Biomolecular Mediators of Aerobic Exercise effects on Cognitive and Brain Health in Remitted Late-life Depression

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

Abstract Late-life depression (LLD) is a leading risk factor for Alzheimer’s disease and related dementias (ADRD) and this risk persists even after depression is successfully treated 1-3. The neurotoxic effects of LLD that may elevate dementia risk include elevated prevalence of cerebral small vessel disease 4-6, hippocampal atrophy6, aberrant neurocircuitry within and across major brain networks (i.e., default mode network, executive control network)7. Current pharmacologic depression treatments do not target persistent cognitive impairments or key neurobiological abnormalities found in those with remitted LLD (rLLD), making it imperative to leverage non-pharmacologic approaches to prevent the clinical onset of dementia. Exercise is currently the most promising approach for preventing dementia 8-10, yet its efficacy to attenuate cognitive and brain health decline in those with rLLD, a group at high-risk for progression to dementia, has not been tested. Exercise training may be an optimal yet untapped intervention for potentially reversing the neurobiological hallmarks of LLD that exacerbate cognitive and functional decline in this high-risk group11. However, to better understand the value of exercise to attenuate cognitive impairment in rLLD, we must identify biomolecular targets of exercise that mediate its downstream systemic brain changes and cognitive benefits in those with rLLD. The goal of this proposal is to identify biomolecular targets within plasma extracellular vesicles that may mediate cognitive benefits of aerobic exercise in older adults with remitted late-life depression, by examining change in neurotrophic and inflammatory protein cargoes of acellular blood biomarkers called extracellular vesicles, and via transcriptomic profiling of plasma EVs. The proposed study leverages blood data from an ongoing K23 trial of 6 months of aerobic exercise training relative to a social engagement group targeting cognitive and brain health in adults aged 60+ years with rLLD. The proposed study complements the parent K23 trial by using innovative methods to identify biomolecular targets of aerobic exercise within plasma EVs, which can cross the blood-brain barrier to influence changes in markers of brain health and cognition. The results of this biomarker ancillary study, interpreted with the primary outcomes of the parent K23 trial, will enable a multi-level characterization (molecular, brain systems, behavioral) of whether and how aerobic exercise may attenuate cognitive impairment among those with rLLD, a group at high-risk for progression to dementia.