New Grant to Investigate Benefits of Exercise in People at Risk for Alzheimer's

Stephen Rao, PhD, of Cleveland Clinic's Lou Ruvo Center for Brain Health, has been awarded a five-year, $8.75 million grant from the National Institute on Aging, part of the National Institutes of Health, to better understand how exercise might modify genetic risk for Alzheimer's disease and reduce or prevent the cognitive decline commonly associated with the disease. The project, called Immunological Mechanisms Underlying Neuroprotection from Exercise in Alzheimer's Disease (IMMUNE-AD), will investigate the complex relationship between APOE4, the most important known genetic risk factor for Alzheimer's, innate immunity and exercise.

Research suggests APOE4—a variant of apolipoprotein E—contributes to the onset and progression of Alzheimer's disease in many ways, including through neuroinflammation caused by activation of the innate immune system.TREM2—another Alzheimer's-related gene—has been shown to be a key player in this pathway.

Much is still unknown about the relationship between APOE4, TREM2 and inflammation in the Alzheimer's disease process. What is widely accepted among researchers, however, is that physical activity has many anti-inflammatory benefits. With this award, Dr. Rao and his team will test whether physical activity can reduce inflammation and other pathological and clinical indicators of Alzheimer's in high-risk individuals who carry the APOE4 gene.

The researchers will follow 150 cognitively intact, healthy older adults both with and without APOE4 and track their level of physical activity. They will measure the effect physical activity has on various indicators of Alzheimer's disease pathology using functional and structural MRI, amyloid PET imaging, cerebrospinal fluid and blood biomarkers and memory and cognition testing. The team will then compare the effects observed in those with APOE4 versus those without APOE4 to determine whether physical activity confers more neuroprotective benefits in the genetically at-risk group.

IMMUNE-AD is uniquely innovative because a complementary study in mice, analogous to the human study, will simultaneously take place at a different laboratory. Bruce Lamb, PhD, Roberts Family Chair in Alzheimer's Disease Research at Indiana University School of Medicine, will lead a team of researchers to investigate the impact of voluntary wheel running and age in a mouse model of Alzheimer's disease. These preclinical studies will help elucidate the potential mechanisms—including the relationship between APOE4 and TREM2—linking inflammation and innate immunity, exercise and pathological and clinical indicators of Alzheimer's in genetically at-risk people.

"Alzheimer's is a devastating disease—one with currently no proven cures, disease-modifying treatments or means of prevention. If exercise—which is free and easy to access—shows positive effects in this study, and is validated by others in the field, it could help to significantly reduce the number of people who develop Alzheimer's," said Dr. Rao. "The concurrent work Dr. Lamb is doing is also important because it will help us understand the specific pathways and mechanisms that exercise may act on. We're especially eager to learn more about the relationship between APOE4 and TREM2, which is currently a hot topic in the field. If we understand the mechanisms at play, we can develop other interventions, such as drugs, that may induce similar positive effects."

Dr. Rao is the Ralph and Luci Schey Endowed Chair and Director of the Schey Center for Cognitive Neuroimaging at Cleveland Clinic.