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 abnormal brain signaling in individuals who are at an increased risk for developing Alzheimer's Disease (AD). The study is looking for individuals who have a parent or sibling with Alzheimer's disease (dementia), and who have memory complaints but are currently performing within normal limits on cognitive testing. During the screening period, a functional MRI (fMRI) scan of the brain will identify those participants who have the abnormal 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.
• Has a friend or family member who has weekly contact with the participant and is willing to sign the study partner informed consent and complete study questionnaires.
• 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.
• Presence of subjective cognitive complaints, indicated by score \>7 on MyCog portion of the Subjective Cognitive Decline Questionnaire (SCD-Q) at Screening.
• Family history of Alzheimer's disease or of dementia suggestive of possible or probable Alzheimer's disease in a first-degree relative.
• Head circumference \<60cm.
• Within normal limits on all domains of the Toronto Cognitive Assessment (TorCA) at Screening or in the previous 6 months, with the exceptions noted below:
‣ A borderline score on the executive domain may be acceptable if in the opinion of the investigator it is solely attributable to the participant having ADHD.
⁃ A borderline score on the language domain may be acceptable if in the opinion of the investigator it is solely attributable to English not being the participant's primary language.
• Known to be within normal limits on the Montreal Cognitive Assessment (MoCA), Cogniciti Brain Health Assessment (BHA), or Toronto Cognitive Assessment (TorCA) in the previous 6 months, or within normal limits on the MoCA at Screening.
• Hippocampal hyperactivation, defined as activation \>1.5 SD above the mean, during the pattern separation task (PST) on BOLD fMRI.