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NCT07234695: Levetiracetam for Alzheimer's Disease in Down Syndrome

Overview

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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

...

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 dysfunction

The 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 function

Neuroprotective 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 neurodegeneration

Rationale 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 population

Study 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 AD

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

[Fortea J et al., Alzheimer's Disease associated with Down syndrome: a genetic form of dementia. Lancet Neurol. 2021](https://pubmed.ncbi.nlm.nih.gov/34687637/)

[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/)

[Lott IT, Head E. Down syndrome and Alzheimer disease: exploring the intersection. Nat Rev Neurol. 2016](https://pubmed.ncbi.nlm.nih.gov/27224252/)

[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/)

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📊 Evidence Profile Foundational

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levetiracetam-down-syndrome-ad-nct07234695

NCT07234695: Levetiracetam for Alzheimer's Disease in Down Syndrome

Overview

Trial Details

NCT07234695: Levetiracetam for Alzheimer's Disease in Down Syndrome

Overview

Trial Details

Background: Down Syndrome and Alzheimer's Disease

Genetic Basis of AD in Down Syndrome

Additional Chromosome 21 Genes Contributing to Neurodegeneration

Seizures in Down Syndrome-Associated Alzheimer's Disease

Levetiracetam: Mechanism of Action

SV2A Modulation

Neuroprotective Properties

Rationale for Use in DS-AD

Clinical Evidence for Levetiracetam in Neurodegeneration

Cognitive Effects in AD

Use in Down Syndrome

Synaptic Dysfunction in DS

Trial Design and Objectives

Primary Objectives

Study Population

Key Inclusion/Exclusion Criteria

Treatment Regimen

Outcome Measures

Risks and Benefits

Potential Benefits

Potential Risks

Biomarkers and Monitoring

Blood-Based Biomarkers

Neuroimaging

Related Research and Trials

Other Active Trials in DS-AD

Future Directions

Current Status and Enrollment

Scientific Rationale Summary

See Also

External Links

References

cites (1)

derives from (12)

supports (10)

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