The UW ADRC celebrated its 30th anniversary with a day filled with talks about recent advances in precision medicine therapeutics, diagnostic tools, and neurogenetics.
The UW Alzheimer’s Disease Research Center (ADRC) is one of the country’s top such NIH-sponsored centers for Alzheimer research, known for strengths in genetic risk factors, biomarkers, and experimental therapeutics. In honor of its 30th anniversary, the ADRC’s researchers, staff, and community partners recently gathered at the Seattle’s Talaris Conference Center in celebration. The daylong event featured talks by the center’s leading minds and rising stars about innovative efforts to halt neurodegenerative disease in its tracks.
“Today’s talks wouldn’t have happened 10 years ago. It would have been unheard of 20 years ago,” said Tom Montine, Professor of Pathology, who has served as the Director of the UW ADRC since 2013. “There’s really been a sea change in this field.”
This sea change has arrived in a wave over the last decade, propelled by the development of tools to detect the brain’s level of amyloid plaques, one of the major pathological culprits in Alzheimer disease. Researchers have found that amyloid starts to accumulate in the brain 10 to 25 years before tangles of tau protein and cognitive impairment occur, much like cholesterol plaques slowly build up in arteries decades before causing heart attacks or strokes. The conclusion: catching the disease early is key.
In a decision that embraces the future, the UW ADRC recently shifted its focus to precision medicine, which seeks ways to tailor treatment plans to an individual’s unique profile of risk. On that front, Suman Jayadev, Assistant Professor of Neurology, gave an update on several of the UW ADRC's upcoming or enrolling clinical trials of new antibodies against amyloid, including the A4 Study, DIAN-tu, and Biogen's EMERGE. These trials are, or will be, enrolling people with confirmed amyloid build-up in their brains or individuals at a high genetic risk of Alzheimer disease. Therapeutics, Jayadev emphasized, may be more effective if given to the patients in the earliest stages of neurodegeneration.
Aiming for Precision
With clinical trials for ever-earlier stage disease going full steam ahead, the question of how to measure a drug’s success—and quickly—looms large. Even with the field’s success in establishing spinal fluid, imaging, and cognitive biomarkers of Alzheimer disease, a difficulty remains: how do we detect a medication’s efficacy in people who show minor or no functional impairment? Afterall, the field can’t wait a decade to find out if a medication prevented the disease. Elizabeth Buffalo, Associate Professor in the Department of Physiology and Biophysics, suggested an elegant solution.
Buffalo thinks that eye-tracking technology could provide a measure of subtle impairment or improvement of memory, even before a person experiences changes in real life. From lab experiments with monkeys trained to play memory-intensive videogames, her team has learned that a brain area called the hippocampus plays a key role in guiding the eyes around a scene, according to recently encoded memories. Because the hippocampus gets damaged in early Alzheimer disease in humans, Buffalo thinks that signs of developing disease may first appear in eye movements, which are easy to assess in a clinic setting.
On the subject of biomarkers, Tom Grabowski, Professor of Radiology and Neurology, described work in the UW’s Integrated Brain Imaging Center to better understand how the brain’s electrical networks change in preclinical Alzheimer disease. Data from MRI scans, pooled from groups of people, clearly show that this disease weakens the brain's ‘default mode network’ before symptoms onset. But, does a measure of network connectivity tell us anything useful about the disease status of an individual patient? Grabowski’s team is working on new quantitative methods to determine whether brain network changes can be used to predict Alzheimer-related decline, with enough reliability for clinical use.
Taking the afternoon in a new direction, two researchers spoke about designing and creating small molecules capable of fighting amyloid in the brain. While Vikram Mulligan, a postdoctoral associate in the UW Institute for Protein Design, suggested ways to design artificial proteins that can bind to amyloid, Valerie Daggett, Professor of Bioengineering, described how her lab used computer simulations to model the signature shape of amyloid protein that makes it toxic. Her team is now synthesizing and testing compounds that clamp onto the structure of toxic amyloid, in hopes of silencing the disease.
A Tradition of Innovation and Collaboration
Thinking outside of the box, Matt Kaeberlein, Associate Professor of Pathology and “biogerontologist,” pointed out that aging is the biggest risk factor for Alzheimer's. He's convinced that interventions to slow aging will have a greater impact on quality of life than just disease-focused research. Thus, he studies two important signaling pathways in the nervous system that help the body to deal with amyloid during the aging process. Regulating the activity of these pathways, he suggested, could potentially inform the development of anti-aging measures, with relevance to Alzheimer disease therapies.
In closing, the ADRC’s founding director, George Martin, Professor Emeritus of Pathology, reminisced about the center’s origins back in 1983 when many scoffed at the idea of a “gene for Alzheimer’s.” But with the help of Thomas Bird, now Professor Emeritus of Neurology, who had collected pedigrees of families showing strong patterns of inheritance of Alzheimer disease, Martin soon won NIH funding to open an ADRC at the UW with a focus on neurogenetics. In quick succession, UW researchers discovered three major gene mutations that cause familial forms of Alzheimer disease and frontotemporal spectrum disorders. They created the first presenilin 1 mouse model. “We were off to the races then,” Martin said, “and we haven’t stopped since.”
The event was organized by Pema Richeson, Director of Research Operations for the ADRC.