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Original Investigation
September 27, 2021

Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial

Author Affiliations
  • 1Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco
  • 2N. Bud Grossman Center for Memory Research and Care, Department of Neurology, University of Minnesota, Minneapolis
  • 3Institute for Translational Neuroscience, University of Minnesota, Minneapolis
  • 4Mary S. Easton Center for Alzheimer’s Disease Research, Department of Neurology, David Geffen School of Medicine at UCLA (University of California, Los Angeles), Los Angeles
  • 5Gladstone Institute of Neurological Disease, San Francisco, California
  • 6Biomagnetic Imaging Laboratory, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco
  • 7Minnesota Epilepsy Group, St Paul, Minnesota
  • 8Department of Neurology, University of Minnesota, Minneapolis
  • 9Epilepsy Center, Department of Neurology, University of California, San Francisco, San Francisco
JAMA Neurol. 2021;78(11):1345-1354. doi:10.1001/jamaneurol.2021.3310
Key Points

Question  What is the effect of 4 weeks of treatment with low-dose levetiracetam on cognitive function in patients with Alzheimer disease (AD)?

Findings  In this randomized clinical trial of 34 adults with AD, treatment with levetiracetam did not significantly modify cognitive function. However, the treatment did improve executive function and spatial memory among participants with AD who had seizures or subclinical epileptiform activity that was identified through extended neurophysiological recordings.

Meaning  This study’s findings indicated that extended neurophysiological assessments are important to identify patients with AD who could benefit from antiseizure approaches and that levetiracetam treatment could improve cognitive symptoms in the estimated 60% of patients with AD who have seizures and subclinical epileptiform activity.


Importance  Network hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD).

Objective  To determine the ability of the antiseizure drug levetiracetam to improve cognition in persons with AD.

Design, Setting, and Participants  The Levetiracetam for Alzheimer’s Disease–Associated Network Hyperexcitability (LEV-AD) study was a phase 2a randomized double-blinded placebo-controlled crossover clinical trial of 34 adults with AD that was conducted at the University of California, San Francisco, and the University of Minnesota, Twin Cities, between October 16, 2014, and July 21, 2020. Participants were adults 80 years and younger who had a Mini-Mental State Examination score of 18 points or higher and/or a Clinical Dementia Rating score of less than 2 points. Screening included overnight video electroencephalography and a 1-hour resting magnetoencephalography examination.

Interventions  Group A received placebo twice daily for 4 weeks followed by a 4-week washout period, then oral levetiracetam, 125 mg, twice daily for 4 weeks. Group B received treatment using the reverse sequence.

Main Outcomes and Measures  The primary outcome was the ability of levetiracetam treatment to improve executive function (measured by the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research [NIH-EXAMINER] composite score). Secondary outcomes were cognition (measured by the Stroop Color and Word Test [Stroop] interference naming subscale and the Alzheimer’s Disease Assessment Scale–Cognitive Subscale) and disability. Exploratory outcomes included performance on a virtual route learning test and scores on cognitive and functional tests among participants with epileptiform activity.

Results  Of 54 adults assessed for eligibility, 11 did not meet study criteria, and 9 declined to participate. A total of 34 adults (21 women [61.8%]; mean [SD] age, 62.3 [7.7] years) with AD were enrolled and randomized (17 participants to group A and 17 participants to group B). Thirteen participants (38.2%) were categorized as having epileptiform activity. In total, 28 participants (82.4%) completed the study, 10 of whom (35.7%) had epileptiform activity. Overall, treatment with levetiracetam did not change NIH-EXAMINER composite scores (mean difference vs placebo, 0.07 points; 95% CI, −0.18 to 0.32 points; P = .55) or secondary measures. However, among participants with epileptiform activity, levetiracetam treatment improved performance on the Stroop interference naming subscale (net improvement vs placebo, 7.4 points; 95% CI, 0.2-14.7 points; P = .046) and the virtual route learning test (t = 2.36; Cohen f2 = 0.11; P = .02). There were no treatment discontinuations because of adverse events.

Conclusions and Relevance  In this randomized clinical trial, levetiracetam was well tolerated and, although it did not improve the primary outcome, in prespecified analysis, levetiracetam improved performance on spatial memory and executive function tasks in patients with AD and epileptiform activity. These exploratory findings warrant further assessment of antiseizure approaches in AD.

Trial Registration  ClinicalTrials.gov Identifier: NCT02002819

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