Safety, tolerability and efficacy outcomes of the Investigation of Levetiracetam in Alzheimer's Disease (ILiAD) trial

ObjectiveTo assess whether the antiseizure medication levetiracetam may improve cognition in individuals with Alzheimers disease who have not previously experienced a seizure. MethodsWe performed a randomised, double-blind, placebo-controlled crossover study in individuals with mild-to-moderate Alzheimers disease. Electroencephalography was performed at baseline and those with active epileptiform discharges were excluded. Eligible participants were randomised to placebo for 12 weeks or an active arm of oral levetiracetam (4 weeks up-titration to levetiracetam 500 mg twice daily, 4 weeks maintained on this dose followed by 4 weeks down-titration to nil). Participants then crossed over to the other arm. The primary outcome was change in cognitive function assessed by the Oxford Memory Task, a task sensitive to hippocampal memory binding. Secondary outcomes included tolerability, other neuropsychological scales and general questionnaires. ResultsRecruitment numbers were severely limited owing to restrictions from the COVID-19 pandemic at the time of the study. Eight participants completed both arms of the study (mean age 68.4 years [SD=9.2]; 5 females [62.5%]). No participants withdrew from the study and there was no significant difference between reported side-effects in the active levetiracetam or placebo arm. Measures of mood and quality of life were also not significantly different between the two arms based on participant or carer reports. In limited data analysis, there was no statistically significant difference between participants in the active levetiracetam and placebo arm on the memory task. SignificanceThis pilot study demonstrates that levetiracetam was well tolerated in individuals with Alzheimers disease, who do not have a history of seizures, and has no detrimental effect on mood or quality of life. Larger studies are needed to assess whether levetiracetam may have a positive effect on cognitive function in subsets of individuals with Alzheimers disease. Plain language summaryAbnormal electrical activity within the brain, such as is seen in seizures, might contribute to memory problems in people with dementia. We completed a clinical trial to see if the anti-seizure medication, levetiracetam, could help with memory difficulties in people with Alzheimers disease (the most common cause of dementia). In this pilot study, we could not prove whether levetiracetam helped memory function. We did show that the drug is safe and well-tolerated in people with dementia who have not had a seizure. This work therefore offers a platform for future research exploring anti-seizure medications in people with dementia. Key pointsO_LIEpilepsy may contribute to the aetiopathogenesis of Alzheimers disease C_LIO_LIILiAD is a double-blind, randomised placebo controlled trial of levetiracetam in Alzheimers disease C_LIO_LILevetiracetam was well tolerated in people with AD who have not had a seizure C_LIO_LIOwing to small sample size, effect of levetiracetam on cognition could not be determined C_LIO_LILarger trials of anti-seizure medications in people with dementia are warranted C_LI