Network-Level Mechanisms for Preclinical Alzheimer's Disease Development

Study Overview
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Brief Summary
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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
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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.

Official Title
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Network-Level Mechanisms for Preclinical Alzheimer's Disease Development

Conditions
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APOE 4

Intervention / Treatment
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* Drug: AGB101 220 mg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 75 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: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AGB101 220 mg, then Placebo<br>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. | Drug: AGB101 220 mg<br>* AGB101 oral dose of 220 mg/day capsule, given as once-daily dosing.<br>Other: Placebo<br>* Placebo, oral capsule given once-daily.<br>|
| Experimental: Placebo, then AGB101 220 mg<br>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. | Drug: AGB101 220 mg<br>* AGB101 oral dose of 220 mg/day capsule, given as once-daily dosing.<br>Other: Placebo<br>* Placebo, oral capsule given once-daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 2 weeks after treatment between AGB101 and Placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Placebo vs AGB101 2 weeks after treatment paired t-test | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adult, Healthy, Normal Memory, APOE 4, Brain, Magnetic Resonance Imaging, MRI, Alzheimer's disease, Hippocampus, Genetic testing, Dementia, AGB101