the brain of oxygen for a period of time because they go on a bypass bump because they’re having cardiac bypass surgery or maybe you did an orthopedic procedure and now like little clots are shooting up into the brain from the orthopedic procedure and they’re getting mini strokes.

So now all of a sudden you’ve had a massive insult to the brain in an already compromised brain that didn’t show symptoms, all of a sudden show symptoms. And we call that acute onset of confusion, delirium. That’s a medical term for acute confusion that happens in the setting of a medical event.

It could be an infection like COVID or urine infection, or it could be postoperatively after hip surgery or after anesthesia for something else. Those episodes of confusion will usually get better over days to weeks. But the underlying cognitive problem may now be more apparent.

And I can’t tell you how many people I’ve seen over the years where the family said, “well, they were fine until they had that surgery.”

Well, they developed a delirium from the surgery, which is the confusion the person was asking about. And that delirium may actually get better, but the underlying cognitive problem will be there.

Jeff: Another question from an audience member. If a family member has dementia, how much should you tell them about their condition?

Brent: Another wonderful question, and this depends how aware are they of the problem? How worried are they about the problem? How defended are they about the problem, and in denial? So we use common defense mechanisms unconsciously every day.

You know, if we didn’t use the defense mechanism of denial, we would never get in an airplane. We would never cross a bridge, right?

These are protective mechanisms to keep us from becoming overwhelmed and anxious in stressful situations, right? If the person who is losing their memory is aware of their memory loss and they talk about it, then you should talk to them about it.

If, however, they have no awareness, which does happen in certain people with dementia because of the part of the brain that it attacks, they may have no awareness of their decline. And if you put it in their face, they get agitated or worried, there’s no need to put it in their face.

There’s no need to become like harp on it and dwell on it, move on, talk about something else, focus on what they can do, not what they can’t do. But there’s no one right answer for this question because it’s very person dependent.

This is why working with an outside of the family member, whether it’s a clinician like a primary care doctor or specialist, or a social worker care manager, somebody really specializes in dementia care or maybe somebody from the Alzheimer’s Association called the dementia care consultant who can be awesome.

Work with them on thinking about how best to talk to your loved one with dementia. Because it will depend on the person’s own situation. And by the way, it may change over time.

One day the person may be aware and know what’s going on and be able to talk about it, and the next day we call it the shade is down and they’re more confused, and no matter what you say, it’s actually going to just make them anxious and agitated.

Understanding those fluctuations is also critical and it is so hard, and this is why this is a disease that’s unlike any other disease because this is a family illness. This is not just about the person with the disease.

Jeff: As we wrap things up here, you promised us some hope and I want to ask you to wrap up by offering a message of hope for those with dementia and for those who are caring for somebody with dementia.

Brent: So a colleague of mine, Tom Harrison and I wrote a book that came out this past year called “The Complete Family Guide to Dementia.” And it has a lot of this in there.

A lot of what we talked about is in the book, but part of what we talk about in the book is this message of hope, which is to be very proactive and not reactive, to talk about what people with dementia can do and not what they can’t do.

And so the way I talk about this is I often get the question, “so what’s mom’s prognosis? What’s my husband’s prognosis? What’s my sister’s prognosis?” And I basically say, “look, everyone has a different course of illness, but there are three things that will predict the course of this illness.”

Beyond genetics, beyond the uncontrollable, there are three things that we can do something about, okay? One thing is someone’s physical health. So paying attention to someone’s diabetes with dementia is critical.

Paying attention to their heart failure or their hypertension, preventing falls, you know, minimizing the use of anesthesia, minimizing the use of medicines that have toxic effects on the brain.

All of those things, the medical things that drive dementia. We can do a lot about maximizing medical care and reducing adverse side effects of medicines. And that gives people hope because, oh, I can do something here, okay.

Number two, we just talked about it. It’s the psychiatric and the emotional complications of dementia. There’s a lot we can do to treat those symptoms, to prevent them from worsening, maybe even to prevent them from happening in the first place.

So one is the medical, second is the psychiatric, and then the third is the stuff that we talked about, which is the social engagement, cognitive stimulation, nutrition, and exercise. Those prevention things that may help prevent onset can also help with delaying decline or slowing decline or reducing the risk for decline.

That’s a lot of control. That’s a lot of things that one can do, that one can pay attention to. And at the end of the day, when I’ve talked to probably hundreds and hundreds of people with dementia over the years and their families, what matters most to people with the illness and their families is their quality of life.

That’s what people care about. Focus on their quality of life. This is a chronic illness. This is a lethal and terminal illness. And we have to recognize that first to be able to do something about it. But second, it gives us then hope.

Okay, what can we do despite having an illness that may go on, by the way, for decades, what can we do to maximize someone’s brain health and cognitive functioning and engagement with the world around them? And focus on what they can do and the things they love to do while also making sure they’re safe.

And this is where it becomes really challenging because sometimes the loss of independence is a big damaging blow to someone’s ego and their self-esteem and their mood, can raise anxiety. Like, “I don’t have the ability to drive anymore. What do you mean?”

You know, so although we have to sometimes address challenging issues like driving, we always will at some point have to address that for people who have driven, we have to focus on quality of life as well. You’ll have no quality of life if you get into an accident and hurt yourself and you’re not able to move, right?

Easier for me to say than for us to do. But there are all sorts of strategies that we talk about in the book about how to deal with some of these big safety issues that come up around, for example, driving is one of them.

But anyway, I focus on what people can do. I focus on quality of life and some of those issues that we just talked about.

Jeff: This hour has just flown by and you’ve provided so much expertise on. I just want to thank you on behalf of McLean and the rest of our viewing audience for what you’re doing, the research that you’re doing, and taking time to educate the rest of us. Much appreciate it.

Brent: Thank you so much, thanks for all being here today.

Jenn: Thanks for tuning in to Mindful Things! Please subscribe to us and rate us on iTunes, Spotify, or wherever you listen to podcasts.

Don’t forget, mental health is everyone’s responsibility. If you or a loved one are in crisis, the Samaritans are available 24 hours a day at 877.870.4673. Again, that’s 877.870.4673.

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The McLean Hospital podcast Mindful Things is intended to provide general information and to help listeners learn about mental health, educational opportunities, and research initiatives. This podcast is not an attempt to practice medicine or to provide specific medical advice.

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