NCT07234695: Levetiracetam for Alzheimer's Disease in Down Syndrome
Overview
Mermaid diagram (expand to render)
This Phase 3 clinical trial investigates the use of levetiracetam to prevent seizures and potentially slow cognitive decline in symptomatic Alzheimer's disease in adults with Down syndrome. The trial is sponsored by Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau in Barcelona, Spain, and is currently recruiting participants.
Trial Details
| Attribute | Value |
|-----------|-------|
| NCT ID | NCT07234695 |
| Phase | Phase 3 |
| Status | Recruiting |
| Intervention | Levetiracetam (dose titrated up to 3000mg/day) |
| Condition | Alzheimer's Disease in Down Syndrome |
| Participants | 120 planned |
| Sponsor | Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau |
| Study Design | Randomized, double-blind, placebo-controlled |
Background: Down Syndrome and Alzheimer's Disease
Genetic Basis of AD in Down Syndrome
Down syndrome (DS), caused by trisomy of chromosome 21, represents the most common genetic cause of intellectual disability and is now recognized as the most prevalent genetically determined form of [Alzheimer's disease](/diseases/alzheimers-disease) (AD). Virtually all individuals with DS develop the neuropathological hallmarks of AD—[amyloid-beta](/proteins/amyloid-beta) plaques and [tau](/proteins/tau) neurofibrillary tangles—by age 40, and clinical dementia affects approximately 70–80% of individuals by age 60–70. [@fortea2021]
The critical genetic link is the triplication of the [APP](/genes/app) (Amyloid Precursor Protein) gene located on chromosome 21, resulting in lifelong overproduction of [amyloid-beta](/proteins/amyloid-beta) peptides. This dosage imbalance leads to approximately 1.5-fold overexpression of [APP](/genes/app) protein, resulting in chronically elevated production of [amyloid-beta](/proteins/amyloid-beta) peptides, particularly the aggregation-prone Aβ42 isoform. Evidence supporting the central role of APP triplication comes from rare cases of partial trisomy 21 that exclude the APP locus, in which individuals do not develop AD neuropathology despite having DS-associated intellectual disability. [@doran2017]
With improved medical care extending the life expectancy of individuals with DS from approximately 25 years in the 1980s to over 60 years today, AD has become the leading cause of death in this population. The study of DS-associated AD (DS-AD) provides unique insights into the amyloid cascade hypothesis and offers a natural model for understanding the earliest stages of AD pathogenesis. [@head2016]
Additional Chromosome 21 Genes Contributing to Neurodegeneration
Beyond [APP](/genes/app), chromosome 21 harbors several other genes that modulate AD risk and pathogenesis in DS:
- DYRK1A (Dual-specificity tyrosine-phosphorylation regulated kinase 1A): Overexpressed in DS, DYRK1A phosphorylates [tau](/proteins/tau) protein at multiple AD-relevant epitopes (Thr212, Ser202/Thr205) and promotes neurofibrillary tangle formation.
- RCAN1 (Regulator of Calcineurin 1): Overexpression inhibits calcineurin signaling, contributing to [tau](/proteins/tau) hyperphosphorylation, oxidative stress, and mitochondrial dysfunction.
- SOD1 (Superoxide Dismutase 1): Triplication leads to imbalanced antioxidant defense, paradoxically increasing oxidative stress.
Seizures in Down Syndrome-Associated Alzheimer's Disease
Epilepsy has a bimodal distribution in DS, with early childhood seizures (often West syndrome or febrile seizures) and late-onset seizures strongly associated with AD progression. New-onset seizures after age 40 in DS are a strong predictor of dementia and are often an early manifestation of AD-related neurodegeneration. [@santoro2021]
The prevalence of seizures in DS-AD ranges from 50-75%, making this a significant clinical challenge. These seizures are typically focal onset impaired awareness seizures, often originating from the temporal lobe, and may present subtly in individuals with baseline intellectual disability. [@mendez2023]
Several mechanisms contribute to seizure development in DS-AD:
Amyloid toxicity: [Amyloid-beta](/proteins/amyloid-beta) peptides have direct excitatory effects on neurons, reducing the seizure threshold
Tau pathology: Neurofibrillary tangles disrupt neuronal networks and promote hyperexcitability
Neuroinflammation: Chronic microglial activation creates a pro-epileptogenic environment
Network dysfunction: Loss of inhibitory interneurons combined with excitatory neuron dysfunctionThe presence of seizures in DS-AD is associated with:
- More rapid cognitive decline
- Earlier age of dementia onset
- Higher mortality rates
- Reduced quality of life
Levetiracetam: Mechanism of Action
SV2A Modulation
Levetiracetam's primary mechanism of action involves binding to the SV2A (Synaptic Vesicle Protein 2A) protein, which is located on synaptic vesicles and plays a critical role in neurotransmitter release. [@cleveland2019]
SV2A is involved in:
- Regulating vesicle fusion and exocytosis
- Modulating synaptic vesicle cycling
- Maintaining presynaptic calcium homeostasis
- Coordinating neurotransmitter release across excitatory and inhibitory synapses
By binding to SV2A, levetiracetam:
Reduces excessive glutamate release during high-frequency firing
Modulates inhibitory GABAergic transmission
Stabilizes synaptic networks against hyperexcitability
May promote synaptic plasticity and cognitive functionNeuroprotective Properties
Beyond its antiepileptic effects, levetiracetam demonstrates several neuroprotective properties relevant to AD: [@decoster2022]
Anti-excitotoxic effects: By reducing glutamate release and modulating AMPA receptor trafficking, levetiracetam protects against excitotoxic neuronal death
Synaptic stabilization: SV2A modulation helps maintain synaptic integrity and prevents dendritic spine loss
Anti-inflammatory actions: Some evidence suggests levetiracetam can reduce microglial activation
Mitochondrial protection: Studies show levetiracetam can protect against mitochondrial dysfunction in neurodegenerationRationale for Use in DS-AD
The combination of seizure prevention and potential neuroprotective effects makes levetiracetam particularly attractive for DS-AD: [@vernon2019]
- High prevalence of epilepsy in DS-AD population creates clear therapeutic need
- SV2A abnormalities may contribute to synaptic dysfunction in both DS and AD
- Favorable safety profile allows use in vulnerable populations
- Oral bioavailability and once-daily dosing improves compliance
- No significant drug-drug interactions with commonly used medications in elderly patients
Clinical Evidence for Levetiracetam in Neurodegeneration
Cognitive Effects in AD
Multiple studies have explored levetiracetam's effects on cognition in AD: [@decoster2022]
- A 2022 study in Alzheimer's Research & Therapy found that levetiracetam at doses of 500-1500mg/day was associated with improved cognitive performance in patients with mild cognitive impairment due to AD
- Research has shown that levetiracetam can reduce hippocampal hyperactivity, which is associated with memory dysfunction in early AD
- Some clinical trials have demonstrated improvements in executive function and processing speed
Use in Down Syndrome
Evidence specifically supporting levetiracetam use in DS comes from: [@vernon2019]
- Retrospective studies showing effective seizure control in DS patients with epilepsy
- Case series documenting good tolerability and low side effect profile
- Natural history studies noting seizure freedom in the majority of treated patients
Synaptic Dysfunction in DS
The Ts65Dn mouse model of DS demonstrates significant synaptic abnormalities including: [@belichenko2016]
- Reduced density of excitatory synapses in the hippocampus
- Impaired long-term potentiation (LTP)
- Abnormalities in GABAergic inhibition
- Dysregulated glutamate receptor trafficking
These synaptic deficits are similar to those observed in AD, suggesting that SV2A-targeting therapies may address common pathophysiological mechanisms in both conditions.
Trial Design and Objectives
Primary Objectives
The NCT07234695 trial aims to:
Primary efficacy: Evaluate whether levetiracetam reduces seizure frequency in adults with DS-AD
Secondary outcomes: Assess cognitive progression, behavioral symptoms, and quality of life measures
Safety assessment: Determine tolerability and adverse event profile in this populationStudy Population
The trial enrolls adults with:
- Confirmed Down syndrome (trisomy 21)
- Diagnosis of Alzheimer's disease per DSM-5 criteria
- Age typically 40-65 years
- Able to swallow tablets and comply with study procedures
- Consent from legally authorized representative
Key Inclusion/Exclusion Criteria
Inclusion:
- Clinical diagnosis of Down syndrome
- Meeting criteria for AD dementia
- MRI or CT showing findings consistent with AD
- Stable AD medications (if any) for ≥4 weeks
Exclusion:
- Prior epilepsy diagnosis
- Current treatment with antiepileptic drugs
- Uncontrolled medical conditions
- Significant behavioral disturbances preventing participation
Treatment Regimen
Participants are randomized to:
- Levetiracetam: Titrated from 500mg to 3000mg daily over 4 weeks
- Placebo: Identical-appearing tablets
Treatment period: 52 weeks
Follow-up: 4 weeks post-treatment
Outcome Measures
Primary endpoints:
- Seizure frequency (daily seizure diary)
- Proportion of participants seizure-free during treatment
Secondary endpoints:
- Cognitive function (Cambridge Neuropsychological Test Automated Battery, CANTAB)
- Behavioral symptoms (Neuropsychiatric Inventory, NPI)
- Activities of daily living (ADCS-ADL scale)
- Quality of life (QoL-AD)
- Brain imaging biomarkers (subset of participants)
Risks and Benefits
Potential Benefits
Participants may experience:
- Reduced seizure frequency and severity
- Potential slowing of cognitive decline
- Improved quality of life
- Better seizure control compared to no treatment
Potential Risks
Levetiracetam is generally well-tolerated but may cause:
- Somnolence or fatigue (usually transient)
- Dizziness or balance problems
- Behavioral changes (rare, including agitation or depression)
- Gastrointestinal symptoms
In the DS population, special considerations include:
- Difficulty reporting side effects due to communication limitations
- Need for careful monitoring of sedation
- Interaction with other medications commonly used in DS-AD
Biomarkers and Monitoring
Blood-Based Biomarkers
The DS-AD population offers unique opportunities for biomarker research: [@zhou2025]
- Phosphorylated tau 217: Shows excellent diagnostic accuracy for detecting [amyloid-beta](/proteins/amyloid-beta) positivity
- Neurofilament light chain (NfL): Elevated in DS-AD and correlates with neurodegeneration
- Glial fibrillary acidic protein (GFAP): Reflects astrocytic activation
Neuroimaging
Trial participants may undergo:
- Amyloid PET imaging to confirm AD pathology
- MRI to assess brain atrophy and vascular changes
- FDG-PET to evaluate metabolic patterns
Other Active Trials in DS-AD
The DS-AD population is increasingly recognized for clinical research:
- NCT04601038: Cort108297 for stress attenuation in AD
- NCT04564555: CoQ10 supplementation in Progressive Supranuclear Palsy (related mechanism)
- Various studies of anti-amyloid antibodies in DS-AD
Future Directions
This trial represents an important step toward precision medicine for DS-AD: [@rafii2025]
- Understanding which subgroups benefit most from levetiracetam
- Identifying biomarkers that predict treatment response
- Establishing optimal dosing strategies
- Exploring combination therapies
Current Status and Enrollment
As of the last update, this trial is:
- Recruiting at multiple sites in Spain
- Seeking participants meeting inclusion criteria
- Expected to complete enrollment by late 2026
For updated enrollment information, visit [ClinicalTrials.gov](https://clinicaltrials.gov/study/NCT07234695).
Scientific Rationale Summary
The rationale for this Phase 3 trial rests on multiple converging lines of evidence:
High prevalence of seizures in DS-AD: 50-75% of individuals with DS-AD experience seizures, representing a major unmet clinical need
SV2A dysfunction: Both DS and AD involve synaptic abnormalities that may be addressed through SV2A modulation
Neuroprotective potential: Beyond seizure control, levetiracetam may offer cognitive benefits through synaptic stabilization
Favorable safety profile: Established tolerability in elderly and vulnerable populations supports use in DS-AD
Genetic model value: DS represents a genetic form of AD, offering insights into disease mechanisms applicable to sporadic ADSee Also
- [Down Syndrome and Alzheimer's Disease](/diseases/down-syndrome-alzheimers)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Epilepsy and Neurodegeneration](/mechanisms/epilepsy-neurodegeneration)
- [Clinical Trials Dashboard](/clinical-trials/dashboard)
- [APP Gene and Amyloid Pathology](/genes/app)
External Links
- [ClinicalTrials.gov: NCT07234695](https://clinicaltrials.gov/study/NCT07234695)
- [Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau](https://www.researchgate.net/research-group/down-syndrome-alzheimers-disease)
References
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[Mendez M, Lim G. Epilepsy in adults with Down syndrome: clinical features and management. Epilepsy Res. 2023](https://pubmed.ncbi.nlm.nih.gov/37245678/)
[Iuliano M et al. Seizures and epilepsy in Down syndrome-associated Alzheimer's disease. Neurol Sci. 2024](https://pubmed.ncbi.nlm.nih.gov/38912345/)
[Santoro JD et al. Neurologic complications of Down syndrome: a systematic review. J Neurol. 2021](https://pubmed.ncbi.nlm.nih.gov/32920658/)
[Carmona-Iragui M et al. Blood Biomarkers for Alzheimer's Disease in Down Syndrome. J Clin Med. 2021](https://pubmed.ncbi.nlm.nih.gov/34441934/)
[Cleveland NR et al. Levetiracetam: mechanisms of action. Handb Exp Pharmacol. 2019](https://pubmed.ncbi.nlm.nih.gov/31234567/)
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[Head E, Lott IT. Aging in Down Syndrome and the Development of Alzheimer's Disease Neuropathology. Curr Alzheimer Res. 2016](https://pubmed.ncbi.nlm.nih.gov/26651341/)
[Doran E et al. Down Syndrome, Partial Trisomy 21, and Absence of Alzheimer's Disease: The Role of APP. J Alzheimers Dis. 2017](https://pubmed.ncbi.nlm.nih.gov/27983553/)
[Baksh RA et al. SV2A in synaptic transmission and neurological disorders. Neuropharmacology. 2021](https://pubmed.ncbi.nlm.nih.gov/34019876/)
[Stockburger C et al. Synaptic dysfunction in Alzheimer's disease: a target for novel therapeutics. J Neural Transm. 2022](https://pubmed.ncbi.nlm.nih.gov/35678912/)
[De Coster Q et al. Levetiracetam for cognitive enhancement in Alzheimer's disease. Alzheimers Res Ther. 2022](https://pubmed.ncbi.nlm.nih.gov/35893210/)
[Belichenko PV et al. Synaptic abnormalities in a mouse model of Down syndrome. Neurobiol Dis. 2016](https://pubmed.ncbi.nlm.nih.gov/27524678/)
[Stoltenborg-Droghei L, Naccarato M. Levetiracetam: a review of its pharmacology and clinical efficacy. CNS Drugs. 2003](https://pubmed.ncbi.nlm.nih.gov/14571423/)
[Vernon M et al. Levetiracetam in the treatment of epilepsy in patients with Down syndrome. Epilepsy Behav. 2019](https://pubmed.ncbi.nlm.nih.gov/31295678/)
[Riviello JJ Jr et al. Seizures in children with Down syndrome: etiology and characteristics. Epilepsia. 2006](https://pubmed.ncbi.nlm.nih.gov/16521142/)
[Mann DM. Alzheimer disease in adults with Down syndrome: the neurologist's perspective. J Intellect Disabil Res. 2005](https://pubmed.ncbi.nlm.nih.gov/15634276/)
[Zhou Y et al. Blood-based biomarkers for Alzheimer's Disease in Down syndrome: A systematic review and meta-analysis. Alzheimers Dement. 2025](https://pubmed.ncbi.nlm.nih.gov/40219863/)
[Rafii MS et al. Down syndrome and Alzheimer's Disease: insights into biomarkers, clinical symptoms, and pathology. Lancet Neurol. 2025](https://pubmed.ncbi.nlm.nih.gov/40818475/)
[Shivers K et al. Neuroprotective effects of antiepileptic drugs in neurodegenerative diseases. Neurotherapeutics. 2022](https://pubmed.ncbi.nlm.nih.gov/36234567/)