Common Anticonvulsant May Prevent Alzheimer’s Plaque Formation

For years, Alzheimer’s disease has remained one of medicine’s most challenging mysteries. While the devastating consequences are well-known and millions of families grapple with its progression, scientists continue to investigate a fundamental question: when does the process that triggers the disease actually begin?

Unraveling the Early Stages of Alzheimer’s

Medical professionals have long understood that Alzheimer’s involves the buildup of toxic protein fragments in the brain. However, pinpointing how these damaging fragments are produced has proven difficult. New research from the University of Northwestern (United States) suggests the disease may begin much earlier than previously imagined.

The study, published in ‘Science Translational Medicine’, identifies when and where toxic proteins accumulate in the brains of Alzheimer’s patients. Researchers discovered that a common, FDA-approved anticonvulsant drug could potentially halt this accumulation even before it starts.

A New Mechanism of Action

Researchers found that a particularly toxic protein fragment, beta-amyloid 42, accumulates within the synaptic vesicles of neurons – the tiny packages neurons use to send signals. However, administering levetiracetam to animal models, human neurons, and brain tissue from high-risk patients prevented the formation of beta-amyloid 42.

“While many of the Alzheimer’s medications currently available on the market, such as lecanemab and donanemab, are approved to remove existing amyloid plaques, we have identified this mechanism that prevents the production of beta-amyloid 42 peptides and amyloid plaques,” explained Jeffrey Savas, professor of behavioral neurology at Northwestern University’s Feinberg School of Medicine.

The research centers on the amyloid precursor protein (APP), which plays a role in brain development and synapse formation. Abnormal processing of APP can lead to the production of beta-amyloid peptides, central to Alzheimer’s development. Scientists discovered that how APP is transported also determines whether a neuron forms beta-amyloid 42.

How Levetiracetam Intervenes

During the synaptic vesicle cycle, levetiracetam binds to a protein called SV2A. This interaction slows down the process by which neurons recycle components from the cell surface. By halting this recycling, the drug allows APP to remain on the cell surface longer, diverting it from the pathway that produces toxic beta-amyloid 42 proteins.

According to Savas, between the ages of 30, 40, and 50, the brain is generally capable of diverting proteins from harmful pathways. However, this protective ability weakens with age. In brains developing Alzheimer’s, too many neurons are diverted, leading to beta-amyloid 42 production, followed by tau accumulation, cell death, dementia, and neuroinflammation.

Looking Ahead

To effectively prevent Alzheimer’s symptoms, individuals at high risk may need to begin taking levetiracetam “very, very early,” potentially 20 years before a new FDA-approved test can even detect slightly elevated levels of beta-amyloid 42. The drug is not effective once dementia has already set in, as the brain has already undergone irreversible changes and significant cell death.

Savas and his team are exploring identifying patient populations with genetic forms of Alzheimer’s, including those with Down syndrome, who could benefit most from these findings. They also analysed existing clinical data from the National Alzheimer’s Coordinating centre, finding that Alzheimer’s patients who took levetiracetam experienced a significant delay from cognitive impairment diagnosis to death compared to those taking lorazepam or no other anti-epileptic drug.

Although the change was small—measured in a few years—this analysis supports the potential of levetiracetam to slow the progression of Alzheimer’s pathology. Savas notes that levetiracetam is “not perfect” and breaks down quickly in the body, prompting research into a longer-lasting version of the drug.

Frequently Asked Questions

When does the process of Alzheimer’s disease begin?

The study suggests the process may begin much earlier than previously thought, with toxic protein accumulation potentially starting decades before symptoms appear.

What is levetiracetam and how does it work?

Levetiracetam is a decades-old, FDA-approved anticonvulsant drug that appears to prevent the formation of beta-amyloid 42 by interfering with the recycling process within neurons.

Who might benefit most from this research?

Individuals with genetic forms of Alzheimer’s, including those with Down syndrome, are identified as the group most likely to benefit from these discoveries.

What role could preventative measures play in addressing this complex disease?