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.

People who have a family history of AD or dementia and subjective cognitive complaints (have memory complaints but are normal on memory testing) have been shown to have a somewhat increased risk of developing AD, compared to people without these risk factors. Changes in the brain associated with AD begin years before people start showing symptoms. One of these early changes involves an abnormal increase in brain signaling activity (hyperactivity) in the hippocampus (the memory area of the brain). This increase is similar to what is seen in epilepsy but on a smaller, unrecognizable scale.

Studies have found that small doses of an antiepileptic medication called levetiracetam (LEV) reduce this hippocampal hyperactivity in people with amnestic Mild Cognitive Impairment, the phase of AD when people first begin showing memory symptoms. The study aims to determine if this hyperactivity can be detected and treated even earlier, before individuals start showing any symptoms.

Participation begins with 3 screening visits that are a combination of questionnaires, cognitive tests, brain imaging, and collection of information on participant medical history, medications, and demographics.

If participant eligibility is confirmed after the screening visits, they are randomly enrolled in one of the study arms. There are two treatment periods, one period where participants receive the study drug and one period where they receive a placebo (a substance that looks like the study drug but does not have any active or medicinal ingredients). Half of the study participants will receive LEV first, then placebo, while the other half will receive placebo first, then LEV. This crossover study design allows all eligible enrolled individuals to receive the study drug at some point. The study is double-blinded, meaning that the participants and study staff will not be aware of when participants are receiving the drug.

From the day of consent, those participants who pass screening are expected to be in the study for approximately 6 months. Study procedures include cognitive testing, questionnaires, MRI Scans, EEG-MEG scans, physical and neurological exams, ECGs, blood sample collection for APOE genetic testing & blood biomarker testing, optional blood sample collection for biobanking, and an amyloid PET scan.

This study is only being carried out in Toronto, Canada. Participants will be recruited at several Toronto sites, but most of the study visits (for all participants) will take place at Toronto Western Hospital, part of the University Health Network.

Inclusion Criteria:

• 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:

  1. 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.
  2. 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.

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:

  1. Any type of cognitive impairment
  2. History of transient ischemic attacks within 12 months of Screening
  3. History of seizures within 12 months of Screening
  4. Epilepsy
  5. Parkinson's disease
  6. Stroke (aside from subcortical lacunar infarcts)
  7. Multiple sclerosis
  8. Huntington's disease
  9. Normal pressure hydrocephalus
  10. Brain tumour (aside from benign tumours without mass effect, which are to be judged on a case-by-case basis)
  11. Subdural hematoma
  12. History of traumatic brain injury with persistent neurological deficits
  13. Known structural brain abnormalities

• Significant or unstable psychiatric disease, including but not limited to:

  1. Schizophrenia
  2. Bipolar disorder
  3. Major depression which is not controlled in the opinion of the investigator
  4. Score ≥10 on the Geriatric Depression Scale (GDS) at Screening
  5. 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
  6. Answered "yes" to any of the suicide-related behaviours within the last 3 months on the Suicidal Behavior portion of the C-SSRS
  7. Hospitalized or treated for suicidal behavior within 5 years of Screening
  8. 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
  9. Score ≥9 on the Mild Behavioural Impairment Checklist (MBI-C) at Screening

• 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:

  1. History of malignancy within 3 years of screening (except of basal or squamous cell carcinoma of the skin)
  2. 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:

  1. Severe white matter disease (Fazekas score66 = 3)
  2. Stroke involving a major vascular territory
  3. Subcortical lacunar infarcts >1.5cm in diameter
  4. Encephalomalacia
  5. Vascular malformations that are at high risk of hemorrhage
  6. Infective lesions
  7. Space-occupying lesions
  8. 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:

  1. Anticonvulsant medications
  2. Methotrexate
  3. Anticholinergic agents and medications with anticholinergic properties

• Creatinine clearance <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.

All collected IPD.

Start date: two years after publication of the study results (main publication). No planned end date.

The data will be stored in controlled-access databases, for which access is limited to researchers who submit a study plan to the study publications and data sharing committee, and who sign an agreement to use the coded study data only for that research. The study will be listed in the GAAIN (Global Alzheimer's Association Interactive Network) registry once data becomes available.