Existing epilepsy drug may prevent toxic Alzheimer’s proteins before plaques form

Northwestern University researchers have reported that levetiracetam, a long-established anti-epileptic medicine, prevented formation of the toxic amyloid-beta 42 fragment in preclinical models by altering synaptic vesicle recycling

Physicians and neuroscientists have long known that Alzheimer’s disease involves toxic protein accumulation in the brain, yet researchers have struggled to determine exactly where the most harmful fragments first emerge and how to stop their formation at source.

A team from Northwestern University, Evanston, Illinois, USA, has now reported that amyloid-beta 42 – a key toxic fragment – accumulates within synaptic vesicles inside neurons, and that levetiracetam, which is an anti-epileptic medicine approved for many years by the US Food and Drug Administration, prevented formation of that fragment in experimental conditions.

The study used genetically engineered mouse models, cultured human neurons, and post-mortem brain tissue from people at very high genetic risk of Alzheimer’s pathology. Across these systems, investigators identified a pathway linking synaptic vesicle cycling to amyloid-beta 42 production. They then reported that levetiracetam interrupted this pathway before downstream plaque formation.

“While many of the Alzheimer’s drugs currently on the market – such as lecanemab and donanemab – 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,” Dr. Jeffrey Savas said, corresponding author and associate professor of behavioural neurology at Northwestern University Feinberg School of Medicine.

“Our results uncovered novel biology while also opening doors for novel drug targets,” he added.

At the centre of the mechanism is amyloid precursor protein, a neuronal protein with important roles in brain development and synaptic organisation. Under some conditions, cleavage and trafficking of amyloid precursor protein can favour production of amyloid-beta peptides, including amyloid-beta 42. The team concluded here that intracellular routing of amyloid precursor protein is a major determinant of whether neurons enter this toxic pathway.

The authors described the effect within the synaptic vesicle cycle, a core process that supports neurotransmission and therefore cognition, memory, sensation and movement. Levetiracetam binds synaptic vesicle glycoprotein 2A (SV2A). In this work, that interaction appeared to slow a recycling step that returns vesicle material from the neuronal surface into the terminal. With recycling reduced, amyloid precursor protein remained longer at the cell surface and shifted away from intracellular processing routes 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. This is not a statement of disease; this is just a part of ageing. But in brains developing Alzheimer’s, too many neurons go astray, and that’s when you get amyloid-beta 42 production.

“And then it’s tau, and then it’s dead cells, then dementia, then neuroinflammation – and then it’s too late,” he added.

This timing issue is central to the translational argument with the team proposing that any preventative strategy based on this mechanism would likely require very early use in high-risk groups, potentially up to two decades before current biomarker tests would detect mild biochemical elevation. In practice, this frames levetiracetam not as a rescue therapy for established dementia but as a candidate for pre-symptomatic risk management in narrowly defined populations.

“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 said.

To test whether existing human data aligned with laboratory findings, the researchers analysed records from the US National Alzheimer’s Coordinating Center. In correlative analyses, they reported that Alzheimer’s patients who received levetiracetam showed a statistically significant delay from diagnosis of cognitive decline to death, compared with people who received lorazepam or other, or no, anti-epileptic medicines. The investigators emphasised that effect size was modest.

“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,” Savas said.

A distinctive part of the study examined tissue from donors with Down syndrome who died in early adulthood from causes such as traffic incidents. This cohort allowed researchers to investigate very early pathological states in brains with known genetic predisposition. More than 95 per cent of people with Down syndrome develop an early and aggressive form of Alzheimer’s pathology by about age 40 – linked to trisomy of chromosome 21 – which carries the amyloid precursor protein gene.

“By obtaining Down syndrome patient brains from people who died in their 20s or 30s, we know they would have eventually developed Alzheimer’s, so it gives us an opportunity to study the very initial early changes in the human brain,” Savas said.

The team reported presynaptic protein accumulation in these samples, consistent with earlier findings in engineered mouse models. This early phase appears before synaptic loss and before clinical dementia which suggests a potential intervention window. The authors also noted that levetiracetam is not an ideal endpoint molecule because it breaks down quickly in the body. Savas said his team and collaborators have started work to develop longer-lasting derivatives that retain the same synaptic mechanism with improved pharmacological performance.

Taken together, the findings position synaptic vesicle trafficking as an actionable upstream process in Alzheimer’s biology rather than a secondary consequence of plaque pathology. They also support a wider shift in neurodegeneration research, from plaque clearance after damage to early interception of toxic protein production before irreversible neuronal loss occurs.

Article title: Levetiracetam prevents Aβ production through SV2a-dependent modulation of App processing in Alzheimer’s disease models