APOE 4
Conditions
Keywords
Healthy, Adult, Normal Memory, APOE 4, Brain, Magnetic Resonance Imaging, MRI, Alzheimer's disease, Hippocampus, Genetic testing, Dementia, AGB101
Brief summary
The purpose of this project is to test the hypothesis that AGB101 low dose levetiracetam extended release formulation can reduce abnormal hyperfunctional activity in the hippocampus in normal, healthy adults. The investigators will compare the functional connectivity results after taking AGB101 or placebo.
Detailed description
In this study the investigators want to find out whether the use of a perturbation, such as AGB101 low dose of levetiracetam extended release formulation, in healthy adults can reduce abnormal hippocampal network activity. The investigators also want to study whether this low dose of LEV can improve memory function. Generic levetiracetam is a type of drug called an anti-epileptic or anti-seizure medication. It is FDA approved worldwide for adults and children as young as one month with seizures. It is a generic drug used in long-term epilepsy treatment. It is relatively safe and has an acceptable side-effect profile. AGB101 has been developed as a novel extended release formulation of low dose levetiracetam (below clinically marketed doses for epilepsy) for slowing the progression of amnestic mild cognitive impairment. It is known that age and the APOE 4 gene are important risk factors for late-onset Alzheimer's disease. Further studies have shown that cognitively normal, older adults have more hyperfunctional brain network activity, increased alpha beta accumulation, decreased memory function, and decreased brain volume, which is consistent with Alzheimer's disease patterns.
Interventions
DRUGAGB101 220 mg
AGB101 oral dose of 220 mg/day capsule, given as once-daily dosing.
OTHERPlacebo
Placebo, oral capsule given once-daily.
Sponsors
National Institute on Aging (NIA)
Medical College of Wisconsin
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
This is a randomized, double-blind, placebo-controlled crossover study in which a low dose of AGB101 (220mg QD) or placebo will be administered to 50 healthy 55-75-year-old subjects, with the order of treatments counterbalanced in a within-subject crossover design.
Eligibility
Sex/Gender
ALL
Age
55 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Fluent in English * At least eight (8) years of education * Geriatric Depression Scale (GDS) (62) score \< 6 * Hachinski Ischemic Score ≤ 4 * Normal general cognitive function as well as 1) normal memory function, documented by MOCA score of 23 or greater, and a RBANS Delayed Memory Index score of 85 or greater.
Exclusion criteria
* Neurological disease, such as Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or a history of significant head trauma or known structural brain abnormalities * Major psychiatric disease or chronic unstable medical conditions * History of drug abuse * History of alcohol abuse (4 or greater drinks per day on average) * Unable to complete MRI scans (no Pacemaker/Defibrillator) * Known clinically significant abnormalities in B12 or thyroid function tests * End Stage Renal Disease (ESRD) * Hemodialysis (HD)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Functional Connectivity Strengths of Neural Networks | 2 weeks after treatment between AGB101 and Placebo | The seed-based functional connectivity strengths of the hippocampus network and the default mode network will be employed to measure the changes between AGB101 and Placebo perturbation. The functional connectivity strengths will be measured with the median of the Pearson cross-correlation coefficients over entire brain regions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rey Auditory Verbal Learning Test (AVLT), Delayed Recall Scaled Integer. The Higher is the Better | Placebo vs AGB101 2 weeks after treatment paired t-test | Rey Auditory Verbal Learning Test (AVLT), delayed recall Scaled integer will be employed to measure the episodic memory changes before and after AGB101 treatment. The AVLT score will be recorded as a standard score. The theoretical range: min 50, max 155, the higher the better. The higher the number is, the better the memory. It is an integer number. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AGB101 220 mg, Then Placebo AGB101 220 mg/day capsule, once daily dosing for 2 weeks. After a 4 week washout, to be followed by Placebo, given as a capsule, once daily dosing for 2 weeks.
AGB101 220 mg: AGB101 oral dose of 220 mg/day capsule, given as once-daily dosing.
Placebo: Placebo, oral capsule given once-daily. | 13 |
| Placebo, Then AGB101 220 mg Placebo, given as a capsule, once daily for 2 weeks. After a 4 week washout, to be followed by AGB101 220 mg/day capsule, once daily dosing for 2 weeks.
AGB101 220 mg: AGB101 oral dose of 220 mg/day capsule, given as once-daily dosing.
Placebo: Placebo, oral capsule given once-daily. | 12 |
| Total | 25 |
Baseline characteristics
| Characteristic | AGB101 220 mg, Then Placebo | Total | Placebo, Then AGB101 220 mg |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 16 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 9 Participants | 4 Participants |
| Age, Continuous | 66 years STANDARD_DEVIATION 4 | 66.2 years STANDARD_DEVIATION 4.5 | 67 years STANDARD_DEVIATION 5 |
| Apolipoprotein E (APOE) Status APOE e4 Carrier | 3 Participants | 5 Participants | 2 Participants |
| Apolipoprotein E (APOE) Status APOE e4 Non-Carrier | 10 Participants | 20 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 25 Participants | 12 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 13 Participants | 25 Participants | 12 Participants |
| Region of Enrollment United States | 13 participants | 26 participants | 12 participants |
| Sex: Female, Male Female | 9 Participants | 15 Participants | 6 Participants |
| Sex: Female, Male Male | 4 Participants | 10 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 26 |
| other Total, other adverse events | 6 / 26 | 3 / 26 |
| serious Total, serious adverse events | 0 / 26 | 0 / 26 |
Outcome results
Primary
Functional Connectivity Strengths of Neural Networks
The seed-based functional connectivity strengths of the hippocampus network and the default mode network will be employed to measure the changes between AGB101 and Placebo perturbation. The functional connectivity strengths will be measured with the median of the Pearson cross-correlation coefficients over entire brain regions.
Time frame: 2 weeks after treatment between AGB101 and Placebo
Population: A total of 25 subjects who were treated with AGB 101 and Placebo (order-balanced), then conducted a paired t-test to detect the treatment effect vs placebo.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| AGB101 220 mg | Functional Connectivity Strengths of Neural Networks | 0.233 Pearson coefficient | Standard Deviation 0.132 |
| Placebo | Functional Connectivity Strengths of Neural Networks | 0.318 Pearson coefficient | Standard Deviation 0.127 |
Comparison: The null hypothesis (H0) of this superiority trials asserts that there is no true difference in functional connectivity between the interventions of placebo and AGB101, and the alternative hypothesis (H1) states that there is a difference between the interventions of placebo and AGB101. A type I error is the error of rejecting H0 when it is actually true.p-value: 0.00756795% CI: [-0.0886, -0.0774]t-test, 2 sided
Secondary
Rey Auditory Verbal Learning Test (AVLT), Delayed Recall Scaled Integer. The Higher is the Better
Rey Auditory Verbal Learning Test (AVLT), delayed recall Scaled integer will be employed to measure the episodic memory changes before and after AGB101 treatment. The AVLT score will be recorded as a standard score. The theoretical range: min 50, max 155, the higher the better. The higher the number is, the better the memory. It is an integer number.
Time frame: Placebo vs AGB101 2 weeks after treatment paired t-test
Population: Measure RAVLT Delayed recall standard score memory test
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AGB101 220 mg | Rey Auditory Verbal Learning Test (AVLT), Delayed Recall Scaled Integer. The Higher is the Better | 108 score on a scale | Standard Deviation 17 |
| Placebo | Rey Auditory Verbal Learning Test (AVLT), Delayed Recall Scaled Integer. The Higher is the Better | 105 score on a scale | Standard Deviation 16 |
Comparison: The null hypothesis (H0) of this trial asserts that there is no true difference in AVLT between the interventions of placebo and AGB101, and the alternative hypothesis (H1) states that there is a difference between the interventions of placebo and AGB101. A type I error is the error of rejecting H0 when it is actually true.p-value: 0.90059395% CI: [1.72, 4.52]t-test, 2 sided