MADRID, Feb 12. (EUROPA PRESS) –

For years, Alzheimer’s has been one of the great unknowns of medicine. We know how it ends, we know its devastating consequences and we have seen how millions of families live with its silent advance. But there is a question that continues to worry scientists around the world: when does the process that triggers the disease really begin?

While doctors and scientists have long known that Alzheimer’s disease involves the buildup of toxic protein fragments in the brain, they have had difficulty understanding how these harmful fragments are produced.

ALZHEIMER’S COULD START MUCH EARLIER THAN WE IMAGINE

In a new study, scientists from Northwestern University (United States) have identified when and where toxic proteins accumulate within the Brains of Alzheimer’s patientsand they have discovered a drug approved by the Food and Drug Administration (FDA) decades ago that can stop the buildup process before it even begins.

The study is published in ‘Science Translational Medicine’. Now, by studying animal models, human neurons, and brain tissue from high-risk patients, the team has discovered that a particularly toxic protein fragment, called beta-amyloid 42, accumulates in neurons’ synaptic vesicles (the tiny packets they use to send signals). However, when scientists administered levetiracetam (a cheap, decades-old anti-seizure drug) to animals and human neurons, the drug prevented the neurons from forming beta-amyloid 42.

“While many of the Alzheimer’s drugs currently 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,” said corresponding author Jeffrey Savas, associate professor of behavioral neurology at Northwestern University Feinberg School of Medicine.

“Our new results revealed new biological characteristics and, at the same time, opened the door to new drug targets.”

At the center of the new discovery is amyloid precursor protein (APP), a protein that plays an important role in brain development and synaptic formation. Abnormal processing of APP can lead to the production of beta-amyloid peptides, which play a critical role in the development of Alzheimer’s disease. Northwestern scientists discovered that the way APP is transported also determines whether a neuron forms beta-amyloid 42.

During synaptic vesicle cycling (a fundamental process underlying every thought, movement, memory, or sensation), levetiracetam binds to a protein called SV2A. This interaction slows down a step in which neurons recycle components of cell surface synaptic vesicles. By stopping this recycling process, the drug allows APP to remain on the cell surface for longer, diverting it from the pathway that produces toxic beta-amyloid proteins 42.

“Between the ages of 30, 40 and 50, our brains are generally able to divert proteins away from harmful pathways,” Savas points out. “As we age, that protective ability gradually weakens. This is not a disease statement; it’s just part of aging. But in brains that develop Alzheimer’s, too many neurons go astray, and that’s when beta-amyloid 42 is produced. And then tau (or ‘tangles’) is produced, and then dead cells, then dementia, then neuroinflammation, and then it’s too late.”

To effectively prevent Alzheimer’s symptoms, high-risk people would need to start taking levetiracetam “very, very early,” Savas says, possibly up to 20 years before the new FDA-approved Alzheimer’s test can even detect slightly elevated levels of beta-amyloid 42. “You can’t take this when you already have dementia because the brain has already undergone a series of irreversible changes and a lot of cell death,” Savas says.

THE KEY WOULD BE TO ACT 20 YEARS EARLIER

Therefore, Savas says that he and his team could try to identify populations of patients with genetic forms of Alzheimer’s, including patients with Down syndrome. Although these patients are relatively rare, They constitute the key group that will benefit from these discoveries.

Taking advantage of its status as an FDA-approved and widely used drug, the team analyzed existing human clinical data to investigate whether Alzheimer’s patients who took levetiracetam experienced slower cognitive decline. They obtained clinical data from the National Alzheimer’s Coordination Center and performed a correlative analysis, finding that Alzheimer’s patients who took levetiracetam had a significant delay from the diagnosis of cognitive impairment to death, compared to those who took lorazepam or no other antiepileptic drug.

“Although the magnitude of the change was small (on the scale of a few years), this analysis supports the positive effect of levetiracetam in slowing the progression of Alzheimer’s pathology,” warns Savas.

The study also examined the brains of people with Down syndrome. In addition to using genetically modified mouse models and cultured human neurons, the scientists also studied human brain tissue from Down syndrome patients who died in their 20s and 30s due to traffic accidents or other accidents. More than 95% of patients with Down syndrome will develop an early, aggressive form of Alzheimer’s around age 40, Savas explained, because the APP gene is linked to the chromosome that triples in their genome.

“By obtaining Down syndrome patient brains from people who died in their 20s and 30s, we know that they would have eventually developed Alzheimer’s, which gives us the opportunity to study early changes in the human brain,” says Savas.

The study thus discovered that these brains had the same accumulation of presynaptic proteins that the Savas laboratory had found in mouse models designed in a previous article. “This is what we and others call the paradoxical stage of Alzheimer’s disease, which is that before synapses are lost and dementia occurs, the first thing that occurs is the accumulation of presynaptic proteins,” says Savas. “Therefore, it is possible that if levetiracetam were started in these patients in adolescence, it could have a preventive therapeutic benefit.”

Savas assures that levetiracetam “is not perfect” and points out that the drug breaks down in the body very quickly. He and other researchers are developing an improved version of levetiracetam, which would last longer in the body and help to better act on the mechanism that prevents the formation of plaques.