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BackgroundPhysical exercise may support brain health and cognition over the course of typical aging. The goal of this nonrandomized clinical trial was to examine the effect of an acute bout of aerobic exercise on brain blood flow and blood neurotrophic factors associated with exercise response and brain function in older adults with and without possession of the APOE4 allele, a genetic risk factor for developing Alzheimer’s. We hypothesized that older adult APOE4 carriers would have lower cerebral blood flow regulation and would demonstrate blunted neurotrophic response to exercise compared to noncarriers.MethodsSixty-two older adults (73±5 years old, 41 female) consented to this prospectively enrolling clinical trial, utilizing a single arm, single visit, experimental design, with post-hoc assessment of difference in outcomes based on APOE4 carriership. All participants completed a single 15-minute bout of moderate-intensity aerobic exercise. The primary outcome measure was change in cortical gray matter cerebral blood flow in cortical gray matter measured by magnetic resonance imaging (MRI) arterial spin labeling (ASL), defined as the total perfusion (area under the curve, AUC) following exercise. Secondary outcomes were changes in blood neurotrophin concentrations of insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and brain derived neurotrophic factor (BDNF).ResultsGenotyping failed in one individual (n=23 APOE4 carriers and n=38 APOE4 non-carriers) and two participants could not complete primary outcome testing. Cerebral blood flow AUC increased immediately following exercise, regardless of APOE4 carrier status. In an exploratory regional analyses, we found that cerebral blood flow increased in hippocampal brain regions, while showing no change in cerebellar brain regions across both groups. Among high interindividual variability, there were no significant changes in any of the 3 neurotrophic factors for either group immediately following exercise.ConclusionsOur findings show that both APOE4 carriers and non-carriers show similar effects of exercise-induced increases in cerebral blood flow and neurotrophic response to acute aerobic exercise. Our results provide further evidence that acute exercise-induced increases in cerebral blood flow may be regional specific, and that exercise-induced neurotrophin release may show a differential effect in the aging cardiovascular system. Results from this study build upon previous research in younger adults by providing an initial characterization of the acute brain blood flow and neurotrophin responses to a bout of exercise in older adults with and without this known risk allele for cardiovascular disease and Alzheimer’s disease.Trials registrationDementia Risk and Dynamic Response to Exercise (DYNAMIC); Identifier: NCT04009629FundingThis study was funded by grants from the national institutes of health R21 AG061548, P30 AG072973 and P30 AG035982, and the Leo and Anne Albert Charitable Trust. The Hoglund Biomedical Imaging Center is supported by a generous gift from Forrest and Sally Hoglund and funding from the National Institutes of Health including S10 RR29577, and UL1 TR002366.

Exercise likely has numerous benefits for brain and cognition. However, those benefits and their causes remain imprecisely defined. If the brain does benefit from exercise it does so primarily through cumulative brief, “acute” exposures over a lifetime. The Dementia Risk and Dynamic Response to Exercise (DYNAMIC) clinical trial seeks to characterize the acute exercise response in cerebral perfusion, and circulating neurotrophic factors in older adults with and without the apolipoprotein e4 genotype (APOE4), the strongest genetic predictor of sporadic, late onset Alzheimer’s disease. DYNAMIC will enroll 60 older adults into a single moderate intensity bout of exercise intervention, measuring pre- and post-exercise cerebral blood flow (CBF) using arterial spin labeling, and neurotrophic factors. We expect that APOE4 carriers will have poor CBF regulation, i.e. slower return to baseline perfusion after exercise, and will demonstrate blunted neurotrophic response to exercise, with concentrations of neurotrophic factors positively correlating with CBF regulation. Preliminary findings on 7 older adults and 9 younger adults demonstrate that the experimental method can capture CBF and neurotrophic response over a time course. This methodology will provide important insight into acute exercise response and potential directions for clinical trial outcomes.ClinicalTrials.gov NCT04009629, Registered 05/07/2019.

Substantial evidence suggests physical exercise may sustain cognitive function and perhaps prevent Alzheimer’s Disease(1, 2). Current public health recommendations call for older adults to do at least 150 minutes a week of aerobic exercise (e.g. walking) and twice a week resistance exercise (e.g. weight lifting) for physical health. Yet, much remains unknown about how these exercise modalities support brain health independently or in combination. The COMbined Exercise Trial (COMET) is designed to test the combined and independent effects of aerobic and resistance training specifically focusing on exercise-related changes in 1) cognitive performance, 2) regional brain volume, 3) physical function, and 4) blood-based factors. To explore these questions, we will enroll 280 cognitively normal older adults, age 65–80 years, into a 52-week community-based exercise program. Participants will be randomized into one of four arms: 1) flexibility/toning- control 2) 150 minutes of aerobic exercise only, 3) progressive resistance training only, or 4) combined aerobic and progressive resistance training. Outcomes assessed include a comprehensive cognitive battery, blood biomarkers, brain magnetic resonance imaging, physiological biomarkers, cardiorespiratory fitness, physical function, and battery of psychosocial questionnaires is assessed at baseline, 6 and 12-months. COMET will provide rigorous randomized controlled trial data to understand the effects of the most common exercise modalities, and their combination (i.e., the standard public health recommendation), on brain health.