An Investigation of Levetiracetam in Alzheimer’s Disease (ILiAD): A double-blind, placebo-controlled, randomised crossover proof of concept study
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Abstract
BACKGROUND: Although Alzheimer's disease affects around 800,000 people in the UK and costs almost £23 billion per year, currently licenced treatments only offer modest benefit at best. Seizures, which are more common in patients with Alzheimer's disease than age matched controls, may contribute to the loss of nerve cells and abnormal brain discharges can disrupt cognition. This aberrant electrical activity may therefore present potentially important drug targets. The anti-seizure medication levetiracetam can reduce abnormal cortical discharges and reverse memory deficits in a mouse model of Alzheimer's disease. Levetiracetam has also been shown to improve memory difficulties in patients with mild cognitive impairment, a precursor to Alzheimer's disease. Clinical use of levetiracetam is well-established in treatment of epilepsy and extensive safety data are available. Levetiracetam thus has the potential to provide safe and efficacious treatment to help with memory difficulties in Alzheimer's disease. METHODS: The proposed project is a proof of concept study to test whether levetiracetam can help cognitive function in people with dementia. We plan to recruit thirty patients with mild to moderate Alzheimer's disease with no history of previous seizures or other significant co-morbidity. Participants will be allocated to a double-blind placebo-controlled crossover trial that tests levetiracetam against placebo. Standardised scales to assess cognition and a computer-based touchscreen test that we have developed to better detect subtle improvements in hippocampal function will be used to measure changes in memory. All participants will have an electroencephalogram (EEG) at baseline. The primary outcome measure is a change in the computer-based touchscreen cognitive task while secondary outcomes include the effect of levetiracetam on mood, quality of life and modelling of the EEG, including time series measures and feature-based analysis to see whether the effect of levetiracetam can be predicted. The effect of levetiracetam and placebo will be compared within a given patient using the paired t-test and the analysis of covariance adjusting for baseline values. DISCUSSION: This is the first study to evaluate if an anti-seizure medication can offer meaningful benefit to patients with Alzheimer's disease. If this study demonstrates at least stabilisation of memory function and/or good tolerability, the next step will be to rapidly progress to a larger study to establish whether levetiracetam may be a useful and cost-effective treatment for patients with Alzheimer's disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT03489044 . Registered on April 5, 2018.
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In early stages of AD, AGB101 is supposed to reduce neuronal hyperactivity Aβ-induced, fighting memory impairment and slowing disease progression.
“In the early stages of AD, the drug is supposed to reduce neuronal hyperactivity Aβ-induced fighting the memory impairment and slowing the disease progression [110].”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [110]
The Introduction’s Background and rationale proposes that levetiracetam may improve cognition in mild-to-moderate Alzheimer’s disease by addressing disrupted neuronal activity; it also reports reduced amyloid plaques and memory deficits in mouse models. It does not identify the drug as AGB101, establish that the hyperactivity is Aβ-induced, or propose that treatment slows disease progression. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAGB101 acts by modulating the synaptic protein SV2A.
“AGB101, assessed in a phase III clinical trial (NCT03486938) in MCI patients, acts by modulating the synaptic protein SV2A.”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [110]
The Introduction and Discussion state that levetiracetam binds synaptic vesicle protein 2A (SV2A). Our copy does not identify AGB101 or establish that it is levetiracetam, so it does not verify the mechanism attributed to AGB101 (searched: AGB101 and the trial identifier). (LLM, conf=0.72)
Experimental — accuracy not yet measured
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“In the early stages of AD, the drug is supposed to reduce neuronal hyperactivity A β -induced fighting the memory impairment and slowing the disease progression [110].”
Background
- Authors
- Sen, A., Akinola, M., Tai, X. Y., Symmonds, M., Davis Jones, G., Mura, S., Galloway, J., Hallam, A., Chan, J. Y. C., Koychev, I., Butler, C., Geddes, J., Van Der Putt, R., Thompson, S., Manohar, S. G., Frangou, E., Love, S., McShane, R., & Husain, M.
- Affiliations
- John Radcliffe Hospital (GB)
- Oxford Health NHS Foundation Trust (GB)
- Cardiff University (GB)
- UCB Pharma (United Kingdom) (GB)
- University of Oxford (GB)
- Warneford Hospital (GB)
- Corresponding author
- Sen, Arjune
- ORCID
- Venue
- Trials
- Published
- 2021-07-31
- Volume
- 22
- Issue
- 1
- Pages
- 508-508
- ISSN
- 1745-6215 (ISSN-L)
- PMC
- PMC8325256
- OpenAlex
- W3173559733
- Cited by
- 30
- References
- 36
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 14 · 2022: 4 · 2021: 2
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Trials (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Oxford University Research Archive (ORA) (University of Oxford) (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- Medical Research Foundation (Confidence in Concept - letter attached)
- UCB Pharma (Investigator initiated study - letter attached)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- levetiracetam, Alzheimer's disease, antiepileptic drugs, memory impairment, cognitive function, EEG, hippocampal function, mild cognitive impairment, dementia, seizure activity, drug repurposing, crossover trial, randomised placebo-controlled trial
- MeSH terms
- Proof of Concept Study, Levetiracetam, Alzheimer Disease, Animals, Double-Blind Method, Humans, Quality of Life, Cross-Over Studies, Mice
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