Roughly 7 million Americans aged 65 and older have Alzheimer’s disease, according to the National Institutes of Health. And there’s lots of research into ways to treat it. But, scientists are also working on ways to try to prevent people from developing Alzheimer’s in the first place.
Dr. Eric Reiman, executive director of Banner Alzheimer’s Institute and CEO of Banner Research, said he and some colleagues have been working with a large extended family in Colombia — and they’ve discovered in this family a rare genetic mutation that makes it almost certain that they’ll develop early-onset Alzheimer’s.
Reiman joined The Show to talk about this discovery, as well as the people who have been suffering with it, starting with the backstory on who these family members are and why this was such an interesting group for him to study.
There’s a theoretical question that is often asked when it comes to diseases like Alzheimer’s, if you could know that you’d get a disease later in life, such as cancer, Alzheimer’s or something else, would you want to know, and if you do, how would it change the way you live your life? But, Reiman told The Show, this question was not theoretical, it sounds like, for some of these family members.
Full conversation
ERIC REIMAN: Well, we now know of a number of genetic risk factors for Alzheimer’s disease, including a common genetic risk factor known as APOE, which contributes to the more common form of Alzheimer’s that occurs at older ages.
There’s a rare genetic form of Alzheimer’s disease in which individuals who carry a gene are destined to develop Alzheimer’s disease and become cognitively impaired in their 40s or 50s. And there are about 1,000 of these extended families, all from a common ancestor, in which if they have the gene, they’re going to develop cognitive problems. And their children have a one-in-two chance of inheriting that same gene.
When we first became interested in doing a sufficiently large prevention trial, the world’s first prevention trial for Alzheimer’s disease, we wondered if we could study individuals who are at high imminent risk for developing symptoms. And we were aware of a remarkable kindred, this extended family in the vicinity of Medellín, Colombia, that carry one of these genes. And a friend and partner of mine, who we got to know over the years, was Francisco Lopera, who identified this kindred primarily through baptismal records, all from a common ancestor.
With our help, we now have 6,000 members of this extended family, roughly 1,200 of whom carry a gene that makes them virtually certain to develop Alzheimer’s and become cognitively impaired at the average age of 44.
MARK BRODIE: So what kind of research did you try to do? Obviously, if you know people are destined to get Alzheimer’s, it seems like that sort of a good control group to try to test prevention methods.
REIMAN: Well, first let me mention when I went down to Colombia, this was a life changing experience for my colleagues and me, meeting these families who had been living with this for centuries. And what a joy it has been to empower them in the fight against Alzheimer’s disease, so that we could work together as partners to try to find ways that would be helpful to the family but also helpful to the rest of the world.
And these families and other research participants are my heroes. So we had been planning a prevention trial. This was a prevention trial that got announced way back in 2012. But another thing that one can do is because you know that they developed cognitive impairment at the age of 44, we could characterize the course of biology school changes with brain imaging techniques, spinal fluid measurements and now blood tests for Alzheimer’s disease and see when they begin in relationship to cognitive impairment.
So one of the first studies we did together was characterize the sequence of these biological changes — some of which occur 25 years before the onset of symptoms — to help inform what we would do in terms of prevention trials.
BRODIE: How has that research helped in the fight to try to get a prevention for Alzheimer’s, to try to prevent people from developing it in the first place?
REIMAN: Well, we have had a longstanding interest in Arizona of trying to find and support the approval of prevention therapies. We had this out-of-the-box idea to do that at the time. We proposed two prevention trials, one in this group in Colombia and another in people who were at more common genetic risk factor, two copies of that APOE4, which we did in the United States.
And at the time, we figured that if we could propose a strategy, get academic and industry stakeholders — including makers of the most promising treatments that we need their drugs to evaluate — regulatory agencies like FDA supporting this possibility, it would launch a new era in Alzheimer’s prevention research.
So when our first prevention trial was announced by the director of NIH and secretary of human health services in 2012, it did launch that year in Alzheimer’s prevention research. Other makers of promising treatments knew it was possible, and you started seeing more and more prevention trials starting with that very first trial in Colombia.
BRODIE: So where are you now in terms of, more than a decade later, trying to have therapies that could prevent people both those with the gene and those without from developing Alzheimer’s?
REIMAN: So for that very first trial in Colombia, we conducted a study over five to eight years of a treatment that targets a protein known as amyloid. Amyloid is the major component of amyloid plaques in the brain, which is a cardinal feature of the disease itself. And the particular kind of anti-amyloid treatment we studied didn’t work, but it helped to inform how we go about these prevention trials.
And we, my colleagues at Banner Alzheimer’s Institute and I, have had the privilege of co-leading a growing number of prevention trials. Right now, there are ongoing prevention trials, including of the first two demonstrably effective treatments in patients: amyloid plaque clearing antibody therapies. We and others are conducting the first studies of unimpaired individuals, older adults who have blood-test evidence of Alzheimer’s disease and imaging evidence of Alzheimer’s, to see if the treatment works.
We believe we have a realistic chance — no guarantee, but a realistic chance — to help find and support the approval and accessibility of the first secondary prevention therapies, prevention therapies in unimpaired people with blood-test evidence of the disease, to avert the onset of memory and thinking problems within two to three years.
We think we have a chance to find primary prevention therapies — treatments that are used very infrequently, maybe as infrequently as once per year — in older adults at risk before they do not have any biological evidence of Alzheimer’s disease to try to prevent it completely and have a shot at that within four to five years. Pretty amazing.
BRODIE: You mentioned how going to Colombia was a life-changing experience, and I’m curious about what it was like interacting with members of these extended families, who basically knew that they were going to develop Alzheimer’s while they were sort of working with you and going through clinical trials and knowing that maybe what they were doing wouldn’t necessarily help them but could help other family members or just help humanity.
What were those conversations like? What was it like working with these individuals?
REIMAN: So for context, the family members in Colombia typically do not want to know their genetic status. But if they have a parent who’s developed Alzheimer’s at a young age, they know they have a 50% chance of getting it. So imagine you’re a family member and you have parents, uncles and aunts — that half of family members on average — who develop this disease at a young age, they’re having to change their lives to care for their loved one and worried about the impact that it will have on themselves and their children going forward.
And that’s what they’ve been living like for years, these heroic members of this family. When I first got down there, a common question I would ask is, what could we do to be helpful to you? The most common response was “More adult diapers, please.”
BRODIE: Wow.
REIMAN: It’s been a joy to work with them.
BRODIE: There’s a theoretical question that is often asked when it comes to diseases like Alzheimer’s. If you could know that you’d get a disease later in life, like cancer or Alzheimer’s or something else, would you want to know? And if you do, how would it change the way you live your life? But this question was not theoretical, for the most part, for some of these family members.
REIMAN: You know, when we first started doing this study, we were going to study a drug, an experimental drug in members of the kindred who had one of these mutations, and they didn’t want to know their status. So how did we do that?
Well, what we did was we designed a study in which if they had a mutation that caused Alzheimer’s, they would either get the experimental drug or placebo. And then other members of the family who didn’t have the mutation would get placebo. So that way they didn’t have to learn their genetic status and still get that information.
For other studies of people at risk — either based on whether they have amyloid plaques before the onset of symptoms or a genetic risk factor — we in the field have developed ways to be able to communicate that information to people about their risk in an informed, constructive way; assess the impact on people, to make sure that they’re OK in that regard. And we have colleagues who devote a lot of their time to that very important goal.
Eventually, we’re going to be in a position sooner than you might think to be able to assess individuals who are unimpaired — we don’t recommend that in the clinical setting now — to assess their risk based on their genetic status, their biological measurements of Alzheimer’s disease in an accessible way like a blood test. And we’re going to need to figure out scalable ways to empower them with the information they want to know what to do with it.
BRODIE: But as you referenced, though, some of these folks down in Colombia, even if they didn’t want to necessarily know, if they saw a parent develop Alzheimer’s in their mid-40s, you kind of can’t avoid that knowledge.
REIMAN: Right.
BRODIE: What was it like for them, especially the ones who maybe didn’t want to know what, perhaps what their future held? What was it like for them sort of being faced with it and not only having the knowledge, but also, as you say, caring for their parent and also then thinking about themselves and their kids?
REIMAN: Well, we’ve been doing this study with our friends in Colombia under the auspices of a program we called the Alzheimer’s Prevention Initiative. There’s another study that goes on in the United States and other countries called the Dominantly Inherited Alzheimer’s Network. And we all have the same opportunity to make a difference and challenge of working with and helping these remarkable families.
And all I can tell you is it is a privilege to be working with these individuals. And the families we have been studying in Colombia, they and generations before them have been living with it for decades. And theirs was almost kind of a fatalistic approach to the idea: “Well, our extended family is cursed, so to speak.” They understand biologically why that turns out to be the case.
So to be able to offer them, for the first time, some hope and some empowerment about how they themselves can help lead this fight against the disease has been a remarkable experience.
BRODIE: I want to ask you about, Doctor Francisco Lopera, who, as you reference, was one of the leaders in Colombia of spearheading this research and bringing all these people together. He unfortunately passed away not that long ago from cancer. How would you describe his influence and his impact on the kind of work that you all are doing now?
REIMAN: I remember the first time I invited him up to Arizona. I think it was around roughly around 2006 or 2007. I wanted to introduce Francisco to Gov. (Janet) Napolitano and our commitment to finding a prevention therapy and also to another researcher who’s passed away, Dale Shank, who developed the first immunization therapies targeting amyloid and Alzheimer’s disease.
And that was the start of our work together. He was an individual who was passionate about the families. Imagine we would go into a family’s home. I remember one home we would go into in which, just due to bad luck, six out of the seven siblings developed Alzheimer’s disease. And their children are caring for them. And visited a number of these individuals in their home, and his team knew the story of every single family member in extraordinary detail.
That’s Francisco: his passion, his commitment, the respect he generated from the community. We wanted to set up in Colombia an infrastructure to do a prevention trial, to permit for that first study intravenous therapies, to have the first PET scanners, in Colombia. And because of the respect in which he was held, when we would have those conversations with other members in the community, somehow it happened.
Every time we asked to address a new challenge that most people would think would be impossible, he’d think about it, decide whether he could live up to that expectation, and always exceeded that expectation. And he was somebody who enjoyed celebrating that success. And as we were just about to embark on our next prevention trial, it breaks my heart not to be doing that with Francisco.
What I can say is, when we and the field find the first effective prevention therapies, that will be part of his legacy and that of his colleagues and those remarkable families.
BRODIE: It sounds like one of his great strengths among many was his ability to gain the trust of the individuals with whom he was working, because it sounds like not all of the people who participated in the study were at first willing participants. Like it sounds like he had to do some convincing and some relationship building and some trust building to get them to be OK to partake.
REIMAN: As he showed us, but also we believe, the key to establishing this partnership with your research participants — which we embrace here in Arizona as well — is the idea of communication, transparency, treating them like valued partners. So before we decided to do a prevention trial or chose a drug, we talked to the family members about what kind of treatment they would be comfortable with, how much safety data was needed, how comfortable would they be with a drug that would be administered intravenously or a subcutaneous injection?
They knew we were listening to what they said. We would meet regularly. And that was because of Francisco. So on short notice, when we go down to Colombia for the first time and 700 people show up at a meeting, that’s a testament to Francisco and his leadership abilities.
