CHICAGO — While physicians and scientists have long known Alzheimer’s disease involves the buildup of toxic protein fragments in the brain, they have struggled to understand how these harmful fragments are produced.
Now, in a new study, Northwestern University scientists have pinpointed when and where toxic proteins accumulate within the brains of Alzheimer’s patients — and discovered a decades-old Food and Drug Administration (FDA)-approved drug that can stop the accumulation process before it even begins.
By studying animal models, human neurons and brain tissue from high-risk patients, the team discovered a particularly toxic protein fragment, called amyloid-beta 42, accumulates inside neurons’ synaptic vesicles — the tiny packets that neurons use to send signals. But, when the scientists administered levetiracetam (an inexpensive, decades‑old anti‑seizure drug) to the animals and human neurons, the drug prevented neurons from forming 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 corresponding author 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 will be published Feb. 11 in Science Translational Medicine.
Introduction of anti-seizure drug to the Alzheimer’s fight
At the heart of the new discovery is amyloid precursor protein (APP), a protein that plays important roles in brain development and synaptic formation. Abnormal processing of APP can lead to the production of amyloid‑beta peptides, which play a central role in the development of Alzheimer’s disease. The Northwestern scientists found that how APP is trafficked also controls whether a neuron forms amyloid-beta 42.
During the synaptic vesicle cycle — a fundamental process that underlies every thought, movement, memory or sensation — levetiracetam binds to a protein called SV2A. This interaction slows down a step in which neurons recycle synaptic vesicle components from the cell’s surface. By pausing this recycling process, the drug enables APP to remain on the cell’s surface longer, diverting it away from the pathway that produces toxic amyloid‑beta 42 proteins.
“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.”
Drug would need to be taken ‘very, very early’
To effectively prevent Alzheimer’s symptoms, high-risk individuals would need to begin taking levetiracetam “very, very early,” Savas said, possibly up to 20 years before the new FDA-approved Alzheimer’s disease test would even capture mildly elevated levels of amyloid-beta 42.
“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.
Because of this, Savas said he and his team might attempt to identify patient populations with genetic forms of Alzheimer’s, which includes patients with Down syndrome. Although these patients are somewhat rare, they are the key group to benefit from these discoveries.
Mining existing human clinical data
Leveraging its status as an FDA-approved and widely used drug, the team mined existing human clinical data to investigate whether Alzheimer’s patients who took levetiracetam experienced slowed cognitive decline. They obtained clinical data from the National Alzheimer’s Coordinating Center and conducted a correlative analysis, finding that Alzheimer’s patients who took levetiracetam were associated with a significant delay from the diagnosis of cognitive decline to death compared to those taking lorazepam or no/other anti-epileptic drugs.
“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.
Study also examined Down syndrome brains
In addition to using genetically engineered mouse models and cultured human neurons, the scientists also studied human brain tissue from deceased patients with Down syndrome who died in their 20s or 30s from car accidents or other events. More than 95% of patients with Down syndrome will develop an early and aggressive form of Alzheimer’s by around age 40, Savas said, because the APP gene is linked to the chromosome that is triplicated in their genome.
“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.
The study found these brains had the same accumulation of presynaptic proteins that Savas’ lab had found in engineered mouse models in a previous paper.
“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.”
Savas said levetiracetam “is not perfect,” and noted that the drug breaks down in the body very quickly. He and others are in the process of making a better version of levetiracetam, which would last longer in the body and help better target the mechanism that prevents the production of the plaques.
The study is titled, “Levetiracetam prevents Aβ production through SV2a-dependent modulation of App processing in Alzheimer’s disease models.”
Other Northwestern study authors 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.
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