Cheap drug may prevent plaques linked to dementia from forming

By Stephen Beech

A cheap drug prescribed to prevent seizures may also stop plaques linked to dementia from forming, according to new research.

While other drugs clear existing plaques, scientists say the drug called levetiracetam prevents the production of toxic amyloid beta peptides.

Experts have known for some time that Alzheimer’s disease involves the build-up of toxic protein fragments in the brain.

But they have struggled to understand how the harmful fragments are produced.

Now, American scientists have pinpointed when and where toxic proteins accumulate within the brains of Alzheimer’s patients.

And they discovered that levetiracetam - a cheap, decades‑old anti‑seizure drug - can stop the accumulation process before it even begins.

But the team say patients at risk of developing Alzheimer’s would have to start taking the current form of the drug as teenagers for it to be effective.

Researchers at Northwestern University Feinberg School of Medicine in Chicago found that 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 they scientists administered levetiracetam to animals and human neurons, the drug prevented neurons from forming amyloid-beta 42.

Study corresponding author Professor Jeffrey Savas said: “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.

“Our new results uncovered new biology while also opening doors for new drug targets.”

He explained that amyloid precursor protein (APP), a chemical that plays important roles in brain development and synaptic formation, was central to the breakthrough.

Savas says abnormal processing of APP can lead to the production of amyloid‑beta peptides, which play a "central" role in the development of Alzheimer’s.

The Northwestern team found that how APP is trafficked also controls whether a neuron forms amyloid-beta 42.

Savas explained that during the synaptic vesicle cycle - a process that underlies every thought, movement, memory or sensation - levetiracetam binds to a protein called SV2A.

Thar interaction slows down a step in which neurons recycle synaptic vesicle components from the cell’s surface.

By pausing the 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.

Savas said: “In our 30s, 40s and 50s, our brains are generally able to steer proteins away from harmful pathways.

“As we age, that protective ability gradually weakens. This is not a statement of disease; this is just a part of ageing.

"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.”

He says that to effectively prevent Alzheimer’s symptoms, high-risk patients would need to begin taking levetiracetam “very, very early” - possibly up to 20 years before the new approved Alzheimer’s disease test would even capture mildly elevated levels of amyloid-beta 42.

Savas said: “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."

Because of that, he says he and his team might attempt to identify patients with genetic forms of Alzheimer’s, which includes patients with Down syndrome.

Although those patients are somewhat rare, Savas they are the "key group" to benefit from the discoveries.

The Northwestern team mined existing human clinical data to investigate whether Alzheimer’s patients who took levetiracetam experienced slowed cognitive decline.

They obtained clinical data and conducted an 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, other anti-epileptic drugs or no medication at all.

Savas said: “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."

As well as using genetically engineered mouse models and cultured human neurons, the research team also studied human brain tissue from patients with Down syndrome who died in their 20s or 30s in car accidents or other events.

Savas says that more than 95% of patients with Down syndrome will develop an early and aggressive form of Alzheimer’s by around the age of 40 because the APP gene is linked to the chromosome that is triplicated in their genome.

He said: “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."

The study, published in the journal Science Translational Medicine, found those brains had the same accumulation of presynaptic proteins that Savas’ lab had found in engineered mouse models in a previous paper.

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.

“So conceivably, if you started giving these patients levetiracetam in their teenage years, it could actually have a preventative therapeutic benefit.”

Savas added that levetiracetam “is not perfect” - and noted that the drug breaks down in the body very quickly.

His team is now 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 plaque production.