At the heart of the new discovery is amyloid precursor protein (APP), a protein that plays important roles in brain development and synaptic formation. Abnormal processing of APP can lead to the production of amyloid‑beta peptides, which play a central role in the development of Alzheimer’s disease. The scientists found that how APP is trafficked also controls whether a neuron forms amyloid-beta 42.

During the synaptic vesicle cycle — a fundamental process that underlies every thought, movement, memory or sensation — levetiracetam binds to a protein called SV2A. This interaction slows down a step in which neurons recycle synaptic vesicle components from the cell’s surface. By pausing this recycling process, the drug enables APP to remain on the cell’s surface longer, diverting it away from the pathway that produces toxic amyloid‑beta 42 proteins.

“In our 30s, 40s and 50s, our brains are generally able to steer proteins away from harmful pathways,” the author said. “As we age, that 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 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.”

To effectively prevent Alzheimer’s symptoms, high-risk individuals would need to begin taking levetiracetam “very, very early,” the author said, possibly up to 20 years before the new FDA-approved Alzheimer’s disease test would even capture 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,” the author said.

Leveraging its status as an FDA-approved and widely used drug, the team mined existing human clinical data to investigate whether Alzheimer’s patients who took levetiracetam experienced slowed cognitive decline. They obtained clinical data from the National Alzheimer’s Coordinating Center and conducted a correlative analysis, finding that Alzheimer’s patients who took levetiracetam were associated with a significant delay from the diagnosis of cognitive decline to death compared to those taking lorazepam or no/other anti-epileptic drugs. ScienceMission sciencenewshighlights.

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A research team asked whether rejuvenating these engram neurons could recover memory after decline has already begun? In a study published in Neuron, the team reports that “partial reprogramming” of engram neurons restores memory performance in multiple mouse settings. The approach uses a short, controlled pulse of three genes, Oct4, Sox2 and Klf4 referred together as “OSK”

Previous studies have shown that carefully timed expression of these factors can reset several aging-related features in cells. Here, the team targeted OSK specifically at the engram neurons that are active during learning, rather than broadly across the entire brain.

Working on mice, the researchers used gene therapy vectors (adeno-associated viruses) delivered by precise brain injections. They combined two elements: a system that adds a fluorescent tag to neurons that are activated by learning, and a switch that briefly turns OSK on during a defined time window.

The team used their approach in brain areas known to support different kinds of memory: the dentate gyrus of the hippocampus, which is important for learning and recent recall, and the medial prefrontal cortex, which contributes to remote recall two weeks later.

In aged mice, briefly activating OSK in learning-related hippocampal engram neurons restored memory, essentially bringing performance back to levels seen in young controls. When the same approach was applied to prefrontal cortex engrams, it also recovered remote memories formed weeks earlier.

The reprogrammed engram neurons also showed signs of improved health. They maintained their neuronal identity and displayed molecular features associated with a younger state, including changes in nuclear structure linked to aging.

The team then tested mouse models of Alzheimer’s disease. In a spatial-learning task, the mice showed inefficient navigation and impaired memory strategies. Reprogramming dentate gyrus engrams improved learning strategies during training, while targeting prefrontal engrams restored long-term spatial memory.

Scientists have identified a conserved aging-related protein, EPS8, that promotes toxic protein aggregation linked to neurodegenerative diseases.