Our Evolving Understanding of Mild Cognitive Impairment

Headshot of Ron Petersen, MD, PhD, director of Mayo Clinic's Alzheimer's Disease Research Center
Ronald C. Petersen, MD, PhD

Mild cognitive impairment (MCI) is an emerging term in the field of Alzheimer’s disease and related dementias, characterized as the stage between the expected decline in memory and thinking that happens with age and the more severe decline of dementia. In this episode, Dr. Ronald Petersen joins the podcast to talk about how MCI compares to dementia, its many causes, and the impact of new lifestyle and drug interventions on its progression, as well as how his career led him to study Alzheimer's disease and MCI. This episode is part of a special three-part series highlighting speakers from the Wisconsin Alzheimer’s Institute’s 20th Annual Update in Alzheimer’s Disease and Related Dementias.

Guest: Ronald C. Petersen, MD, PhD, director, Mayo Clinic Alzheimer's Disease Research Center, director, Mayo Clinic Study of Aging, Cora Kanow Professor of Alzheimer’s Disease Research, Mayo Clinic College of Medicine

Show notes

Learn more about the 20th Annual Update in Alzheimer’s Disease and Related Dementias on the Wisconsin Alzheimer’s Institute’s website.

Watch the full keynotes of the event on our YouTube channel. Dr. Petersen’s keynote starts at 22:12 in the recording.

Learn more about Dr. Petersen in his bio on his website.

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Find transcripts and more at our website.

Email Dementia Matters: dementiamatters@medicine.wisc.edu

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Intro: I’m Dr. Nathaniel Chin, and you’re listening to Dementia Matters, a podcast about Alzheimer's disease. Dementia Matters is a production of the Wisconsin Alzheimer's Disease Research Center. Our goal is to educate listeners on the latest news in Alzheimer's disease research and caregiver strategies. Thanks for joining us.

Dr. Nathaniel Chin: Welcome back to Dementia Matters. Today we're highlighting a key speaker and presentation from the Wisconsin Alzheimer's Institute's (WAI) 20th Annual Update in Alzheimer's Disease and Related Dementias. I'm joined by Dr. Ron Petersen, director of the Mayo Clinic Alzheimer's Disease Research Center and the Mayo Clinic Study of Aging. He is also a professor of neurology at the Mayo Clinic College of Medicine. Throughout his research career, he has authored over 1000 peer-reviewed articles on memory disorders, aging and Alzheimer's disease, and earned numerous accolades for his work, including the 2021 Lifetime Achievement Award for Alzheimer's Disease Therapeutic Research. As part of the WAI’s annual update, Dr. Petersen gave a presentation titled “Mild Cognitive Impairment: A Construct in Evolution,” discussing how the field's definition and understanding of mild cognitive impairment (MCI) and cognitive decline has developed over time. Dr. Petersen, it's an honor to have you on Dementia Matters.

Dr. Ron Petersen: Thanks very much for including me in this discussion, Nate. I look forward to the visit.

Chin: You have accomplished a lot so far in your career. But I'd like to go back to the beginning and have you share with us why you got started in this particular field. Why Alzheimer's disease and cognitive disorders?

Petersen: Well, that's an interesting question, Nate. Certainly, in retrospect, it looks like a well-planned pathway. But in fact, the appropriate term to describe it is serendipity: things that happened along the way. I won't bore people to death with this, but I did start undergraduate school with a focus on cognition and memory psychology, but if this were a visual presentation, you could tell by the color of my hair that I've been around a while. I graduated from college around the Vietnam era. At that point in time I was going to go to graduate school. I was actually going to go to the University of Michigan, but the military would have intervened, so I had been working at Honeywell in the summers. During my senior year they offered me a full-time position, which gave me a brief deferment at least for a period of time so I could organize my life because they were doing Department of Defense research. So I did that. I stayed in St. Paul and enrolled at the University of Minnesota in the graduate program. Soon into my first year at Honeywell, I became aware of a program in the army that would allow me to finish graduate school and then go into the army in a professional capacity for an additional four years, so I applied for that and was accepted, finished a PhD in what would they now call cognitive neuropsychology. That was my entry into learning memory, normal cognition and the like. I then spent four years at the Army's Biomedical Research Laboratory in Maryland doing psychopharmacology, drugs and memory. That was evolving very interesting and the folks around me said if you really like doing this work, you probably should become a physician. I applied for medical school, came back to Minnesota, went to Mayo Medical School, did an internship at Stanford, a residency in neurology at Mayo and a fellowship in behavioral neurology at Harvard, then came back to Mayo. If you look at that pathway, it was cognition and memory learning along the way, which evolved into the medical aspects of that, then going into neurology. It seemed like the appropriate specialty, subspecialization in Alzheimer's disease and hence that's where I am now.

Chin: You kind of went all over the country in order to get that training.

Petersen: Absolutely. East coast, west coast, back and forth.

Chin: But you are a Midwest person now and we're gonna claim you for those of us that are in the Midwest.

Petersen: Absolutely. I can even go further. I was born in Wisconsin. I was born in Milwaukee. My family moved to Minnesota early on but I am a Wisconsin native, so to speak.

Chin: Nice. Now I've never heard you say it in any of your presentations or conferences, but many researchers and clinicians in the field have told me that you are the creator of the term and concept that we now call mild cognitive impairment or for our listeners, more commonly called MCI. For our audience, I want to say that this concept of MCI is really one of the most important in the field, and as a clinician who sees people in a memory clinic, it's absolutely essential in talking to people with cognitive change. Because this term, MCI, is not about normal versus dementia, it is about a spectrum of change that emphasizes cognition as well as daily function, and it has really allowed us to address stigma, help people with reversible causes, and truly prepare people for the future. So my obvious request for you, Dr. Petersen, is to please summarize your years to decades of work into two minutes on how you discovered MCI.

Petersen: A real challenge but I'll try. First of all, people have been too kind. We didn't actually invent the term mild cognitive impairment. It was really coined by Barry Reisberg and colleagues at New York University in the late 70s and early 80s, but they attached it to a particular stage in a scale that they'd been using called “the global deterioration scale,” which they called stage 3 as mild cognitive impairment. We then here at Mayo, studying in the Mayo Clinic Study of Aging, which is a population-based study in Rochester, Minnesota, really came to recognize a group of people who were, as you say, Nate, kind of in between. They were aging but not quite normally yet and they clearly did not have dementia. We captured these people and put some boundaries around them being that first, they were memory impaired more so than they used to be and maybe more so than they ought to be compared to normative data; other cognitive functions were relatively well preserved; their function was well preserved and they did not meet the criteria for dementia. So we kind of characterized them and took the NYU term of mild cognitive impairment. But when we published this paper in 1999, characterizing these, people sort of jumped on the fact that we had put out these criteria. I think that's really where it took off. A lot of controversies around the fuzzy edges and all that, but that was the essence of it and then we expanded it in subsequent years.

Chin: For our listeners – and I want you to correct me if I'm wrong, Dr. Petersen – really this criteria, and as I say it in the clinic, is someone experiencing a thinking change. I like to say they've had the courage to come in and be tested because we know how traumatizing that could be for a person, and that testing has to show some lower scores compared to the norms that you're using, but they are functionally independent; they're still doing the things that they're doing. Is that correct? Am I missing anything?

Petersen: That's a pretty good description of it, right? I usually say to people that, to the casual observer, they really look normal, more normal than not, but they know and people around them know that their memory and thinking are not quite what they used to be and maybe not what they ought to be. Consequently, it is a change for them. I think the key thing is a change. Somebody could still be scoring in the normal range on normative data, but this is a change for them to where they used to be and that's the key feature of it. While we use normative data, it's really the notion that people are changing more than what we would expect for aging. Of course, that can become a dicey call so you in the clinic. “I don't remember as well as I used to”. “I have trouble with names and multitasking.” Things like that are where the aging end and where mild cognitive impairment begins. That's a bit of a challenge but you kind of get a clinical feel for it, and neuropsychological cognitive data can help you. It doesn't make the diagnosis but can help you with that. But most importantly, MCI is a syndrome. It's a collection of clinical features, not an etiological diagnosis just like dementia. Dementia is a syndrome, and it can be due to Alzheimer's disease but it can be due to other things similar to MCI. Given MCI is a milder stage of cognitive impairment by definition, a lot of other things can cause this: aging, medical disorders, COPD and diabetes that is out of control, medications I'm taking for my other conditions may contribute to mild cognitive impairment as a syndrome.

Chin: And another clarification question for you: mild cognitive impairment is not pre-dementia. Someone can have mild cognitive impairment and not be on this path toward dementia.

Petersen: That's exactly right. As a syndrome, there can be treatable causes of it. I think one of the things that you and I have come to appreciate in our practices in recent years is sleep disorders. People with undiagnosed sleep apnea can have cognitive impairment during the day. Once you identify their sleep disorder and treat it, they can go back to normal, so it need not lead to dementia, although often in aging it is the earliest form of a cognitive disorder that will progress onto dementia.

Chin: I'll have a question for you later on about that. Before I get to it, this term MCI has been refined multiple times since its original use. In what ways has the field improved upon its meaning in both research or clinical care?

Petersen: Sure so early on as I was describing it earlier. It was largely focused on memory because we were thinking about this being the earliest clinical presentation of Alzheimer's disease. But then we came to appreciate not everything is memory. Even though patients may come in and say I'm not remembering as well as I used to, when you drill down, it could be a language disorder. They're really having prominent anomia. They may have trouble concentrating, so it's an attention executive function problem. As we refined the construct over the years we went into an amnestic form and a non-amnestic form. With the amnestic form, meaning memory is the primary feature. You can have other cognitive domains impaired to a lesser degree, but that fell under the amnestic MCI domain, but there is a non-amnestic MCI domain that could be the forerunner of a language disorder, attention concentration, even visual-spatial skills. For example, dementia with Lewy bodies at the MCI stage may not be a memory problem. You may have cognitive difficulties in attention concentration and visual-spatial skills, and that is sort of a footprint of evolving Lewy body disorders which can go on to dementia with Lewy bodies, but there isn't an MCI stage for that. We tried to look at it again as a syndrome with memory without memory and are there other cognitive domains impaired as well.

Chin: It seems like the earlier you are in thinking change, the more sensitive or helpful those thinking tests can be in separating what is amnestic and what is non-amnestic, and those patterns can be helpful to specialists in getting closer to what the underlying cause is since we can't get into the brain right now and look for those changes.

Petersen: Absolutely. I think clinical acumen is important here and you can do some of this in the office. You may need a neuropsychologist to help you out really characterize which domains are involved and to what extent they're involved which gives you the best signature of what this MCI might be, but you're right. There can be multiple presentations and the better characterization you can give to it clinically, the more likely you may be thinking, well this might be due to this or due to that.

Chin: That really emphasizes the importance of people coming in sooner to really address their thinking concerns about these changes that you've described.

Petersen: Because they might be treatable. There might be very easily identifiable, treatable causes that can return them to normal.

Chin: Now in 2018, there was a foundational change in how scientists viewed Alzheimer's disease. It went from being a clinical entity with some persistent element of uncertainty since we can't do a brain biopsy or we don't do that for sure, to a biological process with clinical staging. Can you expand on how this change in the landscape has impacted MCI?

Petersen: Yes. This was a research proposal which still remains a research proposal, meaning that it's not really adopted in the clinic yet, but the authors of that paper proposed that Alzheimer's disease be defined on its biological basis, that is by the presence of amyloid and tau. You could pick it up by biomarkers like at the time of autopsy, or in life with biomarkers, but that was independent of the clinical presentation. This is a big deal. This changes the field rather dramatically because now it's saying that somebody who is clinically normal but harbors the biological changes of amyloid and tau would be labeled as having Alzheimer's disease being normal. Similarly at the MCI stage and the dementia stage, and the proponents were saying we're trying to put Alzheimer's disease on the same ah same platform as other medical disorders. If you have a biopsy of your prostate and it's positive, you have prostate cancer. Whether you're symptomatic or not you have prostate cancer, breast cancer and like. They're saying if in fact, we have evidence of the biological underpinnings, you have the disease. Well, that takes a lot of adaptation for all of us. They did say though that there still is a parallel, corresponding clinical spectrum, and the clinical spectrum could be cognitively unimpaired, MCI, dementia, or they also proposed a six-stage scheme for people who are amyloid positive. Stages one and two were sort of normal cognition. One being squeaky clean normal, two being normal but I'm experiencing some subtle changes, and stage three was kind of MCI. Four, five and six were mild, moderate and severe stages of dementia, but they're not part of the definition, they just go along in parallel to the underlying biological spectrum.

Chin: In your presentation, you mentioned that MCI is “bouncy,” which I think is a very good way of describing it. In research, we certainly tell our participants this. But what do you mean by “bouncy”? In essence, is MCI truly a precursor to dementia?

Petersen: In our longitudinal studies, and certainly you have them in Wisconsin the WRAP study, our ADRC follows people longitudinally over time. In our Mayo Clinic Study of Aging, we've been following people for up to 17 years now – not many but some for many many years. We make our diagnoses independently each year, independent of their previous diagnosis and independent of their history of cognitive testing. As such, this early diagnosis of mild cognitive impairment might be subject to the “bounciness.” That is, I may see them this time they look like they have subtle cognitive impairment and I’ll label them as MCI. In fact, they just had a bad burrito for lunch. Okay? Next year we see them and they're squeaky clean, normal. So there that's the bounce. But, we've also looked at these data longitudinally as you have. In fact, when a person is once identified as having mild cognitive impairment, odds are they're on the road and things are going to decline. They may go back and forth back and forth, but ultimately following people out eight to ten years, two-thirds of those who “bounce”, ultimately declare themselves as having MCI going on to dementia. The Cardiovascular Heart Study out of Pittsburgh has identified the same features. I characterize it as “labile hypertension.” Up and down, up and down, but odds are, you're going to go down. Glucose intolerance: normal abnormal, normal abnormal, but you may be on the road to diabetes if you don't do something about it. I think of MCI much along the same line that it's sort of a warning that things may be brewing. There may be treatable entities, but if nothing is done, it may progress in the future.

Chin: I'm glad you added that last sentence because I was wondering while you were saying that, what if it’s sleep apnea? We identify it. They get treated. We’ve seen that in clinics, people return and have completely normal testing and continue to not have symptoms.

Petersen: Exactly. If there are medical elements, especially as folks get older, their resilience, their ability to respond to medical insults, fevers, infections and things like that, is lessened and it can affect your cognitive function, but that doesn't mean you're on the road to Alzheimer's disease.

Chin: So how common is mild cognitive impairment?

Petersen: We looked at the literature. We, meaning a committee from the American academy of neurology, looked at the literature about three or four years ago and it's a huge literature. We had over 11,000 studies to look at. Now we culled that down to a few hundred that met the very strict criteria for an evidence-based medicine review of the literature, but these were international studies and population-based studies. We actually found that there were probably 20 studies that met class one criteria for prevalence, which is outstanding when you do an evidence-based medicine review of the literature. We came to the conclusion that MCI in people 65 or 70 and older, the prevalence was probably in the 10 to 20 percent range. We at Mayo have found a 16 percent prevalence in our population 70 years and older, so I think that's probably a good ballpark figure for individuals. Again, this is MCI, it is a syndrome, not Alzheimer's disease, but as a syndrome, it's probably in the 10 to 20 percent range in the appropriate age groups.

Chin: People often will ask, particularly in a clinic, what's the progression, how many people or what percentage of people progress to dementia every year over five years. What do you say in your clinic?

Petersen: Again, it depends on the source. If people come to a physician or seek out the physician so to a memory disorders clinic with that concern, then the rate is probably 10 to 15 percent per year if there's an underlying neurodegenerative process. If it's one of those treatable conditions then all bets are off, but if it's an underlying neurodegenerative disease probably 10 to 15 percent per year. However, if the people are identified in an epidemiologic study like we do here – so we go out and knock on their door, “Would you like to participate” – then the rates are a bit lower. I'd say eight to nine to 10 percent per year. You're finding it sort of as it exists in the community, but if people are seeking care, coming to the physicians, probably a higher rate.

Chin: I think it's so important to emphasize that context matters. Who is coming into a clinic? Are you as a researcher going to them? That does change how you're looking at progression.

Petersen: Absolutely.

Chin: Speaking of progression, if someone, let's say in this case, does have Alzheimer's disease that is causing the symptoms that we are characterizing as MCI and they eventually do progress to dementia, how long do people typically live in the stage of MCI?

Petersen: Again, good question, relevant clinical question. Very variable of course, but we've had the luxury of following people in the study of aging here who started out in the study as cognitively unimpaired, progressed to MCI, continue to follow them that progressed to dementia.  We looked at their so-called “dwell time”: how long were they in that state, and in general, large variability of about three years, a ballpark figure that people will hang around at MCI for three years, but that can be very variable and there are more aggressive forms. In general, three to four years is probably a reasonable estimate.

Chin: We talk a lot about lifestyle interventions on this podcast. I don't need you to go into great detail about any particular one, but I am wondering which ones you think are most impactful for people living with mild cognitive impairment.

Petersen: I think that this actually is an important issue because I tend to view aging as not necessarily a passive process. That is, we can do things about the course. I don't go as far as to say that if I run three miles a day and eat blueberries, I'm going to prevent Alzheimer's disease. I can't say that, but I think we can impact the trajectory, especially if somebody has mild cognitive impairment. I'm sure you've covered this Nate, but aerobic exercise I think that's probably the best one. I think there's a good deal of biological evidence and epidemiologic evidence that aerobic exercise – maybe with some interval training and a little strength exercise as well – may in fact have an impact on the rate at which we progress. We, of course, talk about staying intellectually active: keeping the mind working one way or another. I'm not sure one brain game is better than another. A recent paper in the New England Journal touted crossword puzzles over some brain games, maybe. But I think keeping active is a good thing, maintaining your social network, staying out with the family, and doing things to avoid the tendency to withdraw. I think we also emphasize good sleep hygiene as we've already talked about and a reduction in over excessive stress. I think these kinds of lifestyle factors – again, diets come in, but I am not sure if there is any supplements or anything that's particularly useful. A good heart-healthy diet and a Mediterranean diet is probably the best bet, but I think a combination of these can actually have an impact on the rate at which we might progress if we have mild cognitive impairment.

Chin: Clinical trials and Alzheimer's disease are moving earlier and earlier along this cognitive change spectrum with MCI being of great focus and importance. What are your thoughts about amyloid removing therapies in people living with mild cognitive impairment?

Petersen: Very timely question, Nate. Just came from the Clinical Trials at the Alzheimer's Disease conference in San Francisco where I think some very exciting data were presented on one of the monoclonal antibodies called lecanemab that actually showed it did remove amyloid from the brain over the course of the 18-month study. Others have shown this aducanumab that received accelerated approval last year. Another one was presented at the meeting – gantenerumab – which removed some of the amyloids. Another one, donanemab, will be read out in early 2023. I think these monoclonal antibodies do what they're supposed to do. They do reduce the amyloid plaque level in the brain, but the study on lecanemab last week really talked about the fact that it may slow the progression of the disease. Doesn't stop it, doesn't make anybody better, but it may slow the rate of progression. They estimated about 27 percent slowing over the course of 18 months and interestingly, in all of these monoclonal antibody studies, the majority of the people have the clinical diagnosis of mild cognitive impairment. It varies the percentage, but this is the predominant stage of the disease at which they're intervening with these antibodies and it appears to be helping. These are not cures for the disease by any means, but in this particular study the primary outcome measure and the four secondary outcome measures are all positive. They projected that over the course of about 18 months, you may have a 4.5 month slowing of the disease process. Then we get into this argument about “Well is that a big deal or not.” I think for people with mild cognitive impairment, if they can maintain their overall level of function given the inconveniences of the memory problems, they can still drive, pay their bills and do their taxes, that's a big deal. If we can prolong that period for them, I think we've done a clinically meaningful benefit for them, so I'm excited that these new studies now are really intervening in a meaningful fashion and I'm hopeful that we'll get even more of these available so that we have something to say to our patients that, in addition to lifestyle factors, we now can intervene pharmacologically and it'll probably take a combination of these two to really work.

Chin: In your presentation for the WAI, you also commented about this cumulative effect in that the study can only speak to the 18 months, but if you truly change the rate of progression of a disease that is progressive, later on, there could actually be a greater benefit, relative to people who are were not taking the medication. Did I say that correctly?

Petersen: Yes you did. There is a certain amount of assumption, in the progression that the curves are diverging. The treatment curve is flattening and the placebo group is continuing to decline. We don't know that we're most comfortable staying within the data, but if we extrapolate out, in fact, these curves are diverging. We might see a greater benefit two years or three years out. I won't say forever. I'm not sure that these are going to remain linear, but I think over the course of the disease process, since we talked about a three year duration earlier, if we can extend that out by six, 12 or 18 months, that might be meaningful for our patients.

Chin: To end our conversation today, I'd like to hear your final thoughts on the future of cognitive disease research and clinical therapy. Where are we going? What still needs to be done?

Petersen: I think really, the field is making tremendous advances. I used to say that I think we're doing a better job on the diagnostic side than we are on the treatment side. That's probably still true. I think the clinicians' acumen using some of the tools we discussed. I think the advent of biomarkers has been big for the field of Alzheimer's disease so that we can now identify who might have amyloid in the brain, who might have tau and other features. Other medical comorbidities, maybe other neuropathologic entities that may be present so that we can talk to our patients and say, “here's what your syndromic appearance is – mild cognitive impairment dementia – and here might be some of the contributing factors. We think you may have amyloid tau, etc.” I think ultimately though, that we shouldn't focus too much on any single disease, like Alzheimer's disease because almost everybody has a combination of factors. Maybe some amyloid, maybe some tau, maybe some alpha-synuclein forming Lewy bodies, maybe TDP-43 which can impact the brain in the medial temporal lobe and vascular disease. Almost everybody has some element of vascular disease so likely down the road, in addition to perhaps some disease-modifying therapies for the individual proteinopathies, I think we'll end up with a combination of therapies so that we'll start treating these disorders with a biomarker profile that tells you, you have a certain amount of amyloid, you have a certain amount of TDP-43, and here's what we're going to do about it. This is not today or tomorrow, but I think that's the direction in which we're heading, and perhaps, people will come to their geriatrician, their primary care physician to get their lipid screen of course but also get their cognitive screen where their profile of biomarkers will be presented. Hopefully, then we have some therapies to intervene. I think I may have said in the presentation that we do this now with hypertension. Somebody has elevated blood pressure. Well, how do we treat that? It could be a diuretic, could be a beta blocker, calcium channel antagonist, angiotensin receptor blocker, ACE inhibitor, etc. Different mechanisms to treat the same symptom and I think cognitive function and cognitive impairment may be that symptom that's ultimately going to require combination therapy to attack it.

Chin: Very exciting. With that thank you, Dr. Petersen, for being on Dementia Matters, and I certainly hope to have you on in the future. 

Petersen: My pleasure, Nate. Thanks for having me.

Outro: Thank you for listening to Dementia Matters. Follow us on Apple Podcasts, Spotify, Google Podcasts, or wherever you listen or tell your smart speaker to play the Dementia Matters podcast. Please rate us on your favorite podcast app -- it helps other people find our show and lets us know how we are doing. Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center at the University of Wisconsin--Madison. It receives funding from private, university, state, and national sources, including a grant from the National Institutes of Health for Alzheimer's Disease Centers. This episode of Dementia Matters was produced by Amy Lambright Murphy and Caoilfhinn Rauwerdink and edited by Haoming Meng. Our musical jingle is "Cases to Rest" by Blue Dot Sessions. To learn more about the Wisconsin Alzheimer's Disease Research Center and Dementia Matters, check out our website at adrc.wisc.edu, and follow us on Facebook and Twitter. If you have any questions or comments, email us at dementiamatters@medicine.wisc.edu. Thanks for listening.