Scientists have made a breakthrough in understanding how Alzheimer’s disease develops, and a decades-old drug could be the key to stopping the condition in its tracks.
It is well established that Alzheimer’s is characterized by an accumulation of toxic proteins in the brain.
Now, scientists at Northwestern University have identified when and where those proteins amass, and they say a drug already on the market could prevent the perilous pile-up.
Analyzing animal models, human neurons and brain tissue from high-risk patients, the Northwestern research team found that the toxic protein amyloid-beta 42 collects inside synaptic vesicles, the tiny sacs that store neurotransmitters.
When scientists applied levetiracetam — a cheap antiseizure drug primarily sold under the brand name Keppra — to animal and human neurons, the medication prevented those neurons from forming amyloid-beta 42.
“While many of the Alzheimer’s drugs currently on the market 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 study author Jeffrey Savas, associate professor of behavioral neurology at Northwestern’s Feinberg School of Medicine.
“Our new results uncovered new biology while also opening doors for new drug targets,” he continued.
Alzheimer’s is the most common form of dementia, marked by a decline in memory, thinking and learning. Nearly 7 million Americans are living with dementia, but researchers say millions more likely have dementia symptoms but no formal diagnosis.
One in every 5 women and 1 out of every 10 men 45 years or older will develop Alzheimer’s in their lifetime.
Key to this new research is the team’s discovery of the amyloid precursor protein (APP), which plays a critical role in synapse formation and brain development.
Abnormal APP processing can trigger the brain’s production of amyloid‑beta peptides, which contribute to the development of Alzheimer’s. However, researchers found that levetiracetam enables APP to divert from the pathways that produce amyloid‑beta 42.
“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. In the brains of people 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.”
Savas and his team analyzed human clinical trials and found that Alzheimer’s patients who took levetiracetam experienced a significant delay between dementia diagnosis and death.
“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,” said Savas.
He shared that to prevent the onset of Alzheimer’s symptoms, high-risk individuals would need to begin a levetiracetam protocol “very, very early,” up to 20 years before current testing could capture even 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 explained.
Due to the preventative, rather than curative, nature of this treatment, Savas and his team will next attempt to identify patients with rare, genetic forms of Alzheimer’s, including patients with Down syndrome.
According to Savas, more than 95% of patients with Down syndrome will develop early Alzheimer’s by age 40.
Studying Down syndrome patients who died in their 20s and 30s, Savas notes that their brains display early, initial changes.
“That is what we 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,” he said.
“Conceivably, if you started giving these patients levetiracetam in their teenage years, it could actually have a preventative therapeutic benefit,” he continued.
Despite the team’s promising findings, Savas maintains that levetiracetam “is not perfect.”
A primary disadvantage of the medication is that it rapidly breaks down in the body. As such, Savas and others are developing an improved, long-lasting version that will amplify its ability to prevent the production of the damaging plaques.
