About once every year and a half, Erin Harvey takes time off of her job as a teacher’s aide and along with her mom, Nancy, makes a two and a half hour drive from her home in central Illinois to the University of Wisconsin-Madison Waisman Center to “embark on an afternoon of adventure.”
At the Waisman Center, Erin, who is 36 years old and has Down syndrome, completes a variety of tasks and tests. Her favorite is a vocabulary exercise where she is asked to match words with correct images.
“I just love it, and I am good at it,” Erin says.
The vocabulary test is a small part of a multi-site National Institutes of Health study – called Neurodegeneration in Aging Down Syndrome or NiAD – that aims to identify biomarkers and track how Alzheimer’s disease progresses in individuals with Down syndrome.
The Waisman Center is a key partner of the NiAD study, which combines sophisticated brain imaging techniques, innovative biomarker assays, and comprehensive cognitive tests to further our understanding of Alzheimer’s.
“Ultimately our goal is to help inform future clinical trials that will treat or prevent Alzheimer’s disease in individuals with Down syndrome that can also be extended to the general population,” says Bradley Christian, co-director of the NiAD study, a Waisman Center investigator, a professor of medical physics and psychiatry and a member of the Alzheimer’s Disease Research Center (ADRC) at UW-Madison.
Down with Alzheimer’s
At the heart of the NiAD initiative are individuals with Down syndrome who volunteer to visit the Waisman Center every 16 months over a four year period to participate in the study.
Megan Layton, who is 37 years old, travels with her parents, Harold and Maureen, from near St. Louis, Missouri, to be a part of the NiAD study at the Waisman Center. She is a self-advocate as an individual with Down syndrome, has two jobs, and is part of a local theater group.
Researchers at the Waisman Center work with Megan and her parents to schedule visits around her work and social commitments. Megan, who has already made three visits to the Waisman Center says, “I do it because I want to help other people.” Her parents support her completely. “We have been blessed with Megan,” says Maureen, “and we want to give back some of that blessing.”
The NiAD study focuses on people with Down syndrome because they are at a much higher risk of developing Alzheimer’s disease than people without Down syndrome.
The National Institutes of Health estimates that more than 5 million people – and more than 10% of individuals over the age of 65 – are living with Alzheimer’s in the United States. But in the Down syndrome population, more than 75% will have Alzheimer’s by the time they hit 65.
In fact, brain changes connected to Alzheimer’s disease – the appearance of protein aggregates called plaques or tangles – can start when individuals with Down syndrome are in their late teens or early twenties.
“The NiAD study is critical for individuals with Down syndrome because they have a really heightened risk for Alzheimer’s disease,” says Sigan Hartley, a NiAD co-researcher, a Waisman Center investigator and associate professor of human development and family studies. “But Alzheimer’s disease can affect any of us, and so what we learn from this study has the potential to help everyone.”
Plaques and tangles
An insidious aspect of Alzheimer’s disease is that changes in the brain begin decades before clinical symptoms appear. A protein called amyloid beta starts to accumulate in the brain and form clumps called plaques. “We now know that people can carry amyloid plaques in their brains and not show any cognitive deficits, or at least not ones that can be detected with standard memory or behavioral measures, for years,” says Christian.
Another protein linked with Alzheimer’s disease is called Tau, which forms tangles and also accumulates in the brain. Researchers now think that as amyloid plaques continue to build up, a threshold is reached, after which Tau tangles spread rapidly through the brain, and symptoms of Alzheimer’s disease can appear quite suddenly.
“The exact links between amyloid plaques and Tau tangles are still a mystery,” says Christain. “It’s something we are researching as part of the NiAD study.”
Fred Kreuser participates in the NiAD study and helps Christian and other researchers understand the connections between plaques and tangles. Fred works at the St. John’s Military Academy in Delafield, Wisconsin. He loves dogs, hanging out with his nieces and nephews, and sports an epic moustache. “Fred is an organizer,” says his sister and guardian Kathy Lyman. “He could spend all day organizing and re-organizing!”
Fred is 53 years old, and Kathy has started noticing changes in his cognitive abilities, especially when trying to learn new things. “Fred would always do the laundry,” she says, giving an example. “We recently got a new laundry machine. It isn’t very different in how it’s operated, but Fred cannot use it.”
Alzheimer’s disease is thought to disrupt how neurons in the brain communicate, affecting learning, memory and other mental abilities. One of the challenges in studying Alzheimer’s disease is that researchers don’t know ahead of time who is going to develop the disease decades in the future. “That makes studies really difficult and expensive because we have to recruit large numbers of participants,” says Christian.
But because the majority of individuals with Down syndrome will develop Alzheimer’s disease, researchers can follow them over time to understand how the disease progresses. “Understanding the natural history of Alzheimer’s and the related biomarkers is key to developing therapies and treatments,” says Christian.
Searching for biomarkers
In the past, researchers have tracked the progression of Alzheimer’s disease using brain imaging techniques like magnetic resonance imaging (MRI) or positron emission tomography (PET). While brain imaging provides detailed and informative data, it can be quite expensive and time-consuming. “We are exploring additional ways to track the progression and development of other biomarkers for Alzheimer’s disease,” says Christian.
The NiAD study is itself part of a larger initiative – the Alzheimer’s Biomarker Consortium–Down syndrome or ABC-DS. The overall goal of ABC-DS is to develop “sensitive neuropsychological measures of cognitive decline, imaging, blood-based, and genetic biomarkers associated with transition from normal aging to mild cognitive impairment to clinical dementia in adults with DS.”
For example, measuring how levels of different proteins in the blood change as Alzheimer’s progresses could yield a quicker, simpler way to diagnose the disease and also test if potential therapeutics are effective.
To test for different biomarkers, the NiAD study collects blood and other body fluids from study participants. Erin Light, who comes from Verona, Wisconsin, to take part in the study, is not a big fan of the blood draw, but she says “it’s pretty cool to be able to help people with Alzheimer’s.”
Erin, who is 44 years old, was diagnosed with Alzheimer’s about a year ago. “She is now a little shaky on her feet and has some issues with short-term memory,” says her mother, Pat. Erin still lives independently with roommates, enjoys creating works of art and zooming down zip lines.
But sometimes, Erin’s diagnosis with Alzheimer’s throws a shadow on her life. “I am afraid,” she whispers. The next second, she is smiling, though. “I love you,” she says to her mom and gives her a big hug.
“I love you too,” says Pat.
Finding accurate tests
Along with Erin Light, more than 180 individuals with Down syndrome participate in the NiAD study at the Waisman Center, the University of Pittsburgh and Cambridge University in England. Each study participant brings unique capabilities and a wide range of expression and vocabulary.
For example, “many of our participants speak very fluidly using complex sentences, while others have more limited verbal expression and primarily use two or three-word responses,” says Hartley, who develops and administers tests that can measure subtle changes in memory, learning and mental abilities. “One of the challenges is to find tests that can reliably capture memory and mental abilities given this wide range. We also want to find tests that can detect the earliest and most subtle declines in functioning,” she says.
Developing tests that can measure cognitive abilities sensitively and accurately is vital because “they can tell us whether potential treatments or therapies are effective,” says Hartley. For example, a word-learning task, where individuals are asked to learn a series of words and remember a series of pictures connected to those words may turn out to be a key measure for future drug trials.
It can be challenging, however, to come up with tests that work for all individuals with Down syndrome, given their different abilities. But whatever their communication skills, the NiAD study would be impossible without participation from the Down syndrome community. “It has been incredible working with our study participants,” says Christian. “We couldn’t have made the progress we have without them.”
Big goals
As researchers learn more about how Alzheimer’s disease progresses in individuals with Down syndrome, their goal is to use that knowledge to develop treatments and therapies for Alzheimer’s.
The NiAD study hasn’t yet progressed to testing specific treatments, but “that’s definitely where we want to go next,” says Christian. “Moreover, if we can leverage our current findings to connect changes in the various biomarkers with changes in cognition, we can define a window of opportunity for when interventions or therapies could be most effective.”
Researchers are also hoping to expand their research paths. For example, Hartley aims to explore how lifestyle may be connected with Alzheimer’s disease. “Sleep problems, for instance, are common in adults with Down syndrome, and there’s been some research linking sleep problems with Alzheimer’s as well,” she says. “But we don’t yet know if there are direct connections between them.”
The interdisciplinary setup at the Waisman Center, where behavioral and biological scientists cross paths often, as well as the availability of an in-house brain imaging core and research recruitment expertise, positions the NiAD study – and its participants – for long-term success.
“This study is an embodiment of the Wisconsin Idea,” says Christian, as the efforts of researchers involved in the NiAD study impact lives across the state and beyond.
Fundamental to these efforts is the proud participation of the individuals with Down syndrome who give so generously of their time to help further the NiAD study.
“When people ask Erin about her activities, she always mentions the NiAD study,” says Nancy Harvey, “It is a hallmark of her adulthood.”
Note: Featured image, top of page: Pat Thompson and her daughter, Erin Light.