Anti-Seizure Drug Levetiracetam Shows Promise in Preventing Alzheimer's Disease

Northwestern University researchers found that the anti-seizure medication levetiracetam prevented the formation of toxic amyloid beta peptides, which are small protein fragments in the brain that are commonly seen in Alzheimer's patients. The medication was found to prevent the formation of amyloid-beta 42 in both animal models and cultured human neurons, according to study findings published in Science Translational Medicine.

The anti-seizure medication, levetiracetam, was first approved by the FDA in November 1999 under the brand name Keppra as a therapy for partial-onset seizures in adults. The approval has since expanded to include children and other types of seizures.

The effect was also seen in post-mortem human brain tissue obtained from individuals with Down syndrome, who are at high risk for Alzheimer's disease. The project started in 2015, driven by a simple question: what goes wrong at the very beginning of Alzheimer's disease?

Using gene-edited mouse models of Alzheimer's, the researchers tracked how quickly proteins were made and broken down in the brain. By feeding the animals a harmless, non-radioactive isotope, they were able to track protein turnover across the brain, and pinpoint which pathways began to break down at the earliest stages of disease. Very few proteins had impaired turnover, but all of the proteins that had impaired turnover were associated with presynaptic terminals and synaptic vesicles.

Presynaptic terminals are the 'sending' side of neurons, where chemical signals are packaged into tiny sacs called synaptic vesicles and released to communicate with other cells. The findings pointed to a problem not with dying neurons, but with how neurons communicate, long before classic Alzheimer's pathology appears.

Using the mouse models, the researchers found that the most toxic form, Aβ42, accumulates inside synaptic vesicles alongside other presynaptic proteins that fail to degrade properly. This buildup disrupts synaptic function early in the disease — before plaques form and before neurons die.

Levetiracetam binds to SV2A and, in both mouse models and human neurons, blocks the production of amyloid-beta. It does this by keeping APP on the cell surface, where it is more likely to be processed in a harmless, non-amyloid-forming way.

The brain is better able to avoid the pathway that produces toxic amyloid‑beta 42 proteins in younger years, but the aging process gradually weakens that ability. 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 42 production. That then leads to tau ("tangles") — abnormal clumps of protein inside brain neurons — which can kill brain cells, trigger neuroinflammation and lead to dementia.

In order for levetiracetam to function as an Alzheimer's blocker, high-risk patients would have to start taking it "very, very early" — up to 20 years before elevated amyloid-beta 42 levels would be detected. 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.

The researchers also did a deep dive into previous human clinical data to determine whether Alzheimer's patients who were taking the anti-seizure drug had slower cognitive decline. They reported that the patients in that category had a "significant delay" in the span from cognitive decline to death compared to those not taking the drug. 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.

The study had several limitations, including that it relied on animal models and cultured cells, with no human trials conducted. Because the study was observational in nature, it can't prove that the medication caused the prevention of the toxic brain proteins.

Levetiracetam is not perfect, as it breaks down in the body very quickly. The team is currently working to create a "better version" that would last longer in the body and "better target the mechanism that prevents the production of the plaques."

The medication's common documented side effects include drowsiness, weakness, dizziness, irritability, headache, loss of appetite and nasal congestion. It has also been linked to potential mood and behavior changes, including anxiety, depression, agitation and aggression. In rare cases, it could lead to severe allergic reactions, skin reactions, blood disorders and suicidal ideation.

Looking ahead, the research team aims to find people who have genetic forms of Alzheimer's to participate in testing. Funding for the study was provided by the National Institutes of Health and the Cure Alzheimer's Fund.