EPFL Scientists Use AAV-Mediated Partial Reprogramming to Restore Memory in Aged and Alzheimer’s Mice

LAUSANNE, Switzerland, Feb. 10, 2026 — Researchers at EPFL’s Brain Mind Institute have demonstrated that targeted, adeno-associated virus (AAV)-mediated partial reprogramming of memory-trace neurons can restore memory performance in aged mice and mouse models of Alzheimer’s disease to levels comparable to healthy young animals.

The study, published in Neuron, provides proof of concept that precise AAV gene therapy approaches can rejuvenate dysfunctional engram neurons and reverse cognitive decline at the cellular level.

AAV Gene Therapy Targets Memory Engrams

Age-related cognitive decline and Alzheimer’s disease are associated with impaired synaptic plasticity and malfunctioning “engrams” — sparse populations of neurons that encode memory traces. While synaptic plasticity underpins learning and recall, aging and neurodegeneration disrupt the molecular programs sustaining these processes.

To address this, the EPFL team used AAV gene therapy vectors delivered through targeted brain injections to introduce a tightly controlled system enabling transient expression of three reprogramming genes: Oct4, Sox2, and Klf4 (OSK).

Rather than broadly distributing AAV across the brain, the researchers engineered the AAV system to selectively label and manipulate learning-activated engram neurons. The AAV vectors combined:

• A fluorescent tagging system to identify active engram cells

• An inducible genetic switch to transiently activate OSK expression

This AAV-based strategy allowed spatially and temporally precise control of partial reprogramming within defined neuronal populations.

Memory Restoration in Aged and Alzheimer’s Models

Using region-specific AAV delivery, the team targeted:

• The dentate gyrus of the hippocampus, critical for recent memory

• The medial prefrontal cortex, associated with remote memory recall

In aged mice, AAV-mediated OSK activation in hippocampal engrams restored recent memory to levels observed in young controls. Similarly, AAV targeting of prefrontal engrams recovered remote memories formed weeks earlier.

In mouse models of Alzheimer’s disease, AAV-driven partial reprogramming improved spatial learning strategies and restored long-term spatial memory. Molecular analyses showed that Alzheimer’s-associated alterations in gene expression and neuronal firing patterns within engram cells were partially reversed following AAV-mediated OSK induction.

Importantly, the AAV-delivered OSK pulse was brief and confined to a small subset of neurons, preserving neuronal identity while promoting molecular features associated with a more youthful state, including improvements in nuclear architecture linked to aging.

Proof of Concept for Targeted AAV Neuro-rejuvenation

The findings position AAV-mediated partial reprogramming as a promising strategy for cognitive rejuvenation. By restricting AAV vector activity to specific engram populations and limiting OSK expression temporally, the approach aims to balance regenerative benefit with cellular safety.

While translation to humans remains distant, the study highlights how precision AAV gene therapy platforms could potentially be adapted to target pathological protein aggregation, synaptic dysfunction, and neuronal aging in disorders such as Alzheimer’s disease and other neurodegenerative conditions.