Genetic Risk for Alzheimer's Disease
Conditions
Brief summary
This study examines the sensitivity of functional MRI to detect brain changes caused by donepezil HCL (a cholinesterase inhibitor) in healthy older adults at genetic risk for Alzheimer's Disease.
Detailed description
This 24-week study will examine the sensitivity of functional MRI to detect brain changes caused by donepezil HCL (a cholinesterase inhibitor) in healthy older adults at genetic risk for Alzheimer's Disease. Participants with a family history of Alzheimer's Disease will be eligible for this study. Participants without a family history of AD will also be enrolled to serve as a control group.
Interventions
DRUGdonepezil HCL
DRUGPlacebo
Sponsors
National Institute on Aging (NIA)
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Normal general cognitive function * High Risk Group Only: Family history (1st degree relative) of AD * Low Risk Group Only: No family history (1st or 2nd degree relative) of AD * Visual and auditory acuity adequate for neuropsychological testing
Exclusion criteria
* Current or past history of * neurological illnesses/conditions * head trauma with significant loss of consciousness * medical illnesses/conditions that may affect brain function * severe psychiatric disorder * substance abuse * unstable or severe cardiovascular disease or asthmatic condition * history of stroke or transient ischemic attack
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in BOLD Response From Baseline to 24 Weeks During Functional Magnetic Resonance Imaging - Left Posterior Cingulate BOLD Signal at 24 Weeks, Adjusting for Baseline Left Posterior Cingulate BOLD | Baseline and 24 Weeks | Changes from baseline to 24 weeks follow-up fMRI - Left posterior cingulate BOLD signal at 24 weeks, adjusting for baseline left posterior cingulate BOLD signal. |
| Left Hippocampus BOLD Signal at 24 Weeks, Adjusted for Baseline Left Hippocampus BOLD Signal | Baseline and 24 Weeks | Left hippocampus BOLD signal at 24 weeks, adjusting for baseline left hippocampus BOLD signal. |
| Right Hippocampus BOLD Signal at 24 Weeks, Adjusted for Baseline Left Hippocampus BOLD Signal | Baseline and 24 Weeks | Right hippocampus BOLD signal at 24 weeks, adjusting for baseline left hippocampus BOLD signal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Brief Visuospatial Memory Test (BVMT) Learning Scores at 24 Weeks, Adjusted for Baseline BVMT Learning Scores | Baseline and 24 Weeks | Brief Visuospatial Memory Test (BVMT) learning scores at 24 weeks, adjusted for baseline BVMT learning scores. The BVMT-R total scare has a minimum of 0 and a maximum of 36 correct items (12 per trial x 3 trials). A higher score means better outcomes. |
| Neuropsychological Testing Scores - Rey Auditory Verbal Learning Test (RAVLT) Sum of Trials (1-5) at 24 Weeks, Adjusted for Baseline RAVLT Score | Baseline and 24 Weeks | Rey Auditory Verbal Learning Test (RAVLT) (Sum of Trials 1-5) , adjusting for baseline RAVLT (Sum of Trials 1-5) score. The RAVLT total score has a minimum of 0 and a maximum of 75 correct items (15 per trial x 5 trials). A higher score means better outcomes. |
| Processing Speed Test (PST) at 24 Weeks, Adjusted for Baseline PST Scores | Baseline and 24 Weeks | Processing speed test (PST) at 24 weeks, adjusting for baseline PST scores. The PST has a minimum of 0 and no upper limit/maximum since it is the number of correct items in 2 minutes. A higher score means better outcome. |
| Left Hippocampus Volume (MRI) at 24 Weeks, Adjusted for Baseline Left Hippocampus Volume | Baseline and 24 Weeks | Left hippocampus volume (MRI) at 24 weeks, adjusting for baseline left hippocampus volume |
| Right Hippocampus Volume (MRI) at 24 Weeks, Adjusted for Baseline Right Hippocampus Volume | Baseline and 24 Weeks | Right hippocampus volume (MRI) at 24 weeks, adjusting for baseline right hippocampus volume |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Donepezil HCL Participants will receive 5mg of donepezil HCL for 4 weeks and then 10mg of donepezil HCL for 20 weeks.
donepezil HCL | 22 |
| Placebo Participants will receive placebo for 24 weeks.
Placebo | 26 |
| Control Group Participants without a family history of AD will undergo the study evaluations but will not receive any study drug | 29 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Drug Non-compliance | 0 | 2 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Not analyzed due to anatomical abnormalities | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 0 | 1 |
Baseline characteristics
| Characteristic | Donepezil HCL | Placebo | Control Group | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 16 Participants | 17 Participants | 18 Participants | 51 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 9 Participants | 11 Participants | 26 Participants |
| Age, Continuous | 66.4 years STANDARD_DEVIATION 4.1 | 66.1 years STANDARD_DEVIATION 3.8 | 67.7 years STANDARD_DEVIATION 4.7 | 66.8 years STANDARD_DEVIATION 4.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 26 Participants | 28 Participants | 76 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 21 Participants | 21 Participants | 27 Participants | 69 Participants |
| Region of Enrollment United States | 22 participants | 26 participants | 29 participants | 77 participants |
| Sex: Female, Male Female | 16 Participants | 14 Participants | 18 Participants | 48 Participants |
| Sex: Female, Male Male | 6 Participants | 12 Participants | 11 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 29 | 0 / 32 |
| other Total, other adverse events | 20 / 28 | 13 / 29 | 0 / 32 |
| serious Total, serious adverse events | 0 / 28 | 0 / 29 | 0 / 32 |
Outcome results
Primary
Change in BOLD Response From Baseline to 24 Weeks During Functional Magnetic Resonance Imaging - Left Posterior Cingulate BOLD Signal at 24 Weeks, Adjusting for Baseline Left Posterior Cingulate BOLD
Changes from baseline to 24 weeks follow-up fMRI - Left posterior cingulate BOLD signal at 24 weeks, adjusting for baseline left posterior cingulate BOLD signal.
Time frame: Baseline and 24 Weeks
Population: Please note that the fMRI result of one subject was collected but could not be processed due to data quality issues. Hence, only 21 subjects in Donepezil HCL arm were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil HCL | Change in BOLD Response From Baseline to 24 Weeks During Functional Magnetic Resonance Imaging - Left Posterior Cingulate BOLD Signal at 24 Weeks, Adjusting for Baseline Left Posterior Cingulate BOLD | 44.68 100 * % Signal Change | Standard Deviation 33.86 |
| Placebo | Change in BOLD Response From Baseline to 24 Weeks During Functional Magnetic Resonance Imaging - Left Posterior Cingulate BOLD Signal at 24 Weeks, Adjusting for Baseline Left Posterior Cingulate BOLD | 50.61 100 * % Signal Change | Standard Deviation 23.46 |
| Control Group | Change in BOLD Response From Baseline to 24 Weeks During Functional Magnetic Resonance Imaging - Left Posterior Cingulate BOLD Signal at 24 Weeks, Adjusting for Baseline Left Posterior Cingulate BOLD | 45.57 100 * % Signal Change | Standard Deviation 25.24 |
Comparison: We are reporting the difference in mean between the Donepezil HCL and Placebo groups.p-value: 0.27395% CI: [-23.12, 6.63]ANCOVA
Primary
Left Hippocampus BOLD Signal at 24 Weeks, Adjusted for Baseline Left Hippocampus BOLD Signal
Left hippocampus BOLD signal at 24 weeks, adjusting for baseline left hippocampus BOLD signal.
Time frame: Baseline and 24 Weeks
Population: Please note that the fMRI result of one subject was collected but could not be processed due to data quality issues. Hence, only 21 subjects in Donepezil HCL arm were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil HCL | Left Hippocampus BOLD Signal at 24 Weeks, Adjusted for Baseline Left Hippocampus BOLD Signal | 19.91 100 * % Signal Change | Standard Deviation 8.69 |
| Placebo | Left Hippocampus BOLD Signal at 24 Weeks, Adjusted for Baseline Left Hippocampus BOLD Signal | 32.31 100 * % Signal Change | Standard Deviation 16.62 |
| Control Group | Left Hippocampus BOLD Signal at 24 Weeks, Adjusted for Baseline Left Hippocampus BOLD Signal | 19.38 100 * % Signal Change | Standard Deviation 14.02 |
Comparison: We are reporting the difference in mean between the Donepezil HCL and Placebo groups.p-value: 0.00195% CI: [-21.09, -5.73]ANCOVA
Primary
Right Hippocampus BOLD Signal at 24 Weeks, Adjusted for Baseline Left Hippocampus BOLD Signal
Right hippocampus BOLD signal at 24 weeks, adjusting for baseline left hippocampus BOLD signal.
Time frame: Baseline and 24 Weeks
Population: Please note that the fMRI result of one subject was collected but could not be processed due to data quality issues. Hence, only 21 subjects in Donepezil HCL arm were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil HCL | Right Hippocampus BOLD Signal at 24 Weeks, Adjusted for Baseline Left Hippocampus BOLD Signal | 24.9 100 * % Signal Change | Standard Deviation 18.72 |
| Placebo | Right Hippocampus BOLD Signal at 24 Weeks, Adjusted for Baseline Left Hippocampus BOLD Signal | 32.78 100 * % Signal Change | Standard Deviation 20.57 |
| Control Group | Right Hippocampus BOLD Signal at 24 Weeks, Adjusted for Baseline Left Hippocampus BOLD Signal | 26.73 100 * % Signal Change | Standard Deviation 18.09 |
Comparison: We are reporting the difference in mean between the Donepezil HCL and Placebo groups.p-value: 0.11595% CI: [-19.33, 2.14]ANCOVA
Secondary
Brief Visuospatial Memory Test (BVMT) Learning Scores at 24 Weeks, Adjusted for Baseline BVMT Learning Scores
Brief Visuospatial Memory Test (BVMT) learning scores at 24 weeks, adjusted for baseline BVMT learning scores. The BVMT-R total scare has a minimum of 0 and a maximum of 36 correct items (12 per trial x 3 trials). A higher score means better outcomes.
Time frame: Baseline and 24 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil HCL | Brief Visuospatial Memory Test (BVMT) Learning Scores at 24 Weeks, Adjusted for Baseline BVMT Learning Scores | 21.41 Total number of correct items | Standard Deviation 6.17 |
| Placebo | Brief Visuospatial Memory Test (BVMT) Learning Scores at 24 Weeks, Adjusted for Baseline BVMT Learning Scores | 23.58 Total number of correct items | Standard Deviation 5.84 |
| Control Group | Brief Visuospatial Memory Test (BVMT) Learning Scores at 24 Weeks, Adjusted for Baseline BVMT Learning Scores | 23.28 Total number of correct items | Standard Deviation 5.07 |
Comparison: We are reporting the difference in mean between the Donepezil HCL and Placebo groups.p-value: 0.00595% CI: [-5.65, -1.04]ANCOVA
Secondary
Left Hippocampus Volume (MRI) at 24 Weeks, Adjusted for Baseline Left Hippocampus Volume
Left hippocampus volume (MRI) at 24 weeks, adjusting for baseline left hippocampus volume
Time frame: Baseline and 24 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil HCL | Left Hippocampus Volume (MRI) at 24 Weeks, Adjusted for Baseline Left Hippocampus Volume | 3309.51 mm^3 | Standard Deviation 300.08 |
| Placebo | Left Hippocampus Volume (MRI) at 24 Weeks, Adjusted for Baseline Left Hippocampus Volume | 3289.36 mm^3 | Standard Deviation 260.1 |
| Control Group | Left Hippocampus Volume (MRI) at 24 Weeks, Adjusted for Baseline Left Hippocampus Volume | 3296.68 mm^3 | Standard Deviation 312.89 |
Comparison: We are reporting the difference in mean between the Donepezil HCL and Placebo groups.p-value: 0.00395% CI: [16.14, 76.53]ANCOVA
Secondary
Neuropsychological Testing Scores - Rey Auditory Verbal Learning Test (RAVLT) Sum of Trials (1-5) at 24 Weeks, Adjusted for Baseline RAVLT Score
Rey Auditory Verbal Learning Test (RAVLT) (Sum of Trials 1-5) , adjusting for baseline RAVLT (Sum of Trials 1-5) score. The RAVLT total score has a minimum of 0 and a maximum of 75 correct items (15 per trial x 5 trials). A higher score means better outcomes.
Time frame: Baseline and 24 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil HCL | Neuropsychological Testing Scores - Rey Auditory Verbal Learning Test (RAVLT) Sum of Trials (1-5) at 24 Weeks, Adjusted for Baseline RAVLT Score | 52.86 Total number of correct items | Standard Deviation 7.76 |
| Placebo | Neuropsychological Testing Scores - Rey Auditory Verbal Learning Test (RAVLT) Sum of Trials (1-5) at 24 Weeks, Adjusted for Baseline RAVLT Score | 53.58 Total number of correct items | Standard Deviation 9.71 |
| Control Group | Neuropsychological Testing Scores - Rey Auditory Verbal Learning Test (RAVLT) Sum of Trials (1-5) at 24 Weeks, Adjusted for Baseline RAVLT Score | 51.41 Total number of correct items | Standard Deviation 7.4 |
Comparison: We are reporting the difference in mean between the Donepezil HCL and Placebo groups.p-value: 0.94195% CI: [-3.94, 4.25]ANCOVA
Secondary
Processing Speed Test (PST) at 24 Weeks, Adjusted for Baseline PST Scores
Processing speed test (PST) at 24 weeks, adjusting for baseline PST scores. The PST has a minimum of 0 and no upper limit/maximum since it is the number of correct items in 2 minutes. A higher score means better outcome.
Time frame: Baseline and 24 Weeks
Population: Please note only those participants who had complete PST data were included in the analysis, which are 12 participants in Donepezil HCL group, 15 participants in Placebo group, and 22 participants in Control group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil HCL | Processing Speed Test (PST) at 24 Weeks, Adjusted for Baseline PST Scores | 44.17 Total number of correct items | Standard Deviation 7.96 |
| Placebo | Processing Speed Test (PST) at 24 Weeks, Adjusted for Baseline PST Scores | 49.8 Total number of correct items | Standard Deviation 4.69 |
| Control Group | Processing Speed Test (PST) at 24 Weeks, Adjusted for Baseline PST Scores | 47.73 Total number of correct items | Standard Deviation 4.87 |
Comparison: We are reporting the difference in mean between the Donepezil HCL and Placebo groups.p-value: 0.01195% CI: [-7.58, -1.02]ANCOVA
Secondary
Right Hippocampus Volume (MRI) at 24 Weeks, Adjusted for Baseline Right Hippocampus Volume
Right hippocampus volume (MRI) at 24 weeks, adjusting for baseline right hippocampus volume
Time frame: Baseline and 24 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil HCL | Right Hippocampus Volume (MRI) at 24 Weeks, Adjusted for Baseline Right Hippocampus Volume | 1810.88 mm^3 | Standard Deviation 231.08 |
| Placebo | Right Hippocampus Volume (MRI) at 24 Weeks, Adjusted for Baseline Right Hippocampus Volume | 1756.92 mm^3 | Standard Deviation 183.39 |
| Control Group | Right Hippocampus Volume (MRI) at 24 Weeks, Adjusted for Baseline Right Hippocampus Volume | 3363.62 mm^3 | Standard Deviation 214.59 |
Comparison: We are reporting the difference in mean between the Donepezil HCL and Placebo groups.p-value: <0.00195% CI: [35.25, 87.46]ANCOVA