 Speaker is Jason Carlawish, Professor of Medicine and Medical Ethics and Health Policy, Director of Neurodegenerative Diseases, Ethics and Policy Program, and Associate Director of the Penn Memory Center at the University of Pennsylvania, continuing a theme while he did his MD at Northwestern. He trained in internal medicine and geriatrics at Hopkins and the University of Chicago a nice axis. And you get 30 minutes as our keynote for this session. Welcome, Jason. Thanks, Dan. It's great to be here. Thank you. The 26th Annual McLean Conference, it occurred to me, and I thought about that number as a geriatrician, that, Mark, you have just about trained a generation. And that very soon you will have a fellow come who was born when this program started. That is really spectacular. So how are we going to live with Alzheimer's disease? I raised this question because I will posit that I don't think a cure is in the offing. And so we're going to have to learn how to live with the disease. And what I want to talk about are the ethical challenges related to current efforts to answer this question. In particular, I want to address the challenges related to efforts to transform the diagnosis from the category of individuals who are demented as a result of Alzheimer's disease to a continuum defined by various risk markers. And what I'll speak about are both two broad categories of challenges. First, challenges related to conducting the research to arrive at this new world of a dimensional construct. And secondly, I'll speak of the challenges as we arrive at that world and to translate into our daily lives. It's a bit of background. I study this issue around the ethical, legal, and social issues related to cognitive aging. Alzheimer's has been a very useful disease paradigm. I also take care of patients at the Penn Memory Center where I deal with some of the issues I'll be talking about on a weekly basis. The disease of Alzheimer's disease is named after this physician, this gentleman here with the spectacles, Dr. Elias Alzheimer's, who in around 1907 wrote his case of an unusual disease of the cerebral cortex. He was referring to this patient here, August D, who subsequently, her name has been known, August Dieter, who was bought in by her husband with the chief complaint was she's not cooking me dinner and she won't have sex with me. And that was his complaint. She was sexually jealous and therefore not doing the duty of a wife. Alois Alzheimer's described a sick person. She was ill. She was demented. And he believed based on his assessment that there was something unusual about her. She wasn't presenting as many of the cases at the asylum were and kept tabs on her. And it's an interesting side note to the story. I mean, we of course know about this story, but one fact which is relatively not spoken about is. He had to leave to go follow his mentor, Emil Kreplin, to another hospital. She of course remained back in the asylum when he first met her and he kept tabs about her. And along, one of his updates he received told him that her husband was tired of paying the cost of her care in the asylum and was going to move her to a lower grade state asylum where it would be cheaper. This of course meant that Alois Alzheimer's would lose track of his unusual case of a disease of the cerebral cortex. He was a neuropathologist as well and he knew what he wanted. And fortunately he had married Wealth, Dr. Alzheimer's, and began to supply the cost of her monthly asylum care until she died and then of course her brain was captured banked. And he then engaged in the classic act of clinical pathologic correlation where he described only a tangle of fibrils indicate the place where a neuron once was previously located. I think this story is interesting as it captures three things about Alzheimer's disease which dominated much of the 20th century. Someone else is complaining about a problem in someone. That someone is disabled and the challenges of taking care of these patients in terms of both social and economic challenges, namely the family was running out of funds to pay for her. And in this case research funds stepped in to keep things going, his own private funds. The other feature of the case of course is it was an act of clinical pathologic correlation, a bedside diagnosis, a sick patient with a history, ultimately tissue was obtained and that history and that tissue were matched up to arrive at the diagnosis. And this graph just kind of depicts the way we understood Alzheimer's disease through much of the 20th century. Simply what I'm describing there is on the x-axis is people are normal until they start to develop signs and symptoms, meeting criteria for dementia, chronic progressive losses and cognition that are disabling, or perhaps an emerging construct of MCI which I'll explain in a minute and over time of course they're getting worse. So this is the disease that I trained in, it's a categorical status based diagnosis that is to say you are ill and that illness based on a history and physical and etc. I believe is most likely explained by the pathology which Alois Alzheimer's described in his case report. The concept of MCI began to be created towards the latter part of the 20th century when studies that captured individuals who had impaired memory, episodic memory performance who then were followed over time, it would begin to show that they were stratifying themselves into being more likely over time to develop dementia, the Alzheimer's type. And so by the late 90s we were beginning to accumulate data that said that you could take an actuarial view of this disease and see forward into its future before it was developing and at the same time that clinical data were being gathered on those people with MCI so too were biological data, imaging scans such as MRI, metabolic imaging such as a PEP scan, spinal fluid samples and the result was this, this is the new vision of of Alzheimer's disease which is emerging now which is this vision not so much of the bedside diagnosis of sick wife bought in by her husband complaining that she's not cooking and doing the wifely duties he expected to a dimensional diagnosis described by a variety of different markers which will signify where you are along the cascade of developing the disease and so in addition to the category of having dementia from Alzheimer's disease on the far right or mild cognitive impairment now has emerged the idea that you could have preclinical Alzheimer's disease now I realize this is a session on clinical ethics but maybe now it's a session on preclinical ethics and and what I've done in this very busy slide that is was created by Cliff Jack at the Mayo Clinic is Dr. Jack began to describe how even before there are the functional losses there is on that blue line the beginning of psychometric changes so you're not functionally impaired but you're not doing as well on cognitive testing as would be expected and even before that we see changes on your MRI in other words your hippocampal region is not as filled with tissue as we would expect and even before that we can see that the physiologic activity of your brain on PET scan and even before that we can measure plaques of amyloid and and and and tangles of tau the things that all of us Alzheimer's observed or the microscope in his postmortem specimen we can observe them with pet imaging of life and so this concept of Alzheimer's disease as this continuum described by these markers has animated the research world at the same time at the very beginning of the 21st century the United States Congress and President Obama did one of their rare bipartisan pieces of legislation of the last six years and past the National Alzheimer's Project Act and the National Alzheimer's Project Act is a federal effort to create a national plan for Alzheimer's disease and it has six goals and one of those six goals is to prevent Alzheimer's disease or cure it by 2025 so the clock is ticking now to do just that so what I want to talk about are the efforts that are underway many of them with taxpayer support and conjunction with industry to do research that is hoped to allow us to achieve the goal of preventing the disease by 2025 this by the way is just an image of that pet imaging just to kind of further give you a little bit of an illustration of it so so on the far right here you see severe Alzheimer's disease meaning all Alzheimer's disease dementia and this is a pet imaging that lights up tau the tangles and you can see here tau pathology and this is someone with mild stage Alzheimer's disease dimension and and this is what's provocative course is that you know someone who has MCI has just a little bit of that pathology now here I've shown you someone who's cognitively normal who has none but of course what the field has discovered is that you can find sorry about that you can find a group of individuals who are cognitively normal but have evidence on pet imaging of tau or amyloid that looks a lot like someone with mild Alzheimer's disease dementia so it's this emerging idea of the preclinical presentation of the disease so what are we investing in right now as a society but we are investing in the trial as what I call an instrument of validation I know we typically think of clinical trials as science studies done to improve the lives of patients show that that a treatment works and that's what all the trials I'm going to tell you about here are designed to do but they're also designed to do another thing which is act as a criterion validation exercise so you take a group of people and you give them an intervention and you measure something about those people and and you give some of the intervention and some you don't give the intervention and and if you see that the people who get the intervention do differently on the thing that you're measuring about them say cognition you can argue that your intervention targeting your biomarker that and link to cognition validates the link between the biomarker and the cognition so for example in the anti-amyloid an asymptomatic Alzheimer's study older adults between the ages of 65 and 80 have a PET scan that measures whether they have elevated amyloid or not they're cognitively normal they would not be diagnosed with Alzheimer's disease dementia they would not be diagnosed with mild cognitive impairment they would be called normal but their PET scan shows elevated amyloid they are being enrolled in a trial where they're assigned to an anti-amyloid drug or a placebo in a blinded fashion followed over three years with cognition measured the goal would be to show that if you can intervene on amyloid and change the rate of decline on cognition now this thing called elevated amyloid in a cognitively normal person becomes the disease of Alzheimer's reified through elevated amyloid linked to this therapy this this drug so that's this concept that's emerged of the theranostic a diagnostic and a therapeutic link together in an individual who's coming to you with no complaints or symptoms so that study is ongoing right now so in that study individuals challenges should we tell them or not the result of their PET scan should they be told that they have elevated amyloid or not elevated amyloid and therefore either are or are not eligible for the clinical trial and I'll talk a bit about that in a moment the second study I have here that is ongoing now is the Diane study or the dominated dominantly inherited Alzheimer's network trial this trial harkens back to August D whose whose brain specimen was found in the in a pathology lab in Germany and she is a carry of one of the dominant mutations that lead to Alzheimer's disease dementia the presinillin mutation and and individuals who carry this dominant mutation if they live long enough generally in about their 40s no more than about their late 50s will develop Alzheimer's disease dementia it's very different than the presentation of Alzheimer's disease typically in the 70s the average age of a patient with Alzheimer's disease in America is about 75 years of age but what these individuals represent is if you will a group who are at heightened risk of developing Alzheimer's disease and so what the dominant inherited Alzheimer's network has done is gathered together across the United States in the world families individuals who have this gene in their family and and enrolled them in a clinical trial to test anti-amaloid agents these individuals are cognitively normal but they have gene so of course the question is is part of the enrollment criteria do you tell them indeed now you do carry this gene so therefore that's why you're eligible for the trial or do you not tell them that and how do you design the study to do that the third study there is the Alzheimer's prevention initiative study they are doing two studies actually one involves individuals with this dominant inherited gene who are residents of the Medellin Columbia region in Columbia where there's a very large cohort of families since about the 18th century who have lived there who carry the presinil and mutation the other study they're doing which I'll focus more on is a study that will enroll individuals who are carriers of two copies of the apoE4 gene the apoE4 gene has been associated with the increased risk of developing late onset Alzheimer's disease the Alzheimer's disease we see in the late 60s or 70s and if you have two copies of that gene you're described as having the highest risk based on a variety of longitudinal cohort studies it's only about 4% of the population carry about two copies of the gene and if you have that carrier that genetic profile your risk of developing Alzheimer's disease depends on the study you look at but it could be as high as 80 or somewhere between about 60 to 80 percent lifetime risk if you live to about 85 years of age so that will be another randomized trial enrolling these people at heightened genetic risk to determine whether we can change the rate of decline in very sophisticated measures of cognition because again like the A4 study like the Diane study these are all cognitively normal individuals and finally the tomorrow trial also uses apoE4 gene as well as another gene that's been discovered to increase risk same design cognitively normal individuals randomized to drug or placebo based on having those genes so I hope the message I'm giving you is a message that harkens back to the early days of cardiovascular disease therapeutics so one of the big breakthroughs in cardiovascular disease therapeutics was gathering together cohorts of individuals who carry dominant genes for familial hyperlipidemia these were individuals who by their thirties had cholesterol plaques on their tendons and by 40 were having heart attacks and strokes and generally the death of cardiovascular disease they were enrolled in a clinical trial to test HMG CoA reductase inhibitors which lowered their cholesterol value decreased the risk of having a heart attack or stroke and therefore established the fact that cholesterol was a was a causal part of the pathway of cardiovascular disease and the rest is of course the story of Lipitor and the rest of us because of course familial hypercluster lemia is quite rare and so these studies particularly the bottom three are very much modeled in that idea of find me a genetically otherwise biomarker heightened risk group of people to help validate the construct of labeling people before they have a heart attack or in the case of Alzheimer's before they're demented again part of this vision of prevention by 2025 where would you like to be well if you talk to the folks in Alzheimer's disease this would might be their vision this is a bus kiosk on 12th and Market Street in my hometown of Philadelphia I don't know if you can read this sign on the side of the bus kiosk but it says know your risk know your a1c hemoglobin a1c or the biomarker measure if you will have diabetic the presence and severity of diabetes the graphic depicts a ambulance that seems to be crashing into a living room because ahead of the ambulance are is I presume it's Hank and his wife and on the side of the ambulance is Hank diabetes complications are coming to get you and so the message here is know your numbers know your a1c because otherwise an ambulance is going to come crashing through your living room and run over you this this this model that has been developed in diabetes and cardiovascular disease is one that the Alzheimer's field lusts after if only we could have our number our measure our biomarker that people would get that would signify now you need your therapeutic in that theranostic model some argue that the likelihood that they'll be just a single number or measures is unlikely and instead probably it'll be something more like this this is the website fracks and this is if you have to pick your country for this but so if you're an American you go to this page you enter your age your gender weight height whether you've had a previous fracture etc. and you click a button and you get your 10-year risk of having a major osteoporotic fracture or hip fracture and then based on that you make your decision about whether or not to treat so what one aspirational goal in the Alzheimer's field is could we get to having this kind of calculator where you would say enter some data like your age your performance on a memory measure your APOE gene and your PET scan for amyloid result and then you would get your risk over time of developing cognitive impairment and that would engender whether or not it's worth you being on and a therapy an anti-amyloid therapy so this the these kinds of actuarial desktop futures of medicine or where the Alzheimer's field wants to be why trust that you've already felt some of the ethical problems of getting there namely how would you do this research I've gestured already to studies that involve measuring amyloid one of the two pathological marks of the disease and normal people and then rolling them in a clinical trial or measuring dominantly inherited genes were non-dominantly inherited genes that increase your risk and the question is is no studies that enroll persons on the basis of having a gene or biomarker associated with Alzheimer's is it ethical to tell the person this result as part of the enrollment criteria or into their research I want to back up and just kind of think about those two broad categories within which we can put Alzheimer's research observational research and interventional research and I think that does I want to depending on your answer to the question I have at the top bullet there really two design options that you have if you don't think that people should know their result then you need to base you need to have designs that use what's called blinded enrollment in other words I'm going to test you because I need to know whether or not you're in my cohort or going to be in my clinical trial but I'm going to do it in a way that's going to keep it hidden from you okay you can do that pretty easily in observational studies you just don't tell people the results in clinical trials what that would require is having an assigned placebo only group so you'd have to take a group of individuals who will test negative you don't tell them that they're negative but you enroll them in the study and they're put in a cohort that gets placebo you don't know that they're in that cohort as the investigator they don't know they're in it they only know as they're getting a blinded study drug and that allows you to not have to tell people oh you're in my study because you had that positive result that's the blinded enrollment approach and and the other approach is transparent where you tell people you have elevated amyloid or you have the APOE4 homozygogene and so therefore you're eligible for my trial so I'd like to sort of make the case that in generally I'm going to argue favors I think favors transparent designs and I'll go through that in a minute the two risks the key issue here around the risks and benefits at stake I think with gene disclosure of genetic information there's obviously the impact on the person of learning that information but there's also issues around consanguous relatives because if I tell you you're an APOE4 homozygote that means that you have consanguous children they are at least an APOE4 heterozygote or you may discover they're actually not your children if they choose to go get tested and they're not an APOE4 heterozygote so that's a very important issue because certainly the people being going in to say the APOE4 homozygote study are older adults with children and they're going to say to them oh you know at Thanksgiving I'm joining this clinical trial and a minute because of I have this gene and so therefore their kids are going to be a finding out that they have a gene there's another issue which I think is the biggest issue and it's why actually we do need to generally disclose which is the psychological harm of disclosure creating the stereotype threat and I'll show you the results of a study that came out American Drill Psychiatry early this year this is a very hard graphic to read given its resolution but the bottom line in a cohort study not a randomized design these investigators disclosed to older adults who are cognitively normal the results of their APOE genotype so they weren't randomized to disclosure so you have the biases of confounding by indication but nonetheless some got the knowledge of their genetic result and then they had a comparison control group who didn't know the APOE result and the take home message from this study as shown here is that those who knew they were an APOE4 carrier rated their memory worse than those who were APOE carriers but didn't know it and those who were APOE carriers and knew it performed worse on measures of memory than those again who were APOE4 carriers and did didn't know it and this is a literature well described in educational psychology of stereotype threat if I tell first described in studies around African Americans and performance on achievement tests if you tell someone is African American this is an achievement test versus the same test given to them and said this is a test of reasoning ability they will do worse on it when it's framed as an achievement test and that's been well described in multiple experimental studies you can do it as well in memory testing with older adults as well if you tell them it's a very hard memory test they'll tend to do worse so the issue that I'm raising here is that if you start telling people their gene or biomarker result you raise the concern of creating a stereotype threat that they'll start to incorporate that into their dare I say mind their sense of their cognition and therefore do worse so okay let's think about analyzing the risks and benefits back to the two broad categories of studies observational studies where the purpose is to inter observe disease in humans versus interventional studies where the purpose is to observe treat humans with a disease in observational studies I would argue you want to simply look at the effect of disease over time and so introducing knowledge of your biomarker and stereotype threat could disrupt measures of disease progression in contrast in interventional study I would argue where it the future of the study is I will now test people and based on their test result I will give them a drug I want to know the compendious effect of not just the intervention but the knowledge of risk marker on outcome of cognition and so there's a argument from scientific value to actually test that effect in addition to testing the effect of the intervention you're giving to people and so it's observational studies I've summed up here it's a bit of a busy table but if you look across issues of scientific validity value favorable risk benefit balance and informed consent I would argue there's a strong argument for blinded designs and observational studies but I think in interventional studies you have a much stronger argument for actually transparent designs tell people they have elevated amyloid tell them they have a double copy of April E4 unless the community of those people who would be recruited make it very clear that they don't want to know that result and there's not a lot of them to recruit from as well in which case you're just not going to be able to fill your study which is what's being done in the dominantly inherited studies however heartbreaking data I've just learned many of the people in the dominant inherited studies are now asking to know what their genotype is because they're tired of the work of being in the study is so arduous in terms of frequent study visits that they'd like to know if it's worth the risks all right we have two studies attached to these clinical trials I'm sort of an observer of them and hang around them the first is the Socrates study the study of knowledge and reactions to amyloid testing people who enroll the study in testing elevated amyloid getting a drug we are interviewing them about three months into drug treatment and then going back a year later and essentially an interviewing a group of non elevated amyloid older adults to better understand the experience of being told you have this particularly with emphasis on the experience of stigma who do they tell what do they tell them and how do people treat you for the April we for study we have two studies that we're going to be running one is to remotely disclose April results because you can't have a genetic counselor everywhere I won't talk more about that but the other is we're going to be testing various interventions designed to reduce stereotype threat to address that very risk I was talking about because of the future of Alzheimer's is this preclinical diagnosis where I label you when you're seemingly well we need to transit that future so that those that label doesn't itself become a harm how bad though it would be enjoyed to a therapy last few points looking forward to this future who will own Alzheimer's all of those tests I told you but especially the imaging tests are owned under the patent laws of America so to the drugs that are being tested and that link of the drug and diagnostic that there are not stick create the opportunity to essentially own Alzheimer's a very fascinating question going forward once you transform Alzheimer's into a preclinical diagnosis on the basis of simple change in a cognitive measure you have the great challenge of how many people treated for how long with a costly therapeutic and diagnostic so Alzheimer's disease in its treatment become an economic problem autonomy becomes an endless trial in this future of Alzheimer's disease where you're at most mildly impaired the need for monitoring if you will about someone's ability to do things because you're sort of now under the surveillance of medicine in your treatment and being followed up on your yearly basis driving laws that require mandatory reporting of diagnoses of Alzheimer's will obviously have to be changed and finally living well in the MCI zone is going to be a real issue if you look at the quality of life measures and people with MCI they're uniformly worse than normal AD dementia people and if we do achieve our goal of prevention we will be living longer in that zone of mildly symptomatic last point at the bad disease this is a patient of mine 91 year old woman lives in assisted living facility many mental of 17 clinical dementia rating of two and this is a drawing she did I know what you're thinking this is this is a bad disease this is like you die twice first in mind and then in body and and you only look at a drawing like this to say how bad it is this little horse that she sketches or whatever she did for activities but actually what this drawing is is a note that she gave to her daughter her daughter wrote me and said this is a map mom made for me one evening when I visited she didn't want me to get lost getting the dining room to meet her at breakfast the big square is the dining room they're the line supposed to show turning left at the elevator again in the hallway the dining room is in the left a short walk down the hall so it's a bad disease we don't want to get it we certainly don't want to die twice and yet I think it's things like this which remind us of the need to help make sense of Alzheimer's and I'll wrap up just please visit this website we've created to do just that help make sense of Alzheimer's I have no more time for questions I do have a question when you compare the study that you presented recently in 2014 to the work by done by Robert Green on the exact issue of disclosing genetic information when we responded with an editorial we thought for the patients that were in the MCI zone it was actually beneficial and we weighed the memory kind of stigma it would present because it is an economic decision when we have a supplement industry that's 33 billion dollars so I can't remember exactly in the 2014 paper did they do a pre and post on the memory capability of those patients or was it simply giving the disclosure of their genetic change pre and post so what was the change over like a bell curve because at the time of the 2010 when Green made the decision it wasn't something that he spursly did he knew perhaps it would bias right so I know you're speaking the reveal study and Robert Green and I have us trial to test just this issue out the bottom line is the reveal study studied 40 to 50 year olds and didn't actually measure cognition so we don't have the ability in the reveal study to know if this bias occurred unfortunately and the MCI study we're doing we also are not measuring cognition so unfortunately the reveal studies don't answer this question about the stereotype threat yeah alright Dan last last question did Jason I like to hear some ideas of how you mitigate the stigma of being diagnosed with MCI yeah so the stigma of disclosure of a biomarker to cartilage normal people right that was what yeah so there is a literature on how to de-bias people to stigma and it involves essentially among other things we're not educating them about the presence of this bias and telling them that this can happen and apparently when you do that intervention you can reduce the effect of of stereotype threat on individuals performing on memory measures for example thanks thank you thank you very much Jason thank you