Being Patient explores the inner workings of the Wisconsin Registry for Alzheimer’s Prevention, a long-running study of people at risk of developing Alzheimer's. We took a closer look at the life of one research participant, the signs of Alzheimer's in the brain prior to the onset of symptoms, and the importance of cultivating relationships in underrepresented communities.
Alzheimer’s is a complex disease, and studies that follow participants over extended periods of time can gather troves of data on the progression of the disease, and the host of factors that influence people’s Alzheimer’s risk, whether it be genetics and family history, or lifestyle choices and comorbidities.
Since 2001, scientists from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) have been studying people at risk of Alzheimer’s, examining the disease from an array of angles including signs of the disease before symptoms appear, the link between Alzheimer’s, lifestyle and other health factors, and strategies to prevent its progression.
Being Patient spoke with Therese Barry-Tanner, producer of Determined, which features the lives of three participants in WRAP and insights from experts involved in the study. She shared about the inspiration behind the documentary, her late mother’s journey with the disease and her own experience as WRAP’s participant.
Barry-Tanner was joined by WRAP’s principal investigator Sterling Johnson, who spoke about the ins and outs of WRAP, and his group’s findings on amyloid plaques and tau tangles, Alzheimer’s hallmarks, and cognitive decline from data of WRAP’s participants. Gina Green-Harris, director of the Wisconsin Alzheimer’s Institute (WAI) Regional Milwaukee Office, discussed her team’s efforts to build trust in underrepresented communities and to recruit people of color into WRAP.
On Therese Barry-Tanner’s personal experience with Alzheimer’s:
Being Patient: Therese, can you share about your late mother’s early symptoms of Alzheimer’s?
Therese Barry-Tanner: In the early 2000s, a couple years after their wedding anniversary, my dad started noticing memory issues that were manifesting in language, the inability to find a word at the end of the sentence. He waited a while before he contacted me. I visited a couple times and was able to see what was going on, and we didn’t do anything right away. Additional issues started to crop up.
I talked to my dad about seeing a neurologist, so we took her in. They did a very short version of a memory test. She didn’t do very well. It was the early stages.
We heard of a different neurologist that had a more patient-centric touch, especially with this type of disease. That neurologist did an MRI (magnetic resonance imaging) and saw how small the size of her hippocampus was. At that time, the neurologist said it was probably Alzheimer’s disease. As time progressed, the symptoms manifested themselves in that way.
Being Patient: Why did you decide to enroll into WRAP?
Therese Barry-Tanner: In the early stages of my mom’s diagnosis, WRAP’s former principal investigator Dr. Mark Sager did a talk as a part of a lecture series on dementia at one of the local hospitals. I thought it would be a good idea for my dad and I to attend those sessions to learn more. There was an overview of dementia given by Dr. Mark Sager and I took furious notes. He mentioned the study, and I followed up on that and joined the study in 2004.
It was such a positive feeling to join that study. I actually might make a difference. I’ve talked to other WRAP participants and that’s a very common motivation.
Being Patient: What inspired the making of Determined?
Therese Barry-Tanner: A discussion with the study coordinator about my own experience being a WRAP participant, plus my creative, wandering mind led me to a thought about trying to tell the story of Alzheimer’s disease in a different way. I’ve been doing a lot of reading on it and had my own experience.
One of the things I heard in the news during those years was that a cure was just around the corner. I heard that very often. From my participation in the study, I knew that that wasn’t the case. I wanted to tell the story of the disease more realistically. I thought it would be interesting to tell it from the perspective of where the research is and where it’s going, but through the eyes of people involved in the research who have had the experience of caring for their parents.
On the nuts and bolts of WRAP:
Being Patient: Sterling, what are WRAP’s main goals?
Sterling Johnson: WRAP has been ongoing since 2001 when Mark Sager put this together. The main objectives then are pretty much what they are now, which is to identify this disease as early as we possibly can, before the symptoms occur even, and then identify what it is that might render a person more vulnerable to getting this disease or more protected from it. What’s their background? What’s their medical situation? What are their genetics? What health and lifestyle factors might influence whether this disease manifests itself? Those are the major goals of the study.
Being Patient: What do WRAP’s participants do in the study?
Sterling Johnson: They come in every two years and they undergo extensive cognitive testing. They allow us to draw blood from them. We do some standard labs, but we put most of it in the freezer for an opportunity like blood-based biomarkers.
At their visit, they will have a fairly large packet of surveys that asks about everything from stress, to eating habits, to physical activity, to cognitive activities, to sleep and other things. We invite them to do sub-studies, imaging-based studies or other studies of interest to them including more direct measurements of physical fitness levels, certain chemical profiles like cortisol, things like that.
Being Patient: Therese, what is it like being a participant?
Therese Barry-Tanner: You’re going in for this battery of cognitive tests. It’s hard not to be nervous about it. Everyone I’ve talked to in the study just naturally has some anxiety around it. It is taxing and the basis of the testing is that you stop in each section when you can’t complete it any further. It’s not something you look forward to, but you do it because you’re dedicated. You want to make a difference. You want this rich data that can be analyzed the way it has, such that great papers can be written about the insights.
On recruitment and fostering relationships in underrepresented communities:
Being Patient: Gina, enrolling people from underrepresented communities into Alzheimer’s research is a major challenge. Why is that the case?
Gina Green-Harris: Sometimes, you just don’t have the time to participate in research, especially when you’re in the trenches. When you think about underrepresented groups, there’s the taxing burden of simply the disease itself. Then, adding into that is the lack of or misunderstanding of resources that are available to you or access to those resources. Tripling that is the mistrust of systems. So, there is an underrepresentation of people of color who are participating in research for those reasons.
But then, there’s also the flip side of it. How are we actually creating opportunities that show value to those communities that they need to be participants in research? Are we making it accessible? Are we making it realistic? A two-hour battery of tests for someone who’s a primary caretaker, has a full-time job and all of these other challenges, may not be optimal.
Being Patient: Can you tell us about the WAI Regional Milwaukee Office’s work in recruiting underrepresented groups for WRAP?
Gina Green-Harris: We’ve taken the time to back up and help the community understand the science of Alzheimer’s and dementia, particularly in underrepresented groups … Once we started talking to the community in real-time, bringing scientists such as Sterling to the community, people began to understand the disease better. We’ve done our homework of figuring out: How do we help the community understand not only the importance of research, but what this disease is and what it’s doing?
Relationship building is not something that happens overnight. It was around 2008 or 2009 when we first started building our relationship with the community. The community was saying, ‘We don’t want to hear about Alzheimer’s disease. We don’t want to think about this thing.’ Now in 2021, people are saying, ‘Let us understand this better.’ But we had to create an educational platform … We did education from A to Z, all the way from getting an understanding of diagnosis, through caring at home, what the stages would look like, the types of dementia.
Being Patient: What are the other programs of the WAI Regional Milwaukee Office that have helped build relationships with underrepresented communities?
Gina Green-Harris: As we learned, we developed more programs. We actually created a dementia wellness program, a lifestyle intervention program for those who were high-risk.
They are folks who are hypertensive. People who have diabetes. People who have these other health, social determinant challenges. The program helps people read labels, understand diabetic numbers, reduce hypertension.
We designed and developed, with the community, programs that they would embrace, keep them safe, and hopefully help reduce their risk. In doing so, the community embraced us by saying, ‘This is helpful for us. How can we give back?’
The same goes for the Amazing Grace Chorus. We’re funded strongly by philanthropy dollars, which is critical to bringing the science and engagement together. We were able to create a chorus of folks who were living with dementia and their caretakers to have this positive experience. We learned this program through NYU (New York University) with Dr. Mary Mittelman, but we made it our own. We grew it within our Wisconsin network. It started in Milwaukee specifically for urban and inner city folks, but it has grown to anyone who’s touched by Alzheimer’s and dementia.
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We’ve done this wraparound for these families. We meet people where they are. If you’re at home, we meet you there. If you’re at a family reunion, we meet you there. If you’re at a hospital, we meet you there. Because of this, I think we’ve been able to create this presence of care, support and service, which has built the community’s trust in us, but also the understanding that we want more than you to be enrolled in research. We want you to be actually safe, healthy as a caregiver, and as healthy as you can be with a mentor. As a result, people have been saying, ‘We want to participate and help and give that essence back.’
On amyloid plaques and tau tangles before the onset of Alzheimer’s symptoms:
Being Patient: Sterling, one of WRAP’s objectives is to study when amyloid plaques and tau tangles begin to form. Before we discuss some of the recent findings from WRAP’s data on biomarkers and cognitive decline, can you tell us what amyloid and tau PET scans are?
Sterling Johnson: Amyloid and tau PET scans are vital ways of understanding whether plaques and tangles are present in the brain. Amyloid plaques are one of the key features of Alzheimer’s disease, and neurofibrillary tangles, composed of tau proteins, are the other. These two proteins self-aggregate, or clump together.
Amyloid clumps with amyloid. Tau clumps with tau. In the case of amyloid, they form plaques. In the case of tau, they form tangles inside neurons. These are the culprits that cause the neurons to eventually die and for the symptoms to eventually appear.
These proteins become abnormal many years before the symptoms appear. In one case that we’ve observed, it looked like close to 30 years before the symptoms. In other cases, it might be five or 10 years before the symptoms. So, there’s quite a range, and why that is is a big focus of our study.
Amyloid plaques and neurofibrillary tangles are the two key pathologies. We can get at these with PET scans. PET stands for positron emission tomography. You inject a small amount of radiotracer, and it’s a little compound that finds its target. In the case of an amyloid PET scan, the target is amyloid. In the case of a tau PET scan, the target is tau. It’s a feat of chemistry for this to even happen because the radiotracer has to get through the blood-brain barrier and navigate its way through the brain tissue and find its target. It has to only bind to that target and nothing else. That’s called specificity.
The PET scanner is like a big Geiger counter. It detects events that are happening in the tissue of interest, in this case the brain. It’s a big circular thing. The physics of this is that positrons are emitted at a 180 degree angle that goes left and right, or up and down. That means you can pick it up on a circular PET scanner, and it forms an image. It’s a remarkable methodology that has changed the way we can think about Alzheimer’s disease, to the point where now we can diagnose and categorize it based on imaging profiles.
Do people have amyloid? Yes or no. Do they have tau? Yes or no. On an MRI, do they have neurodegeneration? Yes or no. Those are A, T and N, the key brain features of Alzheimer’s disease and they can all be looked at with imaging.
Being Patient: In a study published in Alzheimer’s & Dementia, you and your team found that cognitively normal people with elevated amyloid for a longer time had faster cognitive decline, compared to those without elevated amyloid. Can you tell us more about the study’s findings and their implications?
Sterling Johnson: The study, with the first authors being Rebecca Koscik and Tobey Betthauser, is probably the most important finding of my career. I’m so grateful for these two scientists.
We had a decade of amyloid imaging in the WRAP study. We had people with four and five amyloid scans over 10 or 12 years … We developed a simple method of predicting back in time, back towards when they became positive and that allowed us to estimate the age at which a person became positive. We can also try to predict forward in time too. There’s going to be uses for that down the road. But understanding when a person became positive is critical because people who have been positive for longer are more likely to exhibit cognitive decline.
I think this helps us solve the big puzzle in our field. Twenty five percent of healthy older adults are amyloid positive and if you scan a bunch of 85 year olds, it might be 40 percent of them that are positive. But what that doesn’t tell you is when did they become positive? Once you add that variable to the analysis, all of a sudden it becomes very clear.
It doesn’t matter what age you are. The longer you’ve had amyloid in your brain, the more likely you are to decline. The other piece is we’ve observed that a person’s onset of amyloid could be anywhere from age 45 to 85. That’s a 40-year span at which someone can begin to develop this disease. Now we have the ability to pinpoint when it happened and improve our prediction of decline.
We think this is going to be an important tool for our field to understand things like risk and susceptibility, and the other side of that which is resilience and resistance to the symptoms.
Being Patient: Adding to the mix are tau tangles, and in a separate study published in Brain, you and your team found that cognitively normal people with elevated tau and amyloid had faster decline in cognition, compared to those with no elevated amyloid or tau, or just elevated amyloid. Can you tell us more about this study and why the results are important?
Sterling Johnson: Tobey Betthauser is also the first author on this study. It was using the now almost two decades worth of cognitive information that we have on these participants. A number of them have undergone amyloid scans and tau scans, and what we found is that those who are tau positive and amyloid positive had three times faster rate of progression on their cognitive testing. Importantly, there weren’t a lot that had MCI, or mild cognitive impairment, in that group because our cohort is still very young.
But we were able to detect these differences in their rate of change in cognitive decline that are associated with aging during late mid-life to early, old age. It’s incredible, and it’s the value of doing the same tests over and over every two years, even though they are very unpleasant to our participants. Having that kind of stable testing allows us to look at these trajectories and come up with this kind of information, that in fact there are changes happening well before the clinical symptoms or the clinical diagnosis of MCI or dementia.
On takeaways from the documentary Determined:
Being Patient: Therese, what do you hope people can learn from Determined?
Therese Barry-Tanner: The first one is the potential to improve brain health through healthy lifestyle choices. The other is there is still, after all these years, a stigma associated with this disease, and we have got to get rid of it because we need to embrace people in our communities who are dealing with this and find support mechanisms.
There are support mechanisms but we have to help people get to them, and we have to have a more community-oriented approach everywhere. That’s where dementia-friendly communities have come in through the past few years. There are many cities across the country that have embraced this model to provide a better community support system.
Lastly, one of the gaps for research is people participating in a different kind of study, which is clinical drug trials. We need people to feel comfortable participating in research and get more numbers in the various drug trials that are going on.
The interview has been edited for length and clarity.
Contact Nicholas Chan at firstname.lastname@example.org