Levetiracetam for Persons at Risk for Alzheimer's Disease

Inclusion criteria

• 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.

Exclusion criteria

• History of hypersensitivity to levetiracetam or any other ingredients in the study drug or placebo.
• Significant neurological disease, including but not limited to:
• Any type of cognitive impairment
• History of transient ischemic attacks within 12 months of Screening
• History of seizures within 12 months of Screening
• Epilepsy
• Parkinson's disease
• Stroke (aside from subcortical lacunar infarcts)
• Multiple sclerosis
• Huntington's disease
• Normal pressure hydrocephalus
• Brain tumour (aside from benign tumours without mass effect, which are to be judged on a case-by-case basis)
• Subdural hematoma
• History of traumatic brain injury with persistent neurological deficits
• Known structural brain abnormalities
• Significant or unstable psychiatric disease, including but not limited to:
• Schizophrenia
• Bipolar disorder
• Major depression which is not controlled in the opinion of the investigator
• Score ≥10 on the Geriatric Depression Scale (GDS) at Screening
• Presence of active suicidal ideation within the last 3 months as indicated by "yes" response to Question 4 or 5 on the Suicidal Ideation portion of the C-SSRS at Screening
• Answered "yes" to any of the suicide-related behaviours within the last 3 months on the Suicidal Behavior portion of the C-SSRS
• Hospitalized or treated for suicidal behavior within 5 years of Screening
• Psychotic features, agitation, or behavioral problems within the last 3 months that could lead to difficulty complying with the protocol in the opinion of the investigator
• Known or suspected history of drug or alcohol abuse or dependence within 2 years before Screening).
• Significant or unstable systemic illness or medical condition that would in the investigator's judgment make the participant unsuitable for inclusion in the study, including but not limited to:
• History of malignancy within 3 years of screening (except of basal or squamous cell carcinoma of the skin)
• Moderate-severe chronic kidney disease, chronic obstructive pulmonary disease, or congestive heart failure
• Any of the following findings on a current (completed during screening) or previous brain MRI/CT scan:
• Severe white matter disease (Fazekas score66 = 3)
• Stroke involving a major vascular territory
• Subcortical lacunar infarcts \>1.5cm in diameter
• Encephalomalacia
• Vascular malformations that are at high risk of hemorrhage
• Infective lesions
• Space-occupying lesions
• Any other abnormality that would in the opinion of the investigator make the participant unsuitable for participation in the study
• Any contraindications to MRI or MEG (e.g., pacemaker, ferromagnetic metal implants, claustrophobia).
• Treatment with the following medications at time of screening or while in the study:
• Anticonvulsant medications (unless taken for a different indication than seizures)
• Methotrexate
• eGFR \<50ml/min/1.73m2 on screening bloodwork.
• QTc interval \>470 msec (males) or \>480 msec (females) on screening ECG.
• Clinically significant abnormal results on screening bloodwork that would in the opinion of the investigator make the participant unsuitable for inclusion in the study.