Northwestern University researchers have identified a potential way to prevent the formation of Alzheimer’s disease plaques using levetiracetam, a drug already approved by the Food and Drug Administration (FDA) for seizure disorders. Their findings were published in Science Translational Medicine.
The research team discovered that amyloid-beta 42, a toxic protein fragment linked to Alzheimer’s disease, accumulates inside synaptic vesicles within neurons. When levetiracetam was administered to animal models and human neurons, it stopped these neurons from producing 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, 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.”
The study focuses on how amyloid precursor protein (APP) is processed in brain cells. The scientists found that levetiracetam binds to SV2A during the synaptic vesicle cycle. This interaction slows down recycling of vesicle components at the cell surface, allowing APP to remain longer on the surface and diverting it away from pathways that generate harmful amyloid-beta 42.
“In our 30s, 40s and 50s, our brains are generally able to steer proteins away from harmful pathways,” Savas said. “As we age, that protective ability gradually weakens. This is not a statement of disease; this is just a part of aging. But in brains developing Alzheimer’s, too many neurons go astray, and that’s when you get amyloid-beta 42 production. And then it’s tau (or ‘tangles’), and then it’s dead cells, then dementia, then neuroinflammation — and then it’s too late.”
Savas emphasized that if levetiracetam were to be used for prevention rather than treatment, it would need to be started very early—possibly decades before current tests can detect elevated levels of amyloid-beta 42 associated with Alzheimer’s.
“You couldn’t take this when you already have dementia because the brain has already undergone a number of irreversible changes and a lot of cell death,” Savas said.
To identify those who might benefit most from early intervention with levetiracetam, Savas suggested focusing on people with genetic forms of Alzheimer’s disease—including patients with Down syndrome—who are at higher risk.
Researchers analyzed clinical data from the National Alzheimer’s Coordinating Center to see whether patients taking levetiracetam experienced slower cognitive decline compared to those taking lorazepam or other anti-epileptic drugs or none at all. They found that those taking levetiracetam had a significant delay in progression from cognitive decline diagnosis to death.
“Although the magnitude of change was small (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.
The team also studied brain tissue from young adults with Down syndrome who died before developing symptoms but were genetically predisposed to early-onset Alzheimer’s due to an extra copy of chromosome 21 carrying APP. These tissues showed accumulation patterns similar to those observed in mouse models previously studied by Savas’ lab.
“By obtaining Down syndrome patient brains from people who died in their 20s or 30s, we know they would have eventually developed Alzheimer’s, so it gives us an opportunity to study the very initial early changes in the human brain,” Savas said.
“That is what we and others call the paradoxical stage of Alzheimer’s disease, which is that before synapses are lost and dementia ensues, the first thing that happens is presynaptic proteins accumulate,” Savas said. “So conceivably, if you started giving these patients levetiracetam in their teenage years, it could actually have a preventative therapeutic benefit.”
However, he noted limitations: “Levetiracetam is not perfect,” Savas said. The drug breaks down quickly in the body. Researchers are now working on improved versions designed for longer-lasting effects and better targeting.
Other authors involved include Nalini R. Rao, Ivan Santiago-Marrero1, Olivia DeGulis, Toshihiro Nomura, Kritika Goyal, SeungEun Lee, Timothy J. Hark, Justin C. Dynes, Emily X. Dexter, Arun Upadhyay, Robert Vassar and Anis Contractor.
The research received funding support from both the National Institutes of Health and Cure Alzheimer’s Fund.
