Network-Level Mechanisms for Preclinical Alzheimer's Disease Development

Phase 2

Completed

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.

Recruitment & Eligibility

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)

Arm && Interventions

Group	Intervention	Description
AGB101 220 mg, then Placebo	AGB101 220 mg	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.
Placebo, then AGB101 220 mg	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, then Placebo	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.
Placebo, then AGB101 220 mg	Placebo	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.