Antiseizure drug may improve spatial memory, executive function in AD

Levetiracetam was well tolerated and appeared to improve performance on spatial memory and executive function tasks among patients with Alzheimer’s disease, according to results of a randomized clinical trial in JAMA Neurology.

“Preclinical studies in transgenic mouse models of AD found that suppressing epileptiform activity with antiseizure drugs was associated with improvements in behavior as well as histopathological signs of chronic network hyperexcitability in the hippocampus,” Keith Vossel, MD, MSc, of the department of neurology at University of California, Los Angeles’ David Geffen School of Medicine, and colleagues wrote. “Levetiracetam is a widely used antiseizure drug that has been reported to suppress epileptiform spikes and improve synaptic and cognitive function in mouse models of AD.

“Levetiracetam treatment has been found to be well tolerated and successful at suppressing seizures among patients with AD and seizure disorders, often at low doses,” Vossel and colleagues added.

These prior results laid the groundwork for investigators to examine the potential for levetiracetam to boost cognitive function in patients with AD. They conducted the phase 2a randomized, double-blinded, placebo-controlled, crossover clinical trial called the Levetiracetam for Alzheimer’s Disease – Associated Network Hyperexcitability. They analyzed data of 34 adults with AD at two academic institutions between Oct. 16, 2014, and July 21, 2020. Participants were aged 80 years or younger and scored 18 points or higher on the Mini-Mental State Examination and/or less than two points on the Clinical Dementia Rating score.

Overnight video electroencephalography and a 1-hour resting magnetoencephalography examination composed the screening process. One group (n = 17) received placebo twice daily for 4 weeks followed by a 4-week washout period, then 125 mg of oral levetiracetam twice daily for 4 weeks. The other group (n = 17) received treatment via a reverse sequence.

A total of 61.8% of participants were women, and mean participant age was 62.3 years. The ability of levetiracetam treatment to improve executive function according to the NIH Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) composite score served as the primary outcome. Cognition measured via the Stroop Color and Word Test interference naming subscale and the Alzheimer’s Disease Assessment Scale-Cognitive Subscale, as well as disability, served as secondary outcomes. Performance on a virtual route learning test and scores on cognitive and functional tests among participants with epileptiform activity were the exploratory outcomes.

Twenty-eight patients (82.4%) completed the study, with 10 patients (35.7%) exhibiting epileptiform activity. Levetiracetam treatment did not alter NIH-EXAMINER composite scores (mean difference vs. placebo = 0.07 points; 95% CI, 0.18 to 0.32 points) or secondary measures. However, it did improve performance on the Stroop interference naming subscale (net improvement vs. placebo = 7.4 points; 95% CI, 0.2-14.7) and the virtual route learning test (P = .02) among participants with epileptiform activity. No participants discontinued treatment due to adverse events.

“The implications are substantial when considering that an estimated 60% or more of patients with AD experience seizures and subclinical epileptiform activity,” Vossel and colleagues wrote. “Antiseizure approaches would complement and potentially enhance other strategies for treating AD, including those targeting disease protein aggregation as well as spreading and inflammation.

“Future AD clinical trials would benefit from including neurophysiological assessments whenever possible and adding antiseizure drugs when epileptic or epileptiform activity is detected,” they added.