- A new study suggests that a decades-old drug may help slow Alzheimer’s disease progression.
- The research involved animal models, human neurons, and brains from people at a high risk of developing Alzheimer’s.
- Specifically, the drug reduced the buildup of Alzheimer’s-related proteins in neurons.
A new paper, published in Science Translational Medicine, investigated whether levetiracetam, an anti-seizure medication, could form the basis for innovative drug treatments for Alzheimer’s disease.
The researchers’ three-pronged investigation showed that levetiracetam prevents the buildup of faulty amyloid-beta proteins in an animal model. They also found that when given to mice engineered to develop amyloid buildup, fewer synapses were disrupted.
While there is a long road ahead involving much more research before the drug can be repurposed for patients, the authors are optimistic about the mechanism.
With the number of people with Alzheimer’s in the United States predicted to rise to
When one nerve sends a signal to another, it must do so by crossing the gap between, called a synapse.
Once the electrical signal reaches the end of the first neuron — the presynaptic terminal — neurotransmitters are released that travel across the synapse in membrane-bound bubbles called synaptic vesicles.
Once these vesicles reach the second neuron (postsynaptic terminal), they activate receptors, and the electrical signal continues.
Levetiracetam appears to work by binding to receptors on synaptic vesicles at the presynaptic terminal, influencing the amount of neurotransmitter released. This helps calm the overactive neurons responsible for seizures.
How does that relate to Alzheimer’s? Recent research suggests that the presynaptic regions are important in the
For this reason, there has been a fair amount of research into levetiracetam and its potential to improve mild cognitive impairment (MCI) and Alzheimer’s disease. Existing studies have produced some promising results, and overall, the drug does seem to improve cognitive function in people with MCI and Alzheimer’s.
According to the authors, the precise mechanism by which levetiracetam reduces amyloid-beta buildup is unclear. So, their study digs into the mechanisms by which levetiracetam might work.
Other drugs designed to address protein buildups associated with Alzheimer’s can successfully clear proteins that have already accumulated, but they do not provide much benefit for patients.
The authors hope that by preventing the accumulation, rather than clearing the existing accumulation, levetiracetam-based drugs might make more of a difference to disease progression.
Scientists already understood that amyloid precursor protein (APP) is part of the issue in the development of Alzheimer’s disease. If it is processed incorrectly, it creates faulty, misfolded forms of beta-amyloid.
What the new study adds to this is the discovery that the way in which APP is transported also determines whether a neuron forms misfolded protein.
As we explained, vesicles travel between the presynaptic and postsynaptic neurons. As part of this process, synaptic vesicles are recycled at the neuronal cell surface so they can be reused.
The scientists found that levetiracetam slows this recycling, keeping APP at the cell surface for longer, preventing it from heading down the chemical biopathway to become misfolded and toxic.
“In our 30s, 40s, and 50s, our brains are generally able to steer proteins away from harmful pathways,” explains corresponding author Jeffrey Savas, associate professor of behavioral neurology at Northwestern University Feinberg School of Medicine in Chicago, IL.
“As we age, [the brain’s] 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 production. And then it’s tau (or ‘tangles’), and then it’s dead cells, then dementia, then neuroinflammation — and then it’s too late.”
— Jeffrey Savas, corresponding author
Medical News Today reached out to Dr. Christina Ni, a psychiatrist and interventional psychiatry medical director with Mindpath Health, who was not involved in the study.
“A key advance is the reframing of Alzheimer’s as an early presynaptic disorder. This paradigm shift reinforces Alzheimer’s as an early presynaptic disorder, not solely a late-stage plaque-driven disease.”
“This positions the synapse as a viable early therapeutic target,” she concluded.
Sadly, although the mechanism may well help scientists design useful drugs for dementia, as it stands, it will not be the answer we are looking for. According to Savas, for the drug to work, you would need to take it “very, very early.”
You would need to take it long before there were any psychological or neurological signs.
“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,” he explains.
So, for future work, Savas plans to look at populations with significantly elevated risk of Alzheimer’s, like people with Down syndrome, as these people could likely benefit. “If you started giving these patients levetiracetam in their teenage years, it could actually have a preventative therapeutic benefit.”
Another issue is that the drug breaks down very quickly once it is in the body, so Savas and his colleagues are planning on designing similar drugs that persist longer.
Alongside their mechanistic work, the researchers also looked through existing data on the use of levetiracetam. Because it has been FDA-approved for decades, there is ample research into its safety and efficacy.
In particular, they investigated whether people with Alzheimer’s who were prescribed levetiracetam experienced slower cognitive decline compared with people prescribed other anti-epileptics with a different mechanism of action.
As hoped, they found that individuals taking levetiracetam had a longer duration between cognitive decline and death. In other words, disease progression seemed to be slowed.
“Although the magnitude of change was small (on the scale of a few years),” says Savas, “this analysis supports the positive effect of levetiracetam to slow the progression of Alzheimer’s pathology.”
However, more work lies ahead. “While clinical translation remains necessary, caution is warranted,” explained Ni. “These findings are largely preclinical, sex-specific effects were observed, and the relevance to sporadic late-onset Alzheimer’s remains to be fully established. Optimal dosing, timing of intervention, and long-term cognitive outcomes will require further clinical validation.”
