Alzheimer’s scrambles memories while the brain rests

The researchers say their findings, published in Current Biology, could support the development of future drug treatments that target this malfunctioning process. The work may also help guide the creation of new tools for detecting Alzheimer's earlier than is currently possible.

Understanding How Alzheimer's Disrupts Brain Cells

Co-lead author Dr Sarah Shipley (UCL Cell & Developmental Biology) explained that Alzheimer's disease is driven by the accumulation of damaging proteins and plaques in the brain. These changes lead to symptoms such as memory loss and difficulty navigating familiar environments, but the precise ways these plaques interfere with normal brain activity are still unclear.

"Alzheimer's disease is caused by the build-up of harmful proteins and plaques in the brain, leading to symptoms such as memory loss and impaired navigation -- but it's not well understood exactly how these plaques disrupt normal brain processes.

"We wanted to understand how the function of brain cells changes as the disease develops, to identify what's driving these symptoms.

"When we rest, our brains normally replay recent experiences -- this is thought to be key to how memories are formed and maintained. We found this replay process is disrupted in mice engineered to develop the amyloid plaques characteristic of Alzheimer's, and this disruption is associated with how badly animals perform on memory tasks."

How the Brain Replays Memories

This replay activity takes place in the hippocampus, a brain region essential for learning and memory. During rest, specific neurons known as place cells activate in rapid sequences that mirror recent experiences.

Place cells, discovered by Nobel prize-winning UCL neuroscientist Professor John O'Keefe, are neurons (brain cells) that correspond to particular locations. As a person or animal moves through a space, different place cells fire in a specific order. Later, during rest, those same cells typically reactivate in the same sequence, helping the brain store the experience as a memory.

Tracking Brain Activity During Memory Tasks

To study this process, researchers tested how mice performed in a simple maze while recording brain activity at the same time. Using specialized electrodes, they were able to monitor roughly 100 individual place cells simultaneously as the animals explored and then rested.

This approach allowed the team to compare normal brain replay patterns with those seen in mice that had developed amyloid pathology associated with Alzheimer's disease.

Disorganized Replay and Fading Memory Signals

In mice with amyloid plaques, memory replay looked very different. Replay events occurred just as often as they did in healthy mice, but the underlying patterns were no longer organized. Instead of reinforcing memories, the coordinated activity of place cells became scrambled.

The researchers also observed that place cells in affected mice grew less stable over time. Individual neurons stopped reliably representing the same locations, especially after rest periods, which are normally when replay should strengthen memory signals.

Memory Performance Declines in Affected Mice

These changes had clear behavioral effects. Mice with disrupted replay performed worse in the maze, frequently revisiting paths they had already explored and appearing unable to remember where they had been.

Co-lead author Professor Caswell Barry (UCL Cell & Developmental Biology) said the study reveals a failure in memory consolidation that can be seen at the level of single neurons.

"We've uncovered a breakdown in how the brain consolidates memories, visible at the level of individual neurons. What's striking is that replay events still occur -- but they've lost their normal structure. It's not that the brain stops trying to consolidate memories; the process itself has gone wrong."

Implications for Early Detection and Treatment

Professor Barry added that these findings may help researchers identify Alzheimer's earlier or develop treatments that focus on restoring normal replay activity.

"We hope our findings could help develop tests to detect Alzheimer's early, before extensive damage has occurred, or lead to new treatments targeting this replay process. We're now investigating whether we can manipulate replay through the neurotransmitter acetylcholine, which is already targeted by drugs used to treat Alzheimer's symptoms. By understanding the mechanism better, we hope to make such treatments more effective."

The research was carried out by scientists in the UCL Faculties of Life Sciences and Brain Sciences, with support from the Cambridge Trust, Wellcome, and the Masonic Charitable Foundation.