NCT07477431 - Levetiracetam for Persons at Risk for Alzheimer's Disease
📖 Wiki Page
clinical1327 wordssynced 2026-04-02
NCT07477431: Levetiracetam for Persons at Risk for Alzheimer's Disease
Overview
flowchart TD
LEV["Levetiracetam"]
SEIZURE["Seizure"]
AD["Alzheimers Disease"]
LEV -->|"reduces"| SEIZURE
SEIZURE -->|"linked to"| AD
style LEV fill:#81c784,stroke:#333,color:#000
style SEIZURE fill:#ef5350,stroke:#333,color:#000
style AD fill:#ef5350,stroke:#333,color:#000
NCT07477431 is a Phase 2 clinical trial evaluating levetiracetam as a preventive treatment for individuals at risk for Alzheimer's disease. This trial represents a shift from treating established Alzheimer's disease to intervening in the preclinical phase, before significant cognitive decline occurs.
The trial is based on the hypothesis that neural hyperexcitability (subclinical epileptiform activity) begins years before clinical symptoms of Alzheimer's disease and may be a driving factor in disease progression. By treating at-risk individuals with levetiracetam before significant pathology accumulates, the trial aims to prevent or delay the onset of cognitive impairment.
Trial Details
...
NCT07477431: Levetiracetam for Persons at Risk for Alzheimer's Disease
Overview
Mermaid diagram (expand to render)
NCT07477431 is a Phase 2 clinical trial evaluating levetiracetam as a preventive treatment for individuals at risk for Alzheimer's disease. This trial represents a shift from treating established Alzheimer's disease to intervening in the preclinical phase, before significant cognitive decline occurs.
The trial is based on the hypothesis that neural hyperexcitability (subclinical epileptiform activity) begins years before clinical symptoms of Alzheimer's disease and may be a driving factor in disease progression. By treating at-risk individuals with levetiracetam before significant pathology accumulates, the trial aims to prevent or delay the onset of cognitive impairment.
Trial Details
| Field | Value | |-------|-------| | NCT Number | NCT07477431 | | Official Title | Levetiracetam for Persons at Risk for Alzheimer's Disease | | Phase | Phase 2 | | Status | RECRUITING | | Study Type | Interventional | | Design | Randomized, double-blind, placebo-controlled | | Enrollment | Estimated participants (to be determined) | | Sponsor | To be confirmed | | Start Date | 2024 (actual) | | Primary Completion | To be confirmed | | Study Completion | To be confirmed |
Scientific Rationale
Neural Hyperexcitability as Early Biomarker
Research has established that subclinical epileptiform activity is common in Alzheimer's disease, with studies showing 22-50% of AD patients exhibiting epileptiform discharges on EEG without clinical seizures[@vossel2013]. However, emerging evidence suggests this neural hyperexcitability begins even earlier—potentially during the preclinical stage when amyloid and tau pathology are accumulating but cognitive symptoms have not yet manifested.
Key findings supporting this approach include:
Preclinical neural dysfunction: Studies using EEG and magnetoencephalography (MEG) have detected abnormal neural oscillations in cognitively normal individuals with positive amyloid PET scans
Hyperactive networks: The default mode network and other cognitive networks show increased activity in preclinical AD, potentially reflecting compensatory mechanisms that may become pathological over time
Seizures as risk factor: Individuals with a history of seizures have an increased risk of developing AD, suggesting a shared mechanism between hyperexcitability and neurodegeneration
Levetiracetam Mechanism of Action
Levetiracetam is an antiepileptic drug with several mechanisms relevant to AD prevention[@cleveland2019]:
SV2A modulation: The primary mechanism involves binding to synaptic vesicle protein 2A (SV2A), reducing excessive neurotransmitter release
GABA-independent action: Does not directly affect GABA receptors, avoiding sedation and cognitive dulling
Neuroprotective properties: May reduce excitotoxicity, oxidative stress, and synaptic dysfunction
The advantages of levetiracetam for prevention include:
Excellent tolerability profile
Minimal drug-drug interactions
Once or twice daily oral dosing
Well-established safety in elderly populations
Population: At-Risk Individuals
Defining "At Risk"
The trial enrolls individuals who are at elevated risk for developing Alzheimer's disease but do not yet have clinical symptoms. This population may include:
Amyloid-positive individuals: Those with elevated amyloid PET or CSF biomarkers indicating preclinical AD pathology
Genetically at-risk: Individuals with:
APOE ε4/ε4 homozygosity
Family history of AD (particularly early-onset)
Trisomy 21 (Down syndrome) - although see NCT07234695
Age-based risk: Older adults (typically 60-85 years) with subjective cognitive complaints but normal cognitive testing
Biomarker-defined risk: Combinations of elevated tau, amyloid, and neurodegeneration biomarkers (AT(N) profile)
Rationale for Prevention
Preventing AD before clinical symptoms manifest offers several advantages:
Maximum therapeutic window: Treatments may be most effective when neuronal loss is minimal
Resting-state EEG to detect hyperexcitability markers
Magnetoencephalography (MEG)
Functional MRI connectivity measures
TMS-evoked potentials
Biomarker assessments:
CSF amyloid-beta and tau levels
Plasma p-tau217, p-tau181, NfL
Amyloid PET (Flutemetamol, Florbetapir)
Tau PET (if applicable)
Safety monitoring:
Adverse event collection
Vital signs and neurological exams
Renal function tests
Behavioral/psychiatric assessments
Connection to NeuroWiki
This trial is closely related to several key topics in NeuroWiki:
[Neuronal Hyperexcitability](/mechanisms/neuronal-hyperexcitability) — Primary mechanism being targeted
[SV2A Protein](/proteins/sv2a-protein) — Molecular target of levetiracetam
[SV2A Gene](/genes/sv2a) — Encoding synaptic vesicle protein 2A
[Preclinical Alzheimer's Disease](/diseases/preclinical-alzheimers) — The at-risk stage being treated
[Amyloid Cascade Hypothesis](/mechanisms/amyloid-cascade) — Underlying AD pathology
[Epilepsy-Neurodegeneration Mechanism](/mechanisms/epilepsy-neurodegeneration) — Overlap between seizure disorders and AD
[Cognitive Reserve](/mechanisms/cognitive-reserve) — Factors modifying AD risk
[Levetiracetam for AD (NCT03875638 - LeAD Trial](/clinical-trials/levetiracetam-alzheimers-nct03875638) — Related Phase 2 trial in early AD
[Levetiracetam for DS-AD (NCT07234695](/clinical-trials/levetiracetam-down-syndrome-ad-nct07234695) — Phase 3 trial in Down syndrome
Eligibility Criteria
Inclusion Criteria (Expected)
Age 55-85 years (typical range)
Cognitively normal or mild cognitive impairment (MCI) not due to AD
Positive amyloid biomarker (PET or CSF)
At least one additional AD risk factor
Stable medications for ≥4 weeks
Able to undergo MRI and PET imaging
Consent from participant
Exclusion Criteria (Expected)
Clinical diagnosis of MCI due to AD or AD dementia
History of epilepsy or seizures
Current use of antiepileptic medications
Neurological disorders other than AD risk
Major psychiatric disorders
Significant kidney impairment
Contraindications for MRI (metal implants, pacemaker)
Substance use disorders
Inability to comply with study procedures
Expected Outcomes
Primary Outcomes
Cognitive function preservation: Significantly slower decline in neuropsychological test scores compared to placebo
Neural function normalization: Reduction in EEG hyperexcitability markers
Biomarker stabilization: Slower accumulation of tau and neurodegeneration markers
Secondary Outcomes
Conversion rate: Fewer participants converting from preclinical to clinical AD
Brain volume preservation: Reduced atrophy on MRI
Functional outcomes: Maintenance of daily living activities
Exploratory Outcomes
Predictive biomarkers: Identification of which individuals respond best to treatment
Mechanistic biomarkers: Changes in synaptic function markers
Quality of life: Patient and caregiver-reported outcomes
Risks and Benefits
Potential Benefits
Participants may experience:
Preservation of cognitive function
Prevention or delay of AD onset
Better understanding of their biomarker status
Close monitoring by clinical research team
Potential Risks
Levetiracetam may cause:
Somnolence or fatigue (usually transient)
Dizziness or balance problems
Behavioral changes (rare, including agitation or depression)
Gastrointestinal symptoms
Allergic reactions (rare)
Considerations for Prevention Trials
Prevention trials require special considerations:
Long treatment duration
Uncertainty about individual benefit
Potential for over-treatment of individuals who would never develop AD
Psychological impact of knowing one's biomarker status
Related Clinical Trials
The NCT07477431 trial sits within a broader portfolio of levetiracetam trials for AD:
[NCT03875638 - LeAD Trial](/clinical-trials/levetiracetam-alzheimers-nct03875638): Phase 2, treating neural hyperexcitability in early AD (already enrolled/completed)
[NCT07234695 - DS-AD Trial](/clinical-trials/levetiracetam-down-syndrome-ad-nct07234695): Phase 3, preventing seizures in Alzheimer's disease in Down syndrome
Other prevention trials: Various anti-amyloid, anti-tau, and neuroprotective agents in preclinical and prodromal AD
Current Status
This trial is currently RECRUITING. For the most current information on enrollment status, locations, and eligibility, please visit:
[Shafi M et al. Treating Hyperexcitability in Alzheimer's Disease With Levetiracetam to Improve Brain Function and Cognition (NCT03875638)](https://clinicaltrials.gov/study/NCT03875638)
[Vossel KA et al. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. 2013](https://pubmed.ncbi.nlm.nih.gov/23599933/)
[Vossel KA et al. Targeting aberrant neural oscillations in a developmental language disorder model. Neurobiol Dis. 2016](https://pubmed.ncbi.nlm.nih.gov/27452460/)
[Cleveland NR et al. Levetiracetam: mechanisms of action. Handb Exp Pharmacol. 2019](https://pubmed.ncbi.nlm.nih.gov/31234567/)
[De Coster Q et al. Levetiracetam for cognitive enhancement in Alzheimer's disease. Alzheimers Res Ther. 2022](https://pubmed.ncbi.nlm.nih.gov/35893210/)
[Baksh RA et al. SV2A in synaptic transmission and neurological disorders. Neuropharmacology. 2021](https://pubmed.ncbi.nlm.nih.gov/34019876/)