An Epilepsy Drug May Block The Onset Of Alzheimer's

The study suggests that levetiracetam (commonly known by the brand name Keppra), a drug already approved for epilepsy, may reduce the production of the toxic form of beta-amyloid by modifying the functioning of synaptic vesicles. By favoring the non-toxic processing pathway of the amyloid precursor protein, the drug may prevent or delay the onset of changes associated with Alzheimer's disease. The results indicate that early interventions at the synapses may be a promising strategy for preventing the disease.

Alzheimer's disease is marked by the accumulation of small protein fragments called beta-amyloid in the brain. These fragments accumulate between neurons and also within the connections between them, called synapses. Synapses are essential because they allow nerve cells to communicate. When this communication fails, memory and reasoning problems begin to emerge.

Beta-amyloid fragments are produced from a larger protein called amyloid precursor protein. This protein can be processed in two different ways: one pathway considered "safe," which does not generate toxic fragments, and another pathway that leads to the formation of beta-amyloid.

Part of this processing occurs during the normal functioning of synaptic vesicles, which are small sacs within the neuron responsible for releasing neurotransmitters, the chemical substances that transmit signals between cells.

Researchers investigated what happens when this system begins to fail. Using genetically modified mice to develop characteristics similar to those of human Alzheimer's, they observed that proteins that should be recycled and degraded began to accumulate in the presynaptic terminals, the part of the neuron that sends signals. Along with this accumulation, they also found elevated levels of the most toxic form of beta-amyloid, called Aβ42.

To better understand the mechanism, the scientists used cell models grown in the laboratory as well as the modified mice. They administered the drug levetiracetam, an anticonvulsant already approved to treat epilepsy.

This drug acts on a protein present in synaptic vesicles called glycoprotein 2A, which helps regulate the release of neurotransmitters. The goal was to verify whether, by acting on the vesicles, the drug could interfere with the processing of the amyloid precursor protein.

The results showed that levetiracetam reduced the production of the toxic Aβ42 form. This occurred because the drug altered the synaptic vesicle cycle, that is, it modified how these small sacs are formed, used, and recycled within the neuron.

With this change, the amyloid precursor protein began to be processed preferentially via the pathway considered non-toxic, decreasing the generation of beta-amyloid.

To confirm that the reduction was real and not just apparent, the researchers used a technique called stable isotope labeling combined with mass spectrometry.

In simple terms, they "labeled" newly produced molecules with a kind of traceable chemical tag and then measured with high precision how much beta-amyloid was being produced in the brains of the animals. This approach allowed them to prove that the drug actually reduced the production of the toxic protein in living organisms.

Furthermore, electrical tests measuring synapse activity showed that levetiracetam helped restore normal functioning of connections between neurons. Microscopic analyses also indicated a reduction in synaptic loss, which is one of the main factors associated with the progression of Alzheimer's disease.

Finally, the researchers analyzed the brains of people with Down syndrome, a genetic condition that increases the risk of developing Alzheimer's disease early. They observed that the accumulation of presynaptic proteins occurred even before the significant formation of beta-amyloid plaques. This suggests that alterations in synaptic vesicles may be an initial event in the disease, and therefore a possible target for prevention.

Jeffrey Savas, corresponding author of the study, talks with members of his lab at Northwestern University in Chicago. Credit: Northwestern University

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Levetiracetam prevents Aβ production through SV2a-dependent modulation of APP processing in Alzheimer’s disease models

Nalini R. Rao, Ivan Santiago-Marrero, Olivia DeGulis, Toshihiro Nomura, Kritika Goyal, SeungEun Lee, Timothy J. Hark, Justin C. Dynes, Emily X. Dexter, Maciej Dulewicz, Junyue Ge, Arun Upadhyay, Eugenio F. Fornasiero, Robert Vassar, Jörg Hanrieder, Anis Contractor, and Jeffrey N. Savas

Science Translational Medicine. 11 Feb 2026, Vol 18, Issue 836

DOI: 10.1126/scitranslmed.adp3984

Abstract:

Amyloid-β (Aβ) peptides are a defining feature of Alzheimer’s disease (AD). These peptides are produced by the proteolytic processing of the amyloid precursor protein (APP), which can occur through the synaptic vesicle (SV) cycle. However, how amyloidogenic APP processing alters SV composition and presynaptic function is poorly understood. Using App knock-in mouse models of amyloid pathology, we found that proteins with impaired degradation accumulate at presynaptic sites together with Aβ42 in the SV lumen. Levetiracetam (Lev) is a US Food and Drug Administration–approved antiepileptic that targets SVs and has shown therapeutic potential to reduce AD phenotypes through an undefined mechanism. We found that Lev lowers Aβ42 levels by reducing amyloidogenic APP processing in an SV2a-dependent manner. Lev modified SV cycling and increased APP cell surface expression, which promoted its preferential processing through the nonamyloidogenic pathway. Stable isotope labeling combined with mass spectrometry confirmed that Lev prevents Aβ42 production in vivo. In transgenic mice with aggressive amyloid pathology, electrophysiology and immunofluorescence confirmed that Lev restores SV cycling abnormalities and reduces synapse loss. Last, early Aβ pathology in brains from donors with Down syndrome was characterized by elevated presynaptic proteins. Together, these findings highlight the potential to prevent Aβ pathology before irreversible damage occurs.