Exercise to Curb Alzheimer’s Risk? NIA-Funded Clinical Study to Explore Its Potential

A Cleveland Clinic investigator has been awarded a five-year, $8.75 million National Institute on Aging (NIA) grant to study how exercise might modify the genetic risk for Alzheimer’s disease (AD) and reduce or prevent AD-associated cognitive decline.

The award is going to Stephen M. Rao, PhD, Ralph and Luci Schey Endowed Chair, Cleveland Clinic Lou Ruvo Center for Brain Health, for an interdisciplinary project he is leading known as IMMUNE-AD (Immunological Mechanisms Underlying Neuroprotection from Exercise in Alzheimer’s Disease). The project will examine mechanisms by which physical activity counteracts the negative inflammatory effects of the APOE ε4 allele (APOE4), a genetic risk factor for late-onset AD.

Exploring links between exercise, inflammation and genetic risk

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

Much remains unknown about the relationship between APOE4, TREM2 and inflammation in the AD process, but physical activity is widely recognized to have multiple anti-inflammatory benefits. Dr. Rao’s research team will use the NIA award to evaluate whether physical activity can reduce inflammation and other pathological and clinical indicators of AD in high-risk individuals who carry the APOE4 gene.

They will do so in a 24-month longitudinal study tracking the physical activity levels of 150 cognitively intact healthy older adults with and without APOE4. Participants will be assessed for the effect that physical activity has on various indicators of AD pathology, including functional and structural MRI, amyloid PET imaging, analysis of CSF and blood biomarkers, and tests of memory and cognition. Effects will be compared between those with and without APOE4 to determine whether physical activity confers greater neuroprotective benefit in the genetically at-risk group.

“If exercise shows positive effects in this study and this is validated by others in the field, it could help significantly reduce the number of people who develop Alzheimer’s,” says Dr. Rao, Director of Cleveland Clinic’s Schey Center for Cognitive Imaging. “This would be particularly helpful since exercise is free and easy to access.”

Parallel studies in mouse models

Complementary research in mice, led by Bruce Lamb, PhD, of Indiana University School of Medicine (and formerly with Cleveland Clinic’s Department of Neurosciences) will investigate the impact of voluntary wheel running and age in novel transgenic mouse models of AD. This preclinical work will aim to elucidate the potential mechanisms — including any relationship between APOE4 and TREM2 — linking inflammation and innate immunity, exercise, and pathological and clinical indicators of AD in genetically at-risk individuals.

“This concurrent work by Dr. Lamb is important because it will help us understand the specific pathways and mechanisms that exercise may act on,” Dr. Rao explains. “We’re especially eager to learn more about the relationship between APOE4 and TREM2, which is a hot topic in the field. If we understand the mechanisms at play, we can develop other interventions, such as medications, that may induce similar positive effects.”