The Healthcare Triage podcast is sponsored by Indiana University School of Medicine whose mission is to advance health in the state of Indiana and beyond by promoting innovation and excellence in education, research and patient care.
IU School of Medicine is leading Indiana University's first grand challenge, the Precision Health Initiative, with bold goals to cure multiple myeloma, triple negative breast cancer and childhood sarcoma and prevent type 2 diabetes and Alzheimer's disease.
Dr. Aaron Carroll: Hi, this is Dr. Aaron Carroll, and welcome back to the Healthcare Triage podcast. This week we're going to be speaking with Dr. Liana Apostolova, an expert in the care of and research into Alzheimer's disease.
We've taken a bit of a break because we decided we wanted to try something new. So over the course of the next year, we're going to focus on more clinical topics. Talk to you about diseases or conditions that you might have heard about, but wish you knew more about. And we're also going to talk to experts who can help not only talk to us about those diseases or conditions, but also where the current therapies are, where the hope is for research in the future and where we should be looking for things to perhaps get better as time moves on.
Given that these are more clinically focused and we're going to be focusing on conditions, we thought we might partner with a clinical institution in order to get some experts who might be able to talk to us and walk us through some of this important information. And given that I work for Indiana University School of Medicine, they seemed a perfect partner. So this and future Healthcare Triage podcasts are going to be sponsored by Indiana University School of Medicine, whose mission is to advance health in the State of Indiana and beyond by promoting innovation and excellence in education, research and patient care.
Today, we're going to be talking about Alzheimer's disease. And our guest is Liana Apostolova, who is a neurologist at IU School of Medicine. And she's got some fancy titles, which I'm going to let her describe because she can do it much better than me. So please, tell us a little bit about yourself.
Dr. Liana Apostolova: Yeah. My name is Liana Apostolova and I'm a professor of neurology at Indiana University and the Barbara and Peer Baekgaard Professor of Alzheimer's disease research.
Dr. Aaron Carroll: Great. I want to start almost at the beginning, because I think that there's a general curiosity about Alzheimer's disease and everybody sort of knows what it is, but people don't really know what it is. So, if you had to explain to just someone off the street what is Alzheimer's disease, how would you put it?
Dr. Liana Apostolova: Alzheimer's disease is the most common disorder affecting cognition among the elderly. It's a common disease among those who are 70 and 80 year old, although there are variants of it that affect people much, much younger. It starts typically with memory loss. It's usually forgetfulness about recent events or information that was already presented so that the individual repeats asking the same questions or retells the same stories, that kind of forgetfulness rather than, where did I leave my keys? Or, why did I come in this room for? Which happens to all of us.
Also, we often have people complaining about forgetting people's names. That also is not exactly the same thing. It's more information that has been provided and it's completely lost, but not something like a personal name, rather, where are we going? Or, when is this event going to occur? Or, this event already happened, but I have no recollection who was there and that even I was there.
Dr. Aaron Carroll: So what causes it?
Dr. Liana Apostolova: Well, it's still under research. The exact precise mechanism that Alzheimer's comes about, but it's wildly believed that a protein called amyloid builds up in the brain beyond the levels that the body can efficiently take care of. And once this protein becomes elevated, either over-produced or not cleared as fast, it start depositing in the brain and it's very toxic to the brain cells. The areas that are affected first and most vulnerable are really those areas that take care of memory. But as the disease progresses, eventually many other cognitive aspects and aspects of daily life become affected such as attention concentration, ability for somebody to find their way or to express their thoughts and really operate independently in day-to-day living.
Dr. Aaron Carroll: So that seems like a pretty specific thing, amyloid protein being deposited. So can other things mimic this? Or the way that we think, or the way that we remember look the same in the elderly or anyone else? Or is it really just amyloid protein deposits in Alzheimer's? I mean, can other processes mimic that?
Dr. Liana Apostolova: Absolutely. Many other processes can mimic that, which is why it's important for people with memory loss to come to the neurologist, to us, for an expert opinion, evaluation and advice. And the workup will constitute of clinical and cognitive testing and also brain scans and laboratory markers that are important to distinguish Alzheimer's from other diseases that can mimic this type of condition.
Dr. Aaron Carroll: So there are ways that we can detect that there's amyloid protein being deposited in larger amounts either through scans or through lab tests?
Dr. Liana Apostolova: Yes. Most certainly there are. We do have both. We've always had a lumbar puncture, which is taking away some of the fluid that bates the brain through the procedure conducted at the lower back and sending that to an outside laboratory that can determine the levels of amyloid and the second Alzheimer's protein called tau. The other more modern way is to image the brain, inject the radioligand or a contrast dye that can label or bind to amyloid protein in the brain, and we can visualize it. And that has been already FDA approved. The Food and Drug Administration has reviewed and determined it's safe for clinical use. The problem is that we still don't have insurance coverage.
Dr. Aaron Carroll: So, is that how most cases of Alzheimer's are diagnosed today or is a lot of it still done clinically where we give tests of cognition and test of memory, and then assume that it's most likely to be Alzheimer's? Are most people getting the laboratory tests or other tests like that?
Dr. Liana Apostolova: So old people who come to us, especially us the neurologist, we follow the neurology guidelines of the American Academy of Neurology, and they would get a clinical and a cognitive evaluation. They'll get laboratory worker to rule out other conditions that can mimic memory loss due to Alzheimer's, and they will get a brain scan, an MRI or a CT scan, a structural brain scan. While we do have the amyloid PET imaging available clinically and approved by the FDA, it's not covered by insurance and it's quite expensive. So most individuals cannot really afford it.
Dr. Aaron Carroll: So when you say expensive, how much is it?
Dr. Liana Apostolova: $3,500, $4,000, pretty expensive. But we have research studies, ongoing national research studies that hopefully will prove its clinical utility to the Center for Medicare and Medicare Services, so they will start reimbursing for it, and the private insurers will follow.
Dr. Aaron Carroll: Is Alzheimer's disease becoming more common or are we just hearing about it more?
Dr. Liana Apostolova: I think we're becoming more aware and also people live to become much older. So it's a disease of the elderly, normally occurring after 65, but as one ages further, if we follow the population, there is an exponential increase of the cases simply because the longer a person lives, the greater the likelihood they will develop Alzheimer's.
Dr. Aaron Carroll: And about how many Americans right now do you think have Alzheimer's disease?
Dr. Liana Apostolova: Oh, currently in the United States, there are over 5.7 million Americans with Alzheimer's disease.
Dr. Aaron Carroll: And the vast majority of them are over 65?
Dr. Liana Apostolova: Oh yes. Absolutely. About 300,000 are less than 65.
Dr. Aaron Carroll: Okay. And so what makes the cutoff for early Alzheimer's disease?
Dr. Liana Apostolova: 65 years of age. That's typical.
Dr. Aaron Carroll: And is there something different about the disease that hits younger people or is it really all the same thing, it's just some people get it earlier than others?
Dr. Liana Apostolova: So there are differences. The younger the patients, the more likely they would present with an atypical presentation, meaning they might have a non memory presentation. They might come with a presentation affecting their vision or affecting their language or more of a trouble with day-to-day living due to poor judgment and execution rather than a memory predominant form. While the older patients are more likely to have the memory predominant variants of it.
Dr. Aaron Carroll: Is there anything that predisposes someone to getting Alzheimer's disease?
Dr. Liana Apostolova: I don't think that we have thoroughly studied that question. There are definite risk factors for sure, but I believe there are many others that beg to be discovered. First and foremost, if we start with what you're given with from birth, your genes, there are risk factors that can be inherited from parents. Some of those cause a very rare form of Alzheimer's that is genetically predetermined by a single gene that is defective. These forms are super rare. They are less than 1% of the cases with Alzheimer's and occur in young adults actually rather than in the older folks.
And then for the more common variant of Alzheimer's, the one that occurs in the elderly, there are multiple genes that actually contribute fractions of the risk for the overall individual risk to get Alzheimer's that is inherited from the parents. And that is one area, a very active research. We're still trying to explain all of the so-called heritability of Alzheimer's, what is contributed for by the genes that are passed on to us from our parents.
Dr. Aaron Carroll: So, I get a lot of questions about people who are panicked about Alzheimer's disease and then they're like, "What can I do to prevent it?" They try all kinds of diets or they try all kinds of activities. I don't feel like that there's a really good body of evidence explain that, but maybe I'm wrong. Is there anything that people can do right now that we know of to try to limit their risk or to reduce their risk of getting Alzheimer's disease later in life?
Dr. Liana Apostolova: So, unfortunately, the most major risk factor is aging and the genes you got from your parents. There is not much we can do about those. But relatively speaking, there are ways if not to prevent it, to at least slow down its onset. And it's widely believed, and there is some evidence suggesting that exercise, physical and mental is quite helpful because it helps neurons or brain cells bring more connections and become more efficient.
Dr. Aaron Carroll: I'm a huge proponent of physical exercise, don't get me wrong, but do you think that physical exercise keeps people healthier in general and therefore perhaps it prolongs how long it is till they notice, or do you think it's actually reducing the amyloid plaque deposits, if they exercise?
Dr. Liana Apostolova: It's not reducing the deposits, but it's helping the brain cells become more resilient to the toxic effects of the deposits, if you will, because they just become more efficient and build more connections and the brain becomes more resilient. So you're building resilience, you're not dissolving amyloid that's depositing in the brain. We don't really have an intervention that can successfully quite do that yet and show meaningful outcomes. We do have some that are being developed.
Dr. Aaron Carroll: What do we do for people who have Alzheimer's disease in terms of treatment right now?
Dr. Liana Apostolova: So current treatment for Alzheimer's, we have two classes of drugs on the market. One are the cholinesterase inhibitors and the other one is a drug called Memantine. And those are FDA approved and available for treating the dementia stages. Some physicians might also off-label, meaning, without the approval of the FDA, use it in the earlier stages. And these are the only two, but they're not really so powerful.
Dr. Aaron Carroll: Can we talk about the more specifics in general? So you said cholinesterase inhibitors. So what does that do in terms of the body for actually trying to treat Alzheimer's disease? What's the mechanism?
Dr. Liana Apostolova: The mechanism for the cholinesterase inhibitors as the name implies, they block the action of an enzyme that degrades or that discards a specific molecule that is low in the brain. It's called acetylcholine. And for a while, it was thought that this is the main mechanism through which people get Alzheimer's because this particular chemical in the brain is low. So the drug actually elevates the level by blocking its degradation, if you will.
Dr. Aaron Carroll: And the second class of drugs, how does that work?
Dr. Liana Apostolova: Less well-known. The mechanism of action of Memantine is proposed to be through work on cells in an area of the brain called the hippocampus, which is the memory tape recorder, by working on the receptors that have to do with memory storage.
Dr. Aaron Carroll: So is it just a memory booster or is it again trying to interfere with amyloid plaque deposits or some other part of it?
Dr. Liana Apostolova: Neither of these drugs is targeting amyloid.
Dr. Aaron Carroll: It's fascinating. So the treatments have nothing to do with the actual mechanism by which we think it's occurring?
Dr. Liana Apostolova: Currently available treatments don't have, but we have many in the pipeline that are actually addressing amyloid and some have made substantive progress and reported the fact that they lower amyloid in the brain and also can improve cognition in smaller trials. These drugs, specifically one by Biogen called Aducanumab has been taken to large-scale studies, and hopefully we'll keep looking as good as it has to date. We also have drugs targeting the production of amyloid of course, where you want to lower it from that end as well. And some have been pretty helpful in that realm as well, but they're still in research.
Dr. Aaron Carroll: What do you think the most promising areas of research are? Are they focusing on amyloid or are there other things that you think are hopeful as well?
Dr. Liana Apostolova: Because some of the trials that have successfully removed amyloid from the brain have not resulted in substantive cognitive benefit or clinical benefit, I think it's as important to look into other mechanisms. So, no question, we have to keep going after amyloid, but the second protein, tau, is the one actually correlates or associates most with cognitive decline and clinical worsening. It's a protein that if we can slow the deposition of tau or remove tau, might be clinically beneficial to patients, even in the symptomatic stages. While now it's wildly thought that for an effect on the disease, we should remove amyloid before symptoms have started.
Dr. Aaron Carroll: So correct me if I'm wrong, but it feels as if in the news that there were a fairly large number of trials going on recently by drug companies where the drugs did not work as people had hoped. Is that a misreading of sort of what's been going on with some of the trials in Alzheimer's? And if I'm not wrong about that, then what has been the problem do you think?
Dr. Liana Apostolova: So the drugs that have failed targeting amyloid have been largely tested in the symptomatic stages. So the mild dementia MCI stages. And it appears as though it might be too late. At that time, many brain cells might be lost and the tau deposition has started and other cascades downstream from amyloid have been activated. This is why we think going after amyloid early in the presymptomatic stages before somebody has memory loss. A tantalizing idea, I tell you.
Dr. Aaron Carroll: How do we catch people before they're symptomatic?
Dr. Liana Apostolova: And the ones that are symptomatic, we probably should be treating with anti-tau and other mechanisms. So how do we catch the ones with that imaging that I told you about? We can administer-
Dr. Aaron Carroll: Do we screen people universally? I mean, do we start to screening everyone at age 60 or 65?
Dr. Liana Apostolova: I bet you that will be the case once we have a disease modifying drug. For now, there are clinical trials that enroll cognitively normal individuals who are amyloid positive.
Dr. Aaron Carroll: How do we pick those people up?
Dr. Liana Apostolova: They sign up for research, come to the clinic, get tested, we verify they're cognitively normal, and then we do that amyloid PET scan.
Dr. Aaron Carroll: So now you're panicking me. What percentage of people are cognitively normal yet would show up on an amyloid PET scan?
Dr. Liana Apostolova: About 25% of cognitively normal individuals aged 65 and above.
Dr. Aaron Carroll: Really?
Dr. Liana Apostolova: Yes.
Dr. Aaron Carroll: Okay, that's much, much, much higher than have Alzheimer's disease. Or is am I wrong about 25% of people of the age of 65?
Dr. Liana Apostolova: One shouldn't say presence of amyloid in the brain is equivalent to Alzheimer's disease because we do not know. We know for a fact that some people die with brains full of amyloid and haven't had clinical symptoms. So there are some that are resilient, but by and large, having amyloid in the brain is not benign and increases one's risk to develop dementia. Precisely which people of those 25% will progress to dementia? Hard to know. We're doing the science now. We have the tools to ascertain who has amyloid in the brain. So now we can follow them or put them in clinical trials and see if we can do anything to learn more about the disease and slow down progression.
Dr. Aaron Carroll: The health services researcher maybe is thinking, well, okay, if we can pick up people with amyloid, the 25% of Americans over age 65, have we picked up any risk factors yet that tell us which of those 25% will be the ones that have symptomatic Alzheimer's disease later versus those who don't?
Dr. Liana Apostolova: That is where most of the research has been focused now. And we're looking at everything, of the fluid that bates the brain, many imaging modalities, we're looking at blood, and there are some promising biomarkers being developed in blood that can potentially help us stratify risk in amyloid positive cognitively normal individuals. A lot of science is happening. It's a very exciting field and it's simply possible because unfortunately the very first amyloid plaque started developing 20 years before symptoms. There is that window of 20 years of silent progression of changes in the brain, which is a wonderful opportunity for treatment, if you think about it, because we able to identify individuals during those 20 years and stop disease progression. There you go. You've eradicated Alzheimer's dementia.
Dr. Aaron Carroll: The tests, can they quantify the amyloid as well? Of the 25% who have amyloid deposits, but not so dramatic, do they have a spectrum of how much amyloid? And can you tell that or is it just amyloid or no amyloid?
Dr. Liana Apostolova: So the scan is being read as amyloid, no amyloid. There should be some form of a cutoff for positivity to be called. It's a clinical test. In research, we do use a continuous scale for that measure because it provides more power from a statistical perspective. But in the clinic, it's a yes or no question.
Dr. Aaron Carroll: So some of the drugs that target amyloid, and if I remember correctly what you said is that we can slow or reduce amyloid deposits, it's just not showing a difference symptomatically, is that correct or am I wrong in that?
Dr. Liana Apostolova: In some trials, that has been the case.
Dr. Aaron Carroll: Have we then taken those drugs into people who are presymptomatic and seeing if we can prevent those deposits, if that makes a difference down the line? Or is that hard to do because of how long you have to follow people?
Dr. Liana Apostolova: Right. No, we do have active studies like that. We have the A4 study for cognitively normal amyloid positive individuals who are treated with Solanezumab to remove plaques and hopefully prevent cognitive decline from occurring. A group of these patients is on drug. Another group is on placebo. And then we'll see if there any difference between the two groups on the long run.
Dr. Aaron Carroll: So you say we, and I'm curious is that the we as medicine or we as in you're doing this?
Dr. Liana Apostolova: With Indiana University.
Dr. Aaron Carroll: Oh, in IU. Yes, sure.
Dr. Liana Apostolova: Yes, exactly. We absolutely are very active site in many clinical trials. This is one of them. This trial is specifically led by a Harvard researcher by the name of Reisa Sperling. But we are a site and our site is one of the most highly enrolling sites, I must say.
Dr. Aaron Carroll: What age are you enrolling people?
Dr. Liana Apostolova: That study, I think it's 55 or 50 years old.
Dr. Aaron Carroll: How long do you have to follow them?
Dr. Liana Apostolova: The study is set to follow individuals, I believe three to four years, something along this.
Dr. Aaron Carroll: Are the outcomes then amyloid amounts, or are the outcomes more clinical you're looking for no cognitive decline or less cognitive decline?
Dr. Liana Apostolova: Both.
Dr. Aaron Carroll: How much cognitive decline? This is where the researcher in me is kicking. How much cognitive decline would you expect in somebody 55 who's been picked up asymptomatically even if you did nothing? I mean, can you actually detect a difference? Or is it more that we're looking for a difference in a process measure like amyloid deposits?
Dr. Liana Apostolova: Both.
Dr. Aaron Carroll: Okay.
Dr. Liana Apostolova: We would like to see both of course. Yes, if you have serial testing on a cognitively normal individual as they develop the disease, yes, you will be able to detect changes with very sensitive instruments. And the Harvard group has developed such a preclinical instrument and several other groups have their own. So it's looking very promising from the data that I have presented, but still we have to wait for the final outcome of the trial to know if we can succeed in slowing it down.
But yes, you can detect preclinically, changes in cognition. Because, of course when you test somebody in order to tell your cognitively normal versus not, there are some cutoffs, but individuals start way up above. Our cutoffs are the fifth percentile. The majority of the average person is at the 50th percentile. So of course you can track the decline from 50th to fifth, you just have to test them during that stage, and you will be able to quantify.
Dr. Aaron Carroll: I imagine it must be hard to look at 55 year olds who are otherwise normal. How much cognitive decline do you see in people who don't have Alzheimer's disease say from 55 even to 60? Is there a fair amount?
Dr. Liana Apostolova: Not much. There is a little bit associated with aging, but it's not at all on the scale of Alzheimer's.
Dr. Aaron Carroll: Okay. How do the cognitive tests work? I mean, literally, how do they work? What questions do you ask? How long do they take and how are they implemented?
Dr. Liana Apostolova: Again, depends how long of a battery. For a clinical assessment, normally it's between 40 minutes to an hour long assessment to determine overall functioning and language, attention, visual spatial function memory, executive domain. Otherwise if one wants to delve deeper, there are four hour long assessments. There are multiple instruments that can be built into a battery to go very, very sensitive and nitty-gritty.
And the memory test for instance could be either a story read out loud, a story packed with details, and then later tell me as much as you remember, and it's not easy. Or giving an individual 10 or 15 words exposure to these words several times so they can learn them. And then sometime later, can you remember any of the words I gave you? That's where we find memory loss.
Dr. Aaron Carroll: What does your research focus on specifically?
Dr. Liana Apostolova: I focus on imaging and genetic biomarkers. I've always done that over the last 15 years, but even more recently now, I have focused on early onset Alzheimer's, the variant that affects patients that are younger than 65. I lead a national study called Longitudinal Early-Onset Alzheimer's Disease Study or LEADS. We have 17 institutions are participating, 15 sites across the country, and we're enrolling individuals who are either cognitively impaired or cognitively normal. Ages 40 to 64. And we are collecting a host of information really: clinical, cognitive, MRI, amyloid, and tau PET, the imaging modalities I was talking about.
We do blood, we do DNA, so genetics. We do lumbar punctures and we follow along to be able to determine the rate of progression and other things about this unique cohort that is affected so early. And we'll of course study for unknown genes and tap into novel biomarkers that can help us define this part of the disease better, but also potentially will be applicable to all of Alzheimer's disease in general.
Dr. Aaron Carroll: And who funds that kind of work?
Dr. Liana Apostolova: The National Institute on Aging.
Dr. Aaron Carroll: Okay. I mean, all of that is interesting from the sense, are you thinking about this will be more useful to help diagnose, or do you think that this will help drive treatment, a lot of the work that you do?
Dr. Liana Apostolova: So both. First, we're starting with an observational study. The study will run for 24 months. That means three visits, baseline, month 12, month 24. We will determine the rate of progression of those variants. I told you there are some variants that are more often associated with early onset. So we'll be able to really define the disease variants better.
And then we will have all these individuals plus more that are being referred to us, ready for a trial. And if an individual is this young, you can imagine that they really don't have other pathology going on. So there is not much vascular disease. There are not many other diseases affecting the body or the brain. They're pretty healthy. All they have is Alzheimer's. So that makes this cohort ideal for clinical trials. There is no noise from anything else that's going on. And the other kind of sad fact why they're really great candidates for trials is that in these individuals, the disease is really aggressive and progresses fast.
Dr. Aaron Carroll: And actually that's what I wanted to ask about next. So a typical course of Alzheimer's, from diagnosis, how does it progress and how quickly?
Dr. Liana Apostolova: So first individual center a memory only affected stage or a memory plus some other domains, we call it. Where they're though functionally intact, they can drive a car, pay their bills, and that state is called mild cognitive impairment. It can last a few years. Those that are unfortunate to develop dementia will progress to a stage where they can no longer drive or pay their bills or assemble tax records, all of these kinds of things. And that is when we diagnose dementia. And from the diagnosis of dementia to death, usually it's eight to 12 years.
Dr. Aaron Carroll: That seems like a pretty long time still. So how do people usually live at that stage? Do they stay at home with help? Do they go to facilities that might be able to better care for them? Or, what else happens, I suppose?
Dr. Liana Apostolova: It depends on the case and the family. Many individuals stay at home and are taken care of by family members. There comes the point where they need respite and professional caregivers to come and help, and whenever insurance can provide coverage or the family can afford it, that's excellent. But some families resort to institutionalization because of florid, psychosis, agitation, restlessness, the reversal of sleep wake cycle that disturbs everyone's sleep and many other behavioral abnormalities that are problematic and difficult to deal with outside of an inpatient setting.
Dr. Aaron Carroll: This seems like one of those diseases almost more than any other that eventually feel like that they're very difficult for others in a house or those who care for people with Alzheimer's as much as it is for Alzheimer's as well. So, how well do you think the healthcare system does in general for caring around people who have Alzheimer's?
Dr. Liana Apostolova: Yeah. The support services, they're definitely lagging behind. They should be at a much, much higher level. The Alzheimer's Association is a fantastic resource available in every state and multiple cities in every state that also have a 24 hour, 365 days a year helpline with, I think something like 40 languages or more at this point. It's a tremendous resource where one can call in out of the blue and just pose the question or get the advice they need as rapidly as they need it on the line.
The Alzheimer's Association also provides free charge resources and support services for patients and families. So they're a fantastic organization for patients and families to connect with. When it comes to caregivers, that oftentimes goes through the insurance companies and whatever healthcare arrangements an individual and their family have and that depends.
Dr. Aaron Carroll: Given that most people are 65 or above, I imagine a lot of this falls on Medicare. Does Medicare do a good job of providing a lot of these services or these things do people need additional insurance plans for usually?
Dr. Liana Apostolova: Provide some, not enough. Medicaid provides more. So it really depends on studying the various versions of the plan and consulting with a social worker. Also there are many legal matters that have to be resolved with patients and family. So with the elderly attorney, all that is so helpful. Today I had a patient in the clinic, actually in a research study, and his wife, day and night difference, by finally getting Medicaid and caregiver in the house five days a week and all the legal matter set. And it was a different person from last year.
Dr. Aaron Carroll: Right. Do they eventually get to Medicaid because they've depleted resources to the point where they qualify or is it just difficult to jump through hoops?
Dr. Liana Apostolova: Resources are depleted. It's so sad, isn't it?
Dr. Aaron Carroll: Yeah. But such a strange way we do things.
Dr. Liana Apostolova: You have to be driven to poverty to receive the care you need. That's horrible.
Dr. Aaron Carroll: Yeah. That's a thing we discuss all the time in our show in general. Are things that are common comorbidity? I mean, I'm just talking about this and I imagine that anxiety and depression and things like that could easily be associated with Alzheimer's disease. Am I wrong about that? And if I'm not wrong about that, what other things do people need to be on the lookout for that might run along with Alzheimer's disease?
Dr. Liana Apostolova: You're so right. So there is the cognitive decline, which in itself, it's what it is. Families can deal with that. There's the functional decline, which is harder to deal with, but still. But when behavioral changes kick in and that could be anything, agitation, irritability, psychosis, so hallucinations, delusions, aggressive behavior, anxiety, a lot of it, depression. Those are harder to deal with. And they're the prime risk factor for bringing somebody to a nursing home facilities.
The ones that are early on are depression, anxiety, apathy, loss of interest and lack of enjoyment and just becoming overall quieter and irritability. These are the top four for the early stages, but as the disease progresses, the more aggressive behaviors become noticeable and a refusal of care, resistance, overall belligerence, a reversal of sleep awake cycle. It's really a problematic thing. That's when we reach for more behavioral drugs in addition to the ones that we have given for cognition. There is a place for even anti-psychotic medications and sleep aids and stuff like that.
Dr. Aaron Carroll: I mean, given that everything is on a spectrum, how much of that is driven by, do you think, biologic changes or actual changes in the brain and how much is driven by the fact that this has to be incredibly hard to deal with that could leave a person predisposed to mental health issues as well? Or do we just not know?
Dr. Liana Apostolova: Yeah. It's hard to answer this question. At some point of the disease is more the awareness that something is going on with you and you're losing control and you are really becoming this other person who is intellectually inferior to the person you were. That awareness initially, it's the culprit of a lot of the behavioral issues, the depression, the anxiety. As the disease settles, a person becomes a bit oblivious about their symptoms. They lose insight, is what we call it.
If you were to ask them if they have a memory issue, they'll say, "No, I have no memory problem." Same person that two years ago came to you because they're having difficulty with memory, they just lose the insight. And then as the disease progresses, losing the ability to understand the world around you and what's happening becomes a trigger for a lot of the restlessness and aggression because everything becomes unknown and scary.
Dr. Aaron Carroll: Is there a standard progression to how memory is lost? Is it short-term and then long-term or the opposite? I mean, I'm just going to stop there and ask it, is there a standard way that it is lost or is it every person is different?
Dr. Liana Apostolova: Ordinarily, short-term memory first. So things that happened today and yesterday, and then as the disease progresses, it also affects longer term memory and ultimately all of the memory.
Dr. Aaron Carroll: So when a patient is diagnosed, is there are pretty standard protocol that you follow for every patient? Or there are a lot of individual decisions to be made?
Dr. Liana Apostolova: It's pretty standard. I would say that dementia experts across the country do a similar type of approach to evaluation. They might be some individualized differences in preference, which tests to use, cognitive tests. But by and large, we would order the same lab panel, the same MRI or CT scan and conduct a similar interview.
Dr. Aaron Carroll: And then how about for treatment? Is it pretty standard that everybody gets sort of the same treatments of what is available or is it still like a pretty individualized thing based upon how quickly you go, how old you are, any other factors?
Dr. Liana Apostolova: So it's up to the physician to decide when to treat, but once they decide to treat for Alzheimer's, they put the individuals on the two directs I described. Since we don't have a lot more available, there are really not many options.
Dr. Aaron Carroll: Are there major side effects from either of them?
Dr. Liana Apostolova: The drugs are somewhat benign. Memantine is pretty benign. The cholinesterase inhibitors are mouthful. They have some GI side effects, can cause nightmares, can cause some cramping of the muscles, but it occurs in about 20% of patients or so. So 80% can take them without any side effects.
Dr. Aaron Carroll: Given that, I imagine it's enticing for patients, they would like to participate in research. So what percent of patients with Alzheimer's do you think do participate in research studies?
Dr. Liana Apostolova: Small fraction, unfortunately, and really by engaging them in more research, that is how we can find the cure. I would encourage anyone who's listening to contribute. There are many ways one can contribute. One can bring their loved one and be a study partner for research studies or an individual with early onset Alzheimer or late onset Alzheimer's can volunteer to come and enroll in our studies themselves. They can help individuals who have cared for others with Alzheimer's. If the Alzheimer's patient is too advanced, there are other ways one can get engaged and help, by volunteering, by helping us recruit. There are many ways to get engaged in research.
Dr. Aaron Carroll: Clearly there's ways to help in volunteering and in doing good, there's no doubt about that, but given the people are all over the country, specifically how do you get involved in research? I think people don't know that in general. How do you do that?
Dr. Liana Apostolova: There is a fantastic site supported by the Alzheimer's Association called trialmatch.org, I believe. And if one goes into that, they're asked to fill out some basic information about them, their diagnosis, age and so on. And then they will get automatically a list of studies in their area that they're eligible for. Easy breezy. Just go to trialmatch.org, sign up and research will come to you. These opportunities-
Dr. Aaron Carroll: Does it cost money to participate in research?
Dr. Liana Apostolova: No money. Yes, it's free of charge. It's the Alzheimer's Association and they never charge for services.
Dr. Aaron Carroll: Just to clarify, we just looked it up and it's trialmatch.alz.org for anyone that would be interested in looking into research. On Alzheimer's disease, again, that's trialmatch.alz.org. But speaking about research, what are you most excited and optimistic about with respect to where we are and where we might be in treating Alzheimer's disease in the near future?
Dr. Liana Apostolova: I'm very excited of course about any progress we've made with biomarkers, which allow us to identify disease before it's symptomatic and allows us to stratify risk for individuals and about the major genetic efforts going on in the field of Alzheimer's that will allow us to detect more genetic risk factors. I'm also very excited about several promising drug candidates in clinical trials. We will receive some results from a trial at the AAIC. That is the Alzheimer's Association International Conference, and we're of course all are quite enthusiastically following the progress of Aducanumab and other promising drug therapies. Also, some very promising therapies are being developed against tau protein. And that is also quite hopeful. We're looking forward to hearing more about the advanced stages of those trials in the next conference.
Dr. Aaron Carroll: So those are trials in people?
Dr. Liana Apostolova: In people. Exactly. Yes.
Dr. Aaron Carroll: And so what did we know about the drugs that go after tau right now? Have they been through animal studies that appear very promising and therefore we're now doing them in human beings? Where are they in the progression?
Dr. Liana Apostolova: There are multiple that are being developed by a lot of companies and some have advanced to human studies and some have advanced to what we call stage two or phase two clinical trials, which means that is where they're given to Alzheimer's individuals to see tolerability safety kind of profile. Also, of course, they look for any signal of effect. But these studies are not large-scale enough to provide the ultimate evidence that it's therapeutic. After that, after it being ascertained first in cognitively normal young individuals, then in elderly normal individuals and Alzheimer's patients and it looks safe and promising, it's taken to what we call a phase three trial, and that's the large scale multi-site placebo controlled study that we all are looking for because that will deliver the next drug.
Dr. Aaron Carroll: Do you think there's a major breakthrough on the horizon?
Dr. Liana Apostolova: Couple of promising leads, major breakthrough. I'll be reluctant to say because of so many failures in the recent past, but several agents look quite optimistic.
Dr. Aaron Carroll: When we say quite optimistic, what do you think they might do?
Dr. Liana Apostolova: So what we know about them is that they can slow down amyloid deposition or remove amyloid from the brain and show some cognitive effect.
Dr. Aaron Carroll: Do you think we're more likely to find a cure for this? In other words, that we will find a way to stop the amyloid and the tau deposits and just get in its way? Or do you think it's just more likely that given this is a disease that hits the elderly most of all, we'll find a way to slow things to where people then start to die of other causes, which is, I think what we've done with some other diseases?
Dr. Liana Apostolova: I think it's more likely to first have the latter, slowing down, disease modifying drugs. But I don't think it's impossible one day to be able to prevent amyloid accumulation whatsoever. There was a very promising unfortunately interrupted clinical trial. It was due to side effects in patients. It was a vaccine against Alzheimer's, against the amyloid plaques. And individuals who received the vaccine and responded to it by producing antibodies, really didn't have amyloid in the brain. But two problems with that trial or side effects that led to the premature closure of this study due to inflammatory changes in the brain.
Dr. Aaron Carroll: Okay. I was going to say I'm curious, what side effects would they see from the vaccine?
Dr. Liana Apostolova: Encephalitis, overreacting to. In some individuals, that reaction by the immune system attack the brain. Nobody had died in the trial, but unfortunately also the other observation was that these were dementia patients. So in the very symptomatic stages, after removal of the plaques, the disease continued. Indicating that it's perhaps too late to go at that stage, but just being able to remove and prevent amyloid deposition or remove it from the brain by these means is optimistic. And if we are able to do it in the presymptomatic stages and indeed amyloid is what is the very first igniting step for Alzheimer's. Then, yeah, we can do marvels.
Dr. Aaron Carroll: Did this scare research off of the vaccine in general or are others working on different vaccines?
Dr. Liana Apostolova: Absolutely not. Many people are working on versions of the vaccine that is safe.
Dr. Aaron Carroll: Do you think that's more likely to succeed first before treatment? Or we just don't know?
Dr. Liana Apostolova: Yeah, disease modifying would be first and then a vaccine potentially later, if we can get it safe enough.
Dr. Aaron Carroll: Locally, I mean given that you work at IU and that clearly I imagine people listening to this also would be interested in locally, how do they enter in these kinds of trials? How would somebody in Indiana enter trials that you're doing?
Dr. Liana Apostolova: Yeah. We have multiple studies going on. We have observational studies, which are just following individuals, collecting biomarker data, and we have clinical trials. An individual can call us and enroll through the Alzheimer's Disease Center at Indiana University. The Longitudinal Early-Onset Alzheimer's Disease Study is looking for individuals 40 to 64, symptomatic and asymptomatic, willing to contribute and participate in research. And again, that is the same avenue to get them enrolled.
In addition to that, what's being planned and I hope it will come to fruition pretty soon is a pretty major statewide initiative from the Indiana University School of Medicine called the Precision Health Initiative with focus on Alzheimer's Dr. [Seki 00:44:49] and Dr. Lam, Dr. Foroud and I are planning a major recruitment effort of thousands of Hoosiers who will be screened and enrolled in a clinical study with various biomarkers. And we will learn a lot more about Alzheimer's disease, in general, in the State of Indiana. Such big efforts are rarely done, so we'll be on the forefront of being able to accomplish a lot and contribute towards really defeating this disease ultimately.
Dr. Aaron Carroll: I'd love to ask you one or two more questions about that. First of all, what do you mean by Precision Health Initiative?
Dr. Liana Apostolova: So this is a major initiative from the Indiana University School of Medicine, focusing on several critical disorders. Alzheimer's being one of them, multiple myeloma is another, and there are a few more. That's just the way that this school has prioritized those research initiatives and these conditions as the ones being most critical to right now invest in and find the cure for.
Dr. Aaron Carroll: Clearly there are details to work out on how a lot of the Precision Health Initiative studies are going to work, but can you give us some of the broad thoughts on how you might be moving forward to try to do research on Alzheimer's disease through the initiative?
Dr. Liana Apostolova: Yeah. We will be targeting individuals in their fifties and older from the Indianapolis greater area, but also probably statewide. And we will focus on clinical exams in a very creative way to assess cognitive function by using online tools for cognitive testing. In addition to that, there'll be blood collection, DNA collection. One can imagine that genetics will be quite important piece of this. And a subset will continue on to have a more detailed assessment such as MRI scan, amyloid PET scan, tau PET scan, and such.
Dr. Aaron Carroll: So who's funding that work?
Dr. Liana Apostolova: Indiana University School of Medicine.
Dr. Aaron Carroll: Very good. So this has been super informative. Liana thank you for joining us. I can't thank you enough. I assume we'll be allowed to invite you back if and when some of this research comes to fruition?
Dr. Liana Apostolova: It has been a great pleasure to be here and share with you. I love doing research and clinical care for patients, and yes, of course, I'm available. Please reach out.
Dr. Aaron Carroll: Thank you very much. All right. Thank you.
Dr. Liana Apostolova: Thanks.
Dr. Aaron Carroll: Indiana University School of Medicine, again, who I work for, is leading Indiana University's first grand challenge, the Precision Health Initiative, which we talked about in this episode, with bold goals to cure multiple myeloma, triple negative breast cancer and childhoods sarcoma and to prevent other chronic conditions like Type 2 diabetes and Alzheimer's disease, the focus of today's episode.