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In this episode we talk with Dr. Ken Langa about the implications of identification of “preclinical” Alzheimer’s disease (situations where individuals may have biological signs of Alzheimer’s but no symptoms). Ken is a leading dementia researcher and our discussion focuses on an article he published called “Preclinical Alzheimer Disease – Early Diagnosis or Overdiagnosis” that was published in JAMA Internal Medicine. In his article co-authored with Dr. Jim Burke, he brings up some of the potential indirect effects of early detection.

Transcript

Matt Davis:Today we're going to be talking about issues around the diagnosis of Alzheimer's disease. And we're going to be talking about a specific paper, but before we jump in, I was wondering Donovan, if you would give us a really simple overview of what we need to know, from a really high-level perspective, we're talking Wikipedia, maybe even the first paragraph of Wikipedia, what we need to know about amyloid, the biology of Alzheimer's and how it gets diagnosed in clinic?

Donavan Maust:

Okay. First paragraph of Wikipedia would be something like most people with dementia have some types of proteins in their brain that end up clumping up in ways that they're not supposed to in Alzheimer's dementia. Generally, those are two types that you hear of most commonly. Beta amyloid plaques, which accumulate outside of the neurons in the brain, and then tau tangles that clump up inside. Most people with Alzheimer's will have combination of those two kinds of proteins. However, it's not super information to actually help make the diagnosis. Usually it's something that you actually see on autopsy.

There are some tests of say if you have a lumbar puncture, you can actually look at the ratio that you see in the spinal fluid, but rarely is that part of how people make a diagnosis, except for in sort of like fancy academic medical centers. These proteins can start to accumulate in people, which is what we're going to talk about a little bit today. Amyloid, you can have lots of amyloid in people who don't have dementia, or you can have people who have dementia with very little bit of amyloid. It seems like these amyloid plaques and tau tangles are part of the Alzheimer's story, but they definitely aren't the entire story.

Matt Davis:

Yeah. One of our early names for this podcast was untangling tau. I think Julie biting came up with, but then we realized that was a little or two basic science for sort of a more population.

Donavan Maust:

Yeah.

Matt Davis:

Based center. That's great. Why don't we jump into it?

Donavan Maust:

Sure.

Matt Davis:

I'm Matt Davis.

Donavan Maust:

I'm Donovan Maust

Matt Davis:

You're listening to Minding Memory. Today we're joined by Ken Langa a leader in the field of dementia research. Dr. Langa is the Cyrus Sturgis Professor of Medicine and the Department of Internal Medicine at the University of Michigan Medical School. He's a Research Professor at the Institute for Social Research and Professor of Health Management and Policy at the University of Michigan School of Public Health. And I would add to that a wonderful mentor to many emerging scholars at the university. I'm always amazed at how many successful researchers have at one point or another been mentored by you. Ken, thanks so much for joining us today.

Dr. Ken Langa:

Thanks Matt. Great to be here with you and Donovan and especially without a mask on thank you.

Matt Davis:

A year or so ago, Dr. Langa authored a commentary paper with Dr. Jim Burke that was published in JAMA Internal Medicine. The paper was titled Preclinical Alzheimer's Disease, early diagnosis, or over diagnosis the paper discusses some of the issues regarding the identification and treatment of preclinical Alzheimer's disease.

I recall being exposed to issues for what's been called over diagnosis early in my public health training, specifically around cancer. Some of these concepts fundamentally changed what I thought I knew about healthcare. Hence Ken's paper got my attention. As I brought some interesting issues to light specifically for Alzheimer's. You know, there's this notion among the public, that diagnosis is always helpful. However, at the population level, sometimes there can be effects that aren't always beneficial. With that, let's start talking about the paper.

Ken, you mentioned in your article that there's been a shift from focusing on interventions, around treating symptomatic Alzheimer's to more prevention based interventions. And I think the idea here is to try to catch things early, to stop the disease from progressing. Now, if any of my students are listening in, this is an example of secondary prevention. What's your sense for why this shift has occurred?

Dr. Ken Langa:

Well, there has been a number of important trends over the last 20 years or so in terms of the technologies that can be used to try identifies some of those proteins that Donovan was talking about early on, the amyloid and tau specifically what we'll talk about most today. As Donovan said, 20 to 25 years ago, you could only look for those proteins after someone died at autopsy. But new imaging techniques, especially amyloid imaging, amyloid PET imaging, tau PET imaging have allowed us to see the abnormalities in the brain while someone's alive. And also while someone is thinking absolutely normally.

The ability to be able to look now for abnormalities in the brain before someone has symptoms. That's one of the things that have shifted the focus more toward, toward earlier in the disease process. And frankly, I think the other important development over the last 20 years is the failure of lots of the treatment trials for symptomatic Alzheimer's disease. There's basically been no successful trials of interventions when treating people first with dementia, symptomatic dementia, mild cognitive impairment, sort of mild symptoms before someone becomes disabled with dementia, the interventions there have not worked. The theory has been kind of to move earlier and earlier in order to, to intervene before the brain is damaged enough that it won't work anymore.

Donavan Maust:

And a lot of those interventions have focused on amyloid, right? The idea that if you have amyloid accumulating, if you can get rid of the amyloid, that would help the dementia, but that hasn't really panned out. Right?

Dr. Ken Langa:

Right. And again, I think we'll come back to that is the question of what is the right target amyloid tau, other pathologies, but as Donovan said, many of the interventions have been focused on trying to either prevent amyloid from building up or actually removing amyloid from the brain. And under the theory that amyloid is part of this causal pathway that's if you can stop that, you can stop the progression.

Matt Davis:

The idea that amyloid there's sort of like a dose response thing that you get to a point. Both of you mentioned autopsies. Do healthy people have a little bit of amyloid? Right? This is kind of almost sounds like the things you hear about with prostate cancer. Everybody has a little bit of abnormal prostate cells.

Donavan Maust:

You and I Probably have amyloid Matt almost certainly.

Matt Davis:

All right.

Dr. Ken Langa:

And that will be a key issue in terms of the question of over diagnosis. It's this idea that how tightly linked is the pathology that you're picking up to the bad thing that you want to prevent down the road. As Donovan said the population studies now suggest that lots of people have amyloid in their brain. Maybe 30% of folks who are 50 and older is a number we cite in that article. The issue is this bad pathology is not always tightly linked with bad things down the road. And that's a key issue for the discussion of over diagnosis.

Matt Davis:

You mentioning that like some of the trials hadn't really panned out, like treating people with symptomatic Alzheimer's and that in part sort of is causing this shift towards treating more pre-clinical. We might call it. I find that really interesting, because it feels like it'd be harder to find effects when you have smaller levels and potentially outcomes that are much longer down the road, but I guess we'll see what happens. Right?

Dr. Ken Langa:

That's exactly right, Matt. And in some ways the theory is kind of my simplistic way of thinking about it is the horse out of the barn kind of concern that once someone's symptomatic with dementia or Alzheimer's disease their brain is kind of on a pathway that's going to lead down even if you intervene. The horse is out of the barn. If you can stop the pathology from building up the amyloid from building up early on while there are no symptoms and the brain is working better, maybe that's the key to preventing it.

Matt Davis:

Taking a step back for many people that are probably listening to this you sort of make some assumptions that detecting something early is always a good thing. Why wouldn't you want to know as early as possible so that you could do something about it? What do we actually know about this? And what are your thoughts on the early detection of some of these early signs and symptoms?

Dr. Ken Langa:

Great question. And again, I think it gets to the heart of this discussion. In some ways you think about how could more information be a bad thing as we're treating patients or really in any aspect of life, how is it that you do a test, it gives you a bit more information about the state of your brain or the state of the world. How can that be a bad thing? There are a few different ways that unintended consequences can happen from doing tests and picking something up. It might make sense actually to maybe define over diagnosis at this point to hopefully make this clearer. The idea of over diagnosis is that you are diagnosed with or categorized with something that will won't cause you symptoms and won't cause death.

It's picking up an abnormality, but that abnormality wouldn't... Intervening on that abnormality wouldn't change anything in your health or length of life. And how can that happen? Typically, it would be screening procedures, screening tests, where you're purposely going out and testing people that don't have symptoms in order to pick up a pathology. That by intervening on you think [00:10:30] will do good things in terms of preventing symptoms or preventing death. And the other is what sometimes called an incidentaloma, or where you're doing a test for another reason, and you pick up an abnormality.

At that point you start acting on that abnormality, even though if you hadn't found it, it wouldn't have created problems down the road. How can it be bad to do a test and to diagnose something early? If what you're identifying is tightly linked with a bad thing down the road, and there's an intervention to address it. Then the early information is going to do good things. It's this balance of is that information going to allow you to intervene in a way that will prevent a bad thing or cause good things down the road.

Donavan Maust:

It seems like the issue here is early diagnosis that relies on the burden of amyloid doesn't really reliably indicate whether you're going to go on to develop the disease or not. And there's some, perhaps you're at higher risk, but ultimately then you're potentially freaking out a lot of people who would never go on to actually develop the illness. Then, what's the cost involved with that? What's the psychological burden that's involved with that. Is really the issue because the link between these abnormal proteins or the burden of these proteins, isn't that directly linked to the risk of actually developing the disease within a short period of time.

Dr. Ken Langa:

Exactly. And again, the putting a few numbers on this might be helpful here, where there's been a number of sort of modeling exercises and using epidemiologic data where an estimate for a 65 year old woman, for instance, who's thinking normally, but has amyloid shows up with a positive amyloid scan, her risk of developing Alzheimer's disease or dementia by the time she dies is around 30% or so, or even a little less than that. And from a man it's lower than that 20% mainly because men have short of life expectancies.

That's, as Donovan said, the key issue is this balance between identifying the abnormality. But if you're going to die of something else before that abnormality is going to cause a problem in your life, either symptoms or death. By paying attention to that abnormality, you really only get the costs and the potential side effects of interventions rather than the benefits.

And of course the key issue is can you do tests that have a very tight link to the bad outcome as Donovan said. And I should say we're talking about amyloid and that's the sort of imaging that has been developed. And that's been a focus of a lot of testing. There are new technologies looking at tau, looking at other kinds of proteins in the brain or in the spinal fluid. And the hope is perhaps by putting a bunch of these different tests together, you get to that holy grail of a good measure that will allow you to better.

Donavan Maust:

Who's really at high risk.

Dr. Ken Langa:

Who are really the ones that it makes more sense to do these interventions on.

Matt Davis:

Do you think there's some value if it was theoretically possible to really hone down to a very specific subset of people with a set of risk factors or something like that to actually make these things beneficial in that population?

Dr. Ken Langa:

Yes. And again, these are all, these are going to be balance. You're going to have to do tradeoffs and balances on both the diagnostic side, and then also the treatment side. Going to the extreme if you have an intervention that you know is beneficial and has no side effects and is cheap, the idea of treating people that you're not as sure are going to go on to have dementia, for instance, the risks are low, the costs are low, so that.

Donavan Maust:

It's worth it.

Dr. Ken Langa:

It's worth it. It's worth it to do, even though you're probably treating a whole bunch of people that wouldn't go on to have dementia. Thinking about a very low risk vaccine, we're all thinking about vaccines these days. There have been vaccines tested for amyloid getting a vaccine to take the bad protein out of your brain.

Assuming we could do a one shot vaccine that did a great job of this. There were very few side effects, low cost. It's likely that we'd sign up.

Donavan Maust:

Sign me up.

Dr. Ken Langa:

Yeah. We'd err on the side of doing diagnostic tests that even if they weren't perfect, we could intervene. The problem of course, is those kinds of very low cost, low risk interventions are rare. And as well as the issue that as you were saying before, Matt, I think, or maybe it was Donovan that Alzheimer's disease and dementia happens late in life. And therefore if you have to intervene early on in life, earlier on say mid middle age in the fifties, if it it's an ongoing treatment, you're going to have to take it for decades. The risk of side effects increases the costs, et cetera. So those are the things that you need to balance. How well can you risk stratify folks? Can you find the folks that are truly going to go on to dementia and what are the interventions that you have to intervene on them?

Matt Davis:

I remember from epidemiology, sort of playing with how the prevalence effects performance, when you talk about screening, it's like a great example of that actually.

Dr. Ken Langa:

That's Right.

Matt Davis:

So it sounds like there's enormous cost implications in particular. And in terms of like side effects, stress, presumably could people start undergoing treatments that have side effects?

Dr. Ken Langa:

Yeah. Great question again. And I think another of the key issues is what does this new information, like we said how could information more information be a bad thing for patients and physicians. If the information causes people to go on and do things that they wouldn't have done that cause harm, that's obviously a bad thing. That's a bad outcome. Especially if the abnormality isn't going to go on to cause problems in a significant number of people. What kinds of things could that be? I mean people may end up spending more time going to doctors, getting more tests kind of getting into what's often called the clinical cascade that once you're sort of identified with a potential problem, perhaps because you're more sensitive to symptoms, you end up maybe going to the doctor more to check this out.

Even if there's no direct harm from that, it's still time that you're not doing something else. Health economists would be have that be one of the costs of this additional information it could be. And some people argue that this new information could cause people to act in ways that are actually beneficial. For instance, if you know you're at a bit higher risk for Alzheimer's disease or dementia, maybe you will exercise more. Or some of the other preventive behaviors that we think are to decrease risk for dementia later in life maybe having the sort of picture so to speak of, of amyloid in your brain. Some people think, well, maybe that'll actually be beneficial, because it will motivate people.

Matt Davis:

Modifiable risk factors. Right?

Dr. Ken Langa:

Exactly. But there's the flip side, will it just cause anxiety, will it cause people to kind of do things or feel anxious about things, do other things that they wouldn't have done? I will say there's been a number of studies so far of how bad does learning your amyloid status make you feel Josh Grill and Jason Karlawish published a paper a year or two ago looking at that from one of the clinical trials that it's going on. And they actually didn't find, at least in the short term with all the caveats a selected population, probably more educated than the general population. They didn't see a huge amount of the anxiety or other kind of negative psychological effects. But again, I think that needs to get studied a bit more, those are the kind of tradeoffs that we're talking about.

Matt Davis:

This is hard. I know some of the numbers that you were that you were mentioning about how people don't, they aren't destined to get Alzheimer's that may have some abnormal findings. It feels like we should rethink the name. I mean, preclinical or prediabetes it feels like you're destined to get that thing. I don't know what the better name would be, but it feels like maybe that's one place to start. Everybody has those might not think they're going to get it.

Dr. Ken Langa:

That's right. No, I think that's absolutely great point, Matt, and there's been a lot of discussion to that Alzheimer's disease in itself extremely causes fear, and rightly so. It's an awful disease causes awful outcomes for patients, and families, et cetera. And thinking about preclinical Alzheimer's disease. Maybe that maybe we are, we're painting ourself into a corner by calling it.

Matt Davis:

This has been super interesting to think about some of these issues at sort of more the population level. To kind of close things out. I'm hoping that we can maybe pivot back to sort of the patient level, because I often wonder how often when you have these studies that come out, that people are aware of and start thinking about these things, how often does actually change anything at the level of the patient? So from my understanding, it's not unusual for older adults to be pretty fearful about having cognitive issues later. And when I think about that I could see that. It's got to be a horrible thing to think about potentially losing memories of loved ones and those relationships that life is all about Donovan. You've done some work looking at this, right?

Donavan Maust:

Yeah. We actually did a poll. Ken was involved in through the National Poll on Healthy Aging that's administered to through the university and through AARP and we actually wanted to know how do people think about dementia? Are they afraid of memory loss? What are they doing to try to combat the possibility of memory loss? We ask people what do you think the likelihood is of you developing dementia? And basically about half the respondents said, they thought they were either very or somewhat likely to develop dementia. Which is a little bit higher. So Ken mentioned a little while ago that if you're, I think 60 or 65, and you're a woman you have maybe around 30% lifetime risk of developing dementia for, for men, it's a little bit lower than that.

But in general it seems like people sort of perceive their risk as higher than it actually is. I think partly because people, it's perceived as an illness that you don't want to get that really changes your life in a way. And your family's life in a way that you don't want to experience. In clinic, it definitely is a concern sort of ironically it seems like oftentimes the people who are worried about their memory...

I'm a psychiatrist, in my experience, people worried about their memory frequently actually are experiencing symptoms of depression or anxiety or something else kind of ironically, oftentimes people who are experiencing true memory loss don't necessarily perceive it themselves. And it'll be their families who bring them in. But big picture is the concern about memory loss can be kind of an important motivator for people to control their blood pressure. Try to get a little bit more exercise, a little bit more social activity, just because people you do seem to. It is definitely a concern of people as their age. And it's something that people perceive that they really want to avoid. You know what Ken has found.

Dr. Ken Langa:

No, I would agree entirely Donovan. And when I talk, I'm a general internist, when I talk with my middle aged or older patients about cardiovascular risk factor control, blood pressure, physical activity, cholesterol. I do mention that there does seem to be research that in addition to decreasing your risk for a heart attack, it's possible, you'll also be keeping your brain working as it is longer, which is important. I think there is this balance between... Perhaps it will motivate people to address some of these behavioral risk factors, but at the same time, you don't want to get people too focused on the wrong thing, if it isn't something that's going to affect them down the road.

Matt Davis:

I think you both kind of indirectly answered one of my last questions, which was about the value to patients, even knowing about preclinical Alzheimer's, but it sounds like heck if some of the risk factors are modifiable and it doesn't cause too much harm and too much stress, maybe it's an okay thing. I don't know.

Dr. Ken Langa:

Yeah. I think some people would argue, well, these are modifiable risk factors that every older adult should, or every middle aged adult should be focusing on. You know, whether if it's the case that doing some of these diagnostics for amyloid or tau or others truly motivates some people that could be a good outcome again the downsides are, and again, I don't think we talked as much about just the cost. The cost of interventions are a key issue.

You know the interventions, at least the medication interventions that are being tested are like to be quite expensive, these monoclonal antibodies that are done in monthly intravenous infusions. The treatments themselves would take a lot of time and could be burdensome that way thoughts about in the $10,000 a year or so kind of cost range. These tradeoffs that we're talking about, if it's an easy intervention that isn't expensive, less of a concern about the over diagnosis, if it's very expensive, potentially life changing or life modifying interventions, then again, I think we, we want to be more careful about how we interpret the information.

Matt Davis:

So things can change pretty quick in research. And my last question pertains to, since you've published this it has been about a little over a year or so. Has anything sort of changed in terms of how you think about this?

Dr. Ken Langa:

I think the general framework is still similar and the questions, there are hard questions. These aren't easy. There's not going to be one right answer. And it is going to the ultimate good outcome is going to depend on lots of these individual issues around cost and what patients prefer and, and things like that. But as you said, Matt the developments keep happening quickly.

There's more research over the last year about a blood test that might help identify people with amyloid and tau in their brains. If that's a significantly less costly intervention than some of the amyloid pet scanning and things like that. So, you know how that's going to play out in terms of how well can that do at really identifying the high risk folks. And then there's also one of the monoclonal antibodies that's been tested aducanumab which the drug company Biogen had stopped the trials said, it's clear it wasn't working, did some re reassessment of some of the data, and actually think it does have a signal in terms of preventing cognitive decline. That review is actually at the FDA now.

That actually could put all of this theoretical stuff we've been talking about front and center with if the FDA does approve that, how much will that cost, who's going to get it. And it'll sort of have much more real world information about who's getting treated, how's it working in the real world, et cetera.

Donavan Maust:

We'll have to update this episode next year.

Dr. Ken Langa:

I think that'd be great.

Matt Davis:

Exciting things on the horizon. Well, this has been great. I want to thank our guest, Dr. Langa and all of you for listening.

Speaker 1:

If you enjoyed our discussion today, please consider subscribing to our podcast. Other episodes can be found on apple podcasts, Spotify, and SoundCloud as well as directly from us at capra.med.umich.edu. Where a full transcript of this episode is on also available. On our website, you'll also find links to our seminar series and data products we've created for dementia research. Music and engineering for this podcast was provided by Dan Langa more information available at www.danlanga.com. Minding Memory is part of the Michigan Medicine Podcast Network find more shows at uofmhealth.org/podcast. Support for this podcast comes from the National Institute on Aging at the National Institute of Health, as well as the Institute for Healthcare Policy and Innovation at the University of Michigan. The views expressed in this podcast do not necessarily represents the views of the NIH or the University of Michigan. Thanks for joining us. And we'll be back soon.