A Proof-of-Concept, Multicentre, Phase IIb, Randomized Double-Blind Crossover Trial of Levetiracetam vs Placebo for Hippocampal Hyperactivity in Cognitively Normal Individuals at Risk for Alzheimer's Disease
The goal of this clinical trial is to investigate whether very small doses of a drug called levetiracetam (LEV) may reduce elevated brain signaling in individuals who are at an increased risk for developing Alzheimer's Disease (AD). The study is looking for people who are currently performing within normal limits on memory testing but who have one or more of the following risk factors for developing AD: 1. People who feel like their memory is getting worse and who have a parent or sibling with Alzheimer's disease (dementia) 2. People with two copies of the APOE E4 gene 3. People who have tested positive for a biomarker of AD (e.g., blood p-tau test, brain amyloid PET scan) During the screening period, a functional MRI (fMRI) scan of the brain will identify those participants who have the increased brain signaling that the study is looking to treat. All participants will receive 4 weeks of treatment with LEV and 4 weeks of treatment with placebo (a sugar pill), but it will not be known what order they will receive them in. Participants will undergo cognitive testing, genetic testing, and several brain imaging scans as part of the study. This is a pilot study, meaning that it is being carried out for the first time in a small number of participants. If the results show that treatment with LEV appears to be more beneficial than placebo in normalizing brain signaling, a larger study may follow. This study is only being carried out in Toronto, Canada.
• Willing to undergo all study procedures and has signed the informed consent form
• Within normal limits on the Montreal Cognitive Assessment (MoCA) at Screening
• Age 55-85
• Female participants must be post-menopausal (amenorrheic for at least 12 consecutive months without other known or suspected cause) or surgically sterile (bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy)
• Sufficiently fluent in English to undergo cognitive testing, per investigator judgment
• Increased risk of Alzheimer's disease, as indicated by one or more of the following:
‣ Participant has subjective cognitive complaints AND a family history of Alzheimer's disease (or of dementia suggestive of possible or probable Alzheimer's disease) in a first-degree relative; and/or
⁃ Participant is known to be amyloid or tau positive; and/or
⁃ Participant is known to be an APOE e4/e4 homozygote
• Hippocampal hyperactivation, defined as activation \>1.5 MAD above the median, during the pattern separation task (PST) on BOLD fMRI.