Alzheimer Disease 2 Due to Apoe4 Isoform, Healthy Aging
Conditions
Brief summary
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
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.
Interventions
BEHAVIORALModerate Intensity Aerobic Exercise
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.
Sponsors
National Institute on Aging (NIA)
University of Kansas Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention 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)
Eligibility
Sex/Gender
ALL
Age
65 Years to 85 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cerebral Blood Flow Area Under Curve | ~24 minutes | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Vascular Endothelial Growth Factor Change | Pre-to-post intervention (~15 minutes) | Change in circulating Vascular Endothelial Growth Factor from pre-to-post exercise |
| Insulin-like Growth Factor-1 Change | Pre-to-post intervention (~15 minutes) | Change in circulating Insulin-like Growth Factor-1 from pre-to-post exercise |
| Brain Derived Neurotrophic Factor Change | Pre-to-post intervention (~15 minutes) | Change in circulating Brain Derived Neurotrophic Factor from pre-to-post exercise |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| APOE4 Carriers Participants with 1 or 2 copies of the APOE4 allele, the leading genetic risk factor for late-onset Alzheimer's dementia. | 23 |
| APOE4 Non-carriers Participants with 0 copies of the APOE4 allele, the leading genetic risk factor for late-onset Alzheimer's dementia. | 38 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | APOE4 Carriers | APOE4 Non-carriers | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 23 Participants | 38 Participants | 61 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 72.1 years STANDARD_DEVIATION 5.1 | 73.3 years STANDARD_DEVIATION 5.2 | 72.8 years STANDARD_DEVIATION 5.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 37 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 21 Participants | 33 Participants | 54 Participants |
| Region of Enrollment United States | 23 participants | 38 participants | 61 participants |
| Sex: Female, Male Female | 13 Participants | 28 Participants | 41 Participants |
| Sex: Female, Male Male | 10 Participants | 10 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 38 |
| other Total, other adverse events | 1 / 23 | 0 / 38 |
| serious Total, serious adverse events | 0 / 23 | 0 / 38 |
Outcome results
Primary
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
Time frame: ~24 minutes
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| APOE4 Carrier | Cerebral Blood Flow Area Under Curve | 715 mL/100g tissue | Standard Deviation 105 |
| APOE4 Non-carrier | Cerebral Blood Flow Area Under Curve | 751 mL/100g tissue | Standard Deviation 87.6 |
Secondary
Brain Derived Neurotrophic Factor Change
Change in circulating Brain Derived Neurotrophic Factor from pre-to-post exercise
Time frame: Pre-to-post intervention (~15 minutes)
Population: Blood collection failed on three individuals in the APOE4 carrier group. Outcome could not be analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| APOE4 Carrier | Brain Derived Neurotrophic Factor Change | -219 picograms per milliliter | Standard Deviation 641 |
| APOE4 Non-carrier | Brain Derived Neurotrophic Factor Change | 208 picograms per milliliter | Standard Deviation 706 |
Secondary
Insulin-like Growth Factor-1 Change
Change in circulating Insulin-like Growth Factor-1 from pre-to-post exercise
Time frame: Pre-to-post intervention (~15 minutes)
Population: Blood collection failed on three individuals in the APOE4 carrier group. Outcome could not be analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| APOE4 Carrier | Insulin-like Growth Factor-1 Change | 2.25 picograms per milliliter | Standard Deviation 22.8 |
| APOE4 Non-carrier | Insulin-like Growth Factor-1 Change | 5.7 picograms per milliliter | Standard Deviation 27.8 |
Secondary
Vascular Endothelial Growth Factor Change
Change in circulating Vascular Endothelial Growth Factor from pre-to-post exercise
Time frame: Pre-to-post intervention (~15 minutes)
Population: Blood collection failed on three individuals in the APOE4 carrier group. Outcome could not be analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| APOE4 Carrier | Vascular Endothelial Growth Factor Change | -1.01 picograms per milliliter | Standard Deviation 10.6 |
| APOE4 Non-carrier | Vascular Endothelial Growth Factor Change | 1.83 picograms per milliliter | Standard Deviation 11.1 |