Anti-Epileptic Drug Levetiracetam Prevents Alzheimer's Amyloid-Beta Formation in Preclinical Study

Researchers have found that the FDA-approved anti-epileptic drug levetiracetam prevents the production of toxic amyloid-beta 42 peptides, a key driver of Alzheimer’s disease, by altering how neurons recycle synaptic vesicles. The study, published in Science Translational Medicine, used mouse models, cultured human neurons, and brain tissue from individuals at high genetic risk to show that levetiracetam diverts the amyloid precursor protein away from the processing pathway that generates amyloid-beta 42.

The team discovered that amyloid-beta 42 accumulates inside synaptic vesicles—the tiny packets neurons use to send signals—and that the trafficking of amyloid precursor protein within neurons controls whether toxic peptides form. Levetiracetam binds to synaptic vesicle glycoprotein 2A, slowing a recycling step that returns vesicle components from the cell surface into the terminal. This keeps the amyloid precursor protein on the cell surface longer, shifting it away from intracellular processing routes that produce amyloid-beta 42.

“While many of the Alzheimer’s drugs currently on the market, such as lecanemab and donanemab, are approved to clear existing amyloid plaques, we’ve identified this mechanism that prevents the production of the amyloid-beta 42 peptides and amyloid plaques,” said Jeffrey Savas, corresponding author and associate professor of behavioral neurology at Northwestern University Feinberg School of Medicine. “Our new results uncovered new biology while also opening doors for new drug targets.”

Savas noted that as people age, the brain’s ability to steer proteins away from harmful pathways weakens, and in Alzheimer’s, too many neurons produce amyloid-beta 42, leading to tau tangles, cell death, and dementia. The researchers stress that any preventive strategy based on this mechanism would likely require very early use, potentially decades before symptoms or biomarker changes appear, making it a candidate for pre-symptomatic risk management rather than a treatment for established dementia.

To see if real-world data aligned, the team analyzed records from the U.S. National Alzheimer’s Coordinating Center. Alzheimer’s patients who received levetiracetam showed a statistically significant delay from diagnosis of cognitive decline to death compared with those taking lorazepam or other or no anti-epileptic drugs, though the effect size was modest—on the scale of a few years. “This analysis supports the positive effect of levetiracetam to slow the progression of Alzheimer’s pathology,” Savas said.

In a distinctive part of the study, the researchers examined brain tissue from donors with Down syndrome who died young from accidents. Because more than 95% of people with Down syndrome develop an early, aggressive form of Alzheimer’s pathology by about age 40 due to trisomy of chromosome 21, these samples allowed investigation of very early pathological states.