Dementia Risk and Dynamic Response to Exercise

Study Overview
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Brief Summary
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Research suggests that physical exercise supports brain health and cognition as we age. The goal of this project is to examine the specific changes in brain blood flow and biological factors in the blood immediately after exercise in older adults who have the APOE4 gene, a genetic risk factor for developing Alzheimer's. Results from this study will help researchers and clinicians understand and measure changes in the body and brain as a function of exercise, and how those changes relate to Alzheimer's risk.

Detailed Description
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The brain and cardiovascular system share common risk factors for age-related diseases such as hypertension, hypercholesterolemia, and genetics (e.g. APOE4). Because of this link, much work has focused on the role of cerebrovascular health in reducing dementia risk. Regular aerobic exercise has well-established benefits for cardiovascular health and has been repeatedly linked to better cognition, brain health, and lower risk of Alzheimer's disease (AD). Despite strong evidence for sustained cognitive and brain outcomes, the mechanisms relating aerobic exercise with brain health and cognition remain imprecisely defined. Amongst many potential mechanisms, cerebral blood flow (CBF) and blood-based biomarkers, such as neurotrophins, are promising targets for their shared association to brain and cardiovascular health. Prior investigations have largely attempted to measure change in these mechanisms under resting conditions after an extended exercise intervention with mixed and conflicting results. Further, studies have often not accounted for genetic differences that may blunt the effect of exercise. Unlike prior work, our innovative approach is to begin by characterizing the dynamic changes that result from an acute exercise challenge. A single bout of aerobic exercise temporarily increases CBF and prompts neurotrophin release. These transient changes ultimately drive long-term physiologic adaptation to exercise. Therefore, the study team will characterize the dynamic response to an acute, standardized bout of aerobic exercise in a group of nondemented older adults, comparing those who do and do not carry the APOE4 allele. The first aim will test if CBF response to an acute exercise challenge is blunted in APOE4 carriers. The second aim will similarly test the acute exercise response of blood-based biomarkers such as brain derived neurotrophic factor, insulin-like growth factor, and vascular endothelial growth factor in APOE4 carriers versus non-carriers. The study team expects that more accurately understanding the acute effects will provide valuable insight into how aerobic exercise supports cognitive function and brain health. Armed with this knowledge the field can optimize biomarker measurement for future exercise intervention randomized controlled trials, informing our long-term goal of identifying precision exercise prescription for AD prevention.

Official Title
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Dementia Risk and Dynamic Response to Exercise

Conditions
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Alzheimer Disease 2 Due to Apoe4 Isoform, Healthy Aging

Intervention / Treatment
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* Behavioral: Moderate Intensity Aerobic Exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 65-85 English speaking Normal or corrected hearing or vision, Without activity restrictions. Exclusion Criteria: Clinically significant cognitive or psychiatric illness, Anti- coagulant use, High cardiovascular risk without physician clearance for exercise, Exercise-limiting musculoskeletal condition, MRI contraindications

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Single visit, case-control study identified as an intervention due to the use of a single bout of aerobic exercise under NIH rules (grants.nih.gov/policy/clinical-trials/definition.htm)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exercise - apolipoprotein e4 carrier<br>A single 15 minute bout of moderate intensity aerobic exercise for individuals with 1 or 2 copies of the APOE4 allele, the leading genetic risk factor for late-onset Alzheimer's dementia. | Behavioral: Moderate Intensity Aerobic Exercise<br>* Participants will exercise for 15 minutes in a moderate age-predicted heart rate range. The study team will employ an exercise device such as a treadmill, cycle, or recumbent stepper to maintain control over workload.<br>|
| Experimental: Exercise - apolipoprotein e4 non-carrier<br>A single 15 minute bout of moderate intensity aerobic exercise for individuals with 0 copies of the APOE4 allele, the leading genetic risk factor for late-onset Alzheimer's dementia. | Behavioral: Moderate Intensity Aerobic Exercise<br>* Participants will exercise for 15 minutes in a moderate age-predicted heart rate range. The study team will employ an exercise device such as a treadmill, cycle, or recumbent stepper to maintain control over workload.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cerebral Blood Flow Area Under Curve | Cumulative cerebral blood flow measured by Arterial Spin Labeling MRI. The standard arterial spin labeling unit of measure is average milliliters per 100 grams of tissue per minute (mL/100g tissue/minute). For the present analysis, we summed perfusion over the entire acquisition period, 23.2 minutes, rather than averaging. Therefore the units are milliliters per 100 grams of tissue |  24 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin-like Growth Factor-1 Change | Change in circulating Insulin-like Growth Factor-1 from pre-to-post exercise | Pre-to-post intervention ( 15 minutes) | 
| Vascular Endothelial Growth Factor Change | Change in circulating Vascular Endothelial Growth Factor from pre-to-post exercise | Pre-to-post intervention ( 15 minutes) | 
| Brain Derived Neurotrophic Factor Change | Change in circulating Brain Derived Neurotrophic Factor from pre-to-post exercise | Pre-to-post intervention ( 15 minutes) |