A team from Northwestern University identified the location and timing of the accumulation of toxic beta-amyloid proteins in the brain, and discovered a decades-old FDA-approved drug that "stops" this process before it begins.
Although scientists have long known that Alzheimer's disease arises from the accumulation of harmful proteins, they have not been able to understand how these proteins are produced. Using animal models, human nerve cells, and brain tissue from at-risk patients, the research team discovered that the protein amyloid beta 42 accumulates within synaptic vesicles, the tiny bundles of fibers that nerve cells use to transmit signals.
Experiments have shown that administering the drug "levetiracetam," known as an anticonvulsant and used to treat epilepsy and prevent seizures, prevents the formation of the "beta-amyloid 42" protein in nerve cells, opening up prospects for preventing the disease before symptoms appear.
"While most current Alzheimer's drugs aim to remove existing plaques, we discovered a mechanism that prevents the production of 'beta-amyloid 42' proteins before they accumulate, opening up new opportunities for developing preventative treatments," said lead study author Jeffrey Savvas, associate professor of behavioral neuroscience at Feinberg School of Medicine.
The discovery focuses on the amyloid precursor protein (APP), which is responsible for brain development and synaptic formation. Disruptions in APP processing can lead to the production of toxic beta-amyloid proteins.
During the synaptic vesicle cycle (a fundamental process underlying every thought, movement, memory, and sensation), levetiracetam binds to the SV2A protein (found on synaptic vesicles that helps regulate neurotransmitter release), slowing down the recycling of vesicle components and allowing the APP protein to remain on the cell surface longer, away from the pathway that produces beta-amyloid 42 proteins.
Savvas said: "As we age, the brain's ability to steer proteins away from harmful pathways weakens. In the brains of people with Alzheimer's, this leads to an accumulation of toxic proteins, then the formation of tau protein, cell death, dementia, and neuroinflammation."
Savvas emphasized that taking levetiracetam very early, perhaps up to 20 years before the onset of symptoms, is key to prevention, as the drug is ineffective once dementia develops. The team is particularly targeting patients with a genetic predisposition, such as those with Down syndrome, most of whom experience early-onset Alzheimer's due to the presence of a duplicate APP gene on their chromosomes.
Researchers used clinical data from patients taking levetiracetam to investigate its effect on cognitive decline. The analysis showed that patients taking the drug experienced slower disease progression and lived longer after a cognitive decline diagnosis compared to patients who did not take it.
The team also studied the brains of deceased individuals with Down syndrome, and the researchers observed the accumulation of proteins in the same way they had seen in experiments with mice and nerve cells, confirming that the laboratory results also apply to humans.
Savvas explained that "levetiracetam" is not ideal because it breaks down quickly in the body, and the team is working on developing an improved version that lasts longer and better targets the mechanism that prevents plaque buildup.
The study was published in the journal Science Translational Medicine.
