In the United States today, nearly six million people are living with Alzheimer’s disease, already the sixth leading cause of death costing an estimated $290 billion a year from our economy. The prevalence of Alzheimer’s disease is expected to continue to grow and there is no effective treatment for this memory-robbing disorder; clinical trials to date have been largely disappointing. A better understanding of the biological drivers of Alzheimer’s disease are needed to develop new more effective therapeutic strategies.
Scientists at the Institute for Stem Cell and Regenerative Medicine (ISCRM) are using stem cells to model the early biological drivers of Alzheimer’s disease and to identify potential therapeutic targets. While effective therapies are elusive, there is reason for optimism.
Over the last several years, ISCRM faculty member Jessica Young, PhD, Assistant Professor of Laboratory Medicine and Pathology, has partnered with leaders of the UW Alzheimer’s Disease Research Center and the Kaiser Adult Changes in Thought study (ACT), sharing troves of data and human tissue and generating cell lines for the study of Alzheimer’s disease and related dementias.
Collectively, this research community is generating a wealth of genetic and pathological information about the human brain and the nature of neurodegenerative diseases. Over the last three decades, the ACT study has enrolled more than 5,800 older patients, who are then tracked as they age, revealing insights about brain health and about risk and resilience factors related to neurodegenerative diseases like Alzheimer’s.
Grant Will Fund Six Cores and Three Projects
Recently, a multifaceted research effort led by ACT received a major boost in the form of a $56 million grant from the National Institute on Aging. The Co-principal investigators of the study are Dr. Paul Crane, professor of medicine at the UW School of Medicine, Dr. Eric Larson, senior investigator at Kaiser Permanente Washington Health Research Institute, who founded the ACT study in Seattle in 1994, and Andrea LaCroix, professor of and chief of epidemiology at the University of California San Diego.
The five-year grant will fund multiple cores designed to support Alzheimer’s research broadly in addition to three interrelated projects. One effort will focus on the relationship between physical activity, sleep, and dementia. Another will compare patterns in different types of Alzheimer’s based on neuroimaging and neuropathology findings. A third project, led by Dr. Shelly Gray from the School of Pharmacy, and Jessica Young from ISCRM, will study how commonly prescribed classes of medications relate to the incidence of dementia.
Prescription Drugs and Alzheimer’s Risk
In this unique collaboration, Gray will use epidemiological models to characterize how common medications prescribed in older adults are associated with dementia. In conjunction, Young will use stem cells derived from deceased ACT study participants to understand the cellular mechanisms of how these drugs could impair neuronal function that would lead to neurodegeneration. The first class of drugs are known as anticholinergics, which include anti-depressants, anti-histamines, and medications used to treat bladder problems. The second class of drugs are antihypertensives, which are used to treat high blood pressure.
“Different classes of medications that people take as they get older have well-known effects on their symptoms,” says Young. “But the mechanism by which the drugs work may be associated with higher or lower risk of dementia. One important caveat is that sometimes we won’t know if it is the underlying condition that the drug is used for that leads to increased dementia risk or if it is due to the direct action of the drug. By treating stem cells-derived neurons from this clinically characterized population, we can start to tease this out.”
In her lab, Young will treat 14 cell lines of stem cells stratified by Alzheimer’s risk (based on patient genetics) with various classes of these drugs and test for factors associated with neurodegeneration, such as amyloid beta and tau levels, neurotoxicity, synaptic activity, and the action of the medications on cellular receptors. The cell lines will also contribute to a bank of Alzheimer’s disease and control human induced pluripotent stem cell lines that the Young lab is establishing, and which will be available for future studies and to the larger research community.
Finally, this investigation will leverage several ACT cores funded by the NIH grant. This includes the Neuropathology Core, headed by ISCRM affiliate faculty member C. Dirk Keene, PhD, a professor of Lab Medicine and Pathology and the Neuroimaging Core, led by Dr. Christine McDonald, a professor Neurological Surgery. Gray will link her epidemiological data derived from Life Course and Clinical Cores with neuropathological and imaging studies on postmortem brains of the ACT subjects, including the studies that also incorporate stem cell lines.
Young emphasizes the significance of the research she and Gray are leading being connected to a longitudinal clinical study with so many resources. “This is the first study we know of to combine cellular-level mechanistic experiments with organ-level analysis and a broad-based population study. That means we can imagine producing findings that could inform how physicians prescribe medications in older adults, based on risk for dementia.”