Levetiracetam improves cognition in patients with Alzheimer’s disease and epilepsy

Treatment with the anti-epileptic drug levetiracetam was well tolerated and associated with improvements in spatial memory and executive function in patients with Alzheimer’s disease (AD) and epileptiform activity, according to the results of a placebo-controlled randomized phase 2a study conducted in JAMA Neurology was published.

Patients with AD and seizures or subclinical epileptiform activity tend to experience more rapid decline in cognitive function. It is not clear whether epileptiform activity is associated with cognitive deterioration, but previous research has shown that the use of anti-epileptic drugs could be beneficial for this patient population. At low doses, levetiracetam has been shown to be well tolerated and successful in reducing seizures in patients with AD with seizure disorders.

The aim of the current study was to assess whether low-dose levetiracetam treatment could result in a favorable response in patients with AD and in patients with AD with epileptiform activity.

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The study, named Levetiracetam for Alzheimer’s Disease – Associated Network Hyperexcitability Study (LEV-AD) (NCT02002819) included 34 adult patients with AD (mean age 62.3 years).

All patients in the study had to present with a Mini-Mental State Examination Score of ≥18 points and / or a Clinical Dementia Rating Score of <2 points. During the screening, the researchers performed an overnight video electroencephalography and a one-hour resting magnetic encephalography exam.

Patients randomized to Group A (n = 17) received placebo twice daily for a total of 4 weeks, followed by a 4-week washout period and then levetiracetam 125 mg twice daily for 4 weeks. In group B (n = 17) the patients received the same treatment, but in the reverse order.

The researchers rated whether levetiracetam improved executive function as measured by the composite score from the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH EXAMINER). Other secondary endpoints included improvements in cognition as measured by the Stroop Color and Word Test (Stroop) naming subscale and the Alzheimer’s disease subscale – cognitive subscale, and disability.

Approximately 38.2% (n = 13) of the total cohort had epileptiform activity. The majority of the study population (82.4%; n = 28) completed the study, including 10 (35.7%) with epileptiform activity.

Treatment with levetiracetam was not associated with a significant change in the NIH EXAMINER composite scores (mean difference vs. placebo, 0.07 points; 95% CI, -0.18-0.32 points; P = 0.55 ). There was also no change in cognitive improvements (Stroop interference designation, 2.9 points; 95% CI, -1.0-6.8; P = 0.14) or disability (Alzheimer’s Disease Cooperative Study – Daily Living Activities, 0.1 point; 95% CI, -1.1-1.3; P = 0.90).

In the epileptiform activity subgroup, treatment with levetiracetam had improved performance on the Stroop interference naming subscale (net improvement vs virtual route learning test (t = 2.36; Cohen f2 = 0.11; P = 0.02 No treatment discontinuations due to side effects were reported in the overall cohort.

The limitations of the study included the small sample size and the “lack of correction for multiple comparisons in the exploratory analysis”, which could have led to the generation of false positive results and possible subgroup confounders, the researchers found.

They concluded that their “results could lead to future personalized approaches to AD in which patients with the epileptic variant of AD receive different treatments than those without the epileptic variant”.

Disclosure: Several authors stated links to the pharmaceutical industry. For a full list of the details, see the original article.


Vossel K, Ranasinghe KG, Beagle AJ, et al. Effect of levetiracetam on cognition in patients with Alzheimer’s disease with and without epileptiform activity: a randomized clinical trial. JAMA Neurol. Published online September 27, 2021. doi: 10.1001 / jamaneurol.2021.3310

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