Neurons exposed to amyloid-beta formed more connections (SSBs = single synaptic boutons), which could be lessened with cancer drug eFT508.
Image Credit: Figure reproduced from Wu et al. 2026
Scientific Frontline: Extended "At a Glance" Summary: Early Alzheimer's Hyperconnectivity and eFT508
The Core Concept: In the earliest stages of Alzheimer's disease, typically correlating with Mild Cognitive Impairment (MCI), low levels of the amyloid-beta protein induce an abnormal increase in neural connections (hyperconnectivity) prior to widespread cell death and memory loss.
Key Distinction/Mechanism: Challenging the traditional model that Alzheimer's begins primarily with synapse loss, this research demonstrates that the disease may actually initiate with too many poorly organized connections. Amyloid-beta rewires, rather than simply increases or decreases, cellular protein production, pushing neurons into an unstable state. The experimental cancer drug eFT508, which targets MAP kinase interacting kinase (MNK), successfully prevented this hyperconnectivity and restored normalized protein production in laboratory models.
Major Frameworks/Components:
- Amyloid-Beta Induced Synaptogenesis: Exposure to low doses of amyloid-beta over a short five-day period triggers hyperconnectivity and creates a self-reinforcing loop by upregulating the amyloid precursor protein.
- Expansion Microscopy: A state-of-the-art imaging technique that expands biological samples 5 to 6 times, enabling researchers to visualize and quantify individual synapses as small as 30 nanometers.
- Liquid-Chromatography Mass-Spectrometry: An analytical method used to profile internal neuronal changes, identifying 49 specific proteins whose production was altered by amyloid-beta exposure.
- MNK Inhibition (eFT508): The pharmacological mechanism utilized by the repurposed cancer drug to decrease neuroinflammation, inhibit abnormal protein synthesis, and restore approximately 70% of altered protein production.
Branch of Science: Neuroscience, Neurobiology, and Pharmacology.
Future Application: The potential repurposing of eFT508—a clinically licensed drug currently in cancer trials—as an early intervention therapy to halt memory loss and prevent cognitive decline during the MCI phase of Alzheimer's disease, pending further validation in animal models and human clinical trials.
Why It Matters: This discovery fundamentally shifts the therapeutic target for early Alzheimer's disease from preventing synapse loss to correcting initial hyperconnectivity. By identifying a mechanism that occurs before irreversible cellular damage, it opens a vital new window for intervention and demonstrates the viability of drug repurposing in neurodegenerative disease research.
Neuroscientists at King’s College London have pinpointed a mechanism behind the increased neural connectivity seen in very early stages of Alzheimer’s disease.
Published in Translational Psychiatry, the study then demonstrated that a cancer medication has the potential to reverse this early stage hyperconnectivity.
The research conducted in brain cells of rats showed that low levels of the protein amyloid-beta could induce hyperconnectivity, and this pattern closely resembled changes seen in the brains of people with Mild Cognitive Impairment. Amyloid-beta is thought to be instrumental in Alzheimer’s disease, where it creates plaques – or sticky clumps of amyloid-beta proteins – around the neurons.
These new findings suggest that low levels of amyloid-beta alone are enough to trigger early, disease-relevant changes in how brain cells connect.
Changes in neural connectivity in early stages of Alzheimer’s disease
Previous research has found that the number of connections (synapses) between neurons in the brain increases during the earliest stages of Alzheimer’s disease and it has been shown that these initial changes correlate with a mild cognitive impairment (MCI) in patients. MCI is characteristic of the early stages of Alzheimer's disease, prior to widespread cell death and memory loss.
It was previously unknown what causes the initial increase in connectivity, and it remains unclear how it then relates to the progression and ultimate loss of connections later in the disease.
Amyloid-beta is a protein that has been associated with Alzheimer’s disease. Research has shown that in early stages of the disease, neurons start to produce more amyloid-beta than normal. As the disease progresses, the amyloid-beta proteins start to form clumps, known as plaques.
This new study from King’s College London shows that low doses of amyloid-beta over a short period of five days can cause hyperconnectivity between brain cells. The study also identifies a series of changes in levels of other proteins that work together to increase connectivity in the early stages of the disease.
Creating Alzheimer’s disease in the lab
To create the conditions of early stages of Alzheimer’s disease, similar to those seen whilst patients experience mild cognitive impairment, researchers exposed neurons from rats to amyloid-beta for just five days. The neurons soon started to produce more amyloid-beta proteins than normal.
Researchers then used a state-of-the-art microscopy technique called expansion microscopy to look at individual connections – or synapses – between neurons. Expansion of microscopy causes biological samples to expand 5-6 times, allowing researchers to examine structures as small as 30 nanometers in size, with fluorescence microscopy. Expansion microscopy revealed that exposing the neurons to amyloid-beta for five days caused the number of synapses between neurons to increase significantly.
Widespread cellular changes caused by early stages of the disease
The researchers then used a method called liquid-chromatography mass-spectrometry to investigate what was happening inside the neurons exposed to amyloid-beta. Many changes inside neurons involve changes in gene-expression: the process by which genes are ‘read’ and proteins are made, a bit like a production line in a factory. Liquid-chromatography mass-spectrometry allows scientists to see which proteins are being made more than others, a bit like checking the stock in the factory for example.
They found that amyloid-beta didn’t cause the neurons to change how many proteins they produced. Rather, it changed which proteins were being made. The researchers identified 49 proteins that were affected by exposure to amyloid-beta. In healthy neurons, these proteins play important roles, such as maintaining the shape and structure of the cell, signaling between neurons and energy production.
“Amyloid-beta doesn’t simply increase or decrease protein production — it rewires it. This shift may push neurons into an unstable state that promotes abnormal synapse formation,” explained Kaiyu Wu, first author on the study.
One of the proteins that was produced more by neurons exposed to amyloid-beta was amyloid precursor protein, the protein that eventually becomes amyloid-beta.
“This suggests the system may act as a self-reinforcing loop in which amyloid-beta promotes conditions that lead to even more amyloid-beta,” explained Kaiyu Wu.
A drug that helps restore normality
Previous work from the same research group at King’s has identified a drug target that might be able to alter protein production associated with synapse increases. This target, MAP kinase interacting kinase (MNK), is also the target of the clinically licensed drug eFT508, currently used in cancer clinical trials. The drug is also known to decrease neuroinflammation and inhibit the synthesis of proteins involved in tumor growth. It has never been used to investigate or treat Alzheimer’s disease before.
Professor Giese and his team found that eFT508 prevented the increase in connectivity caused by amyloid-beta exposure. Using liquid-chromatography mass-spectrometry, they also found that the drug was also able to restore 70% of the altered protein production after amyloid-beta exposure.
"Our research suggests a promising drug treatment for memory loss in MCI and early Alzheimer’s disease. Next, our findings need to be validated first in suitable animal models, before clinical trials can commence."Professor Karl Peter Giese, Professor of Neurobiology of Mental Health, senior author on the study.
Rethinking how AD begins
“The results of this new study contribute to a new way of thinking about Alzheimer’s disease,” explained PhD student Kaiyu Wu, first author on the paper. “Instead of starting with synapse loss, the disease may begin with too many poorly organized connections, combined with subtle but targeted changes in protein production. Over time, this unstable state could make brain circuits more vulnerable, eventually leading to the synaptic failure and cognitive decline seen in later stages of the disease.”
Michelle Dyson, Chief Executive Officer at Alzheimer’s Society said: “This study builds our knowledge of brain cell changes in early-stage Alzheimer’s disease and suggests that with intervention we may be able to counteract some of these changes as Alzheimer’s disease develops.
“It’s important to note this was very early-stage work in animal cells rather than human participants, so more research is needed. But it shows how drug repurposing is a promising avenue for us to explore if we are to end the devastation of dementia - a condition that affects around one million people in the UK.
“For decades, cancer research has set the benchmark for what can, and should, be done for dementia. Research will beat dementia and we look forward to seeing how this research progresses.”
Funding: This research was funded by the Alzheimer’s Society.
Published in journal: Translational Psychiatry
Authors: Kaiyu Wu, Suji Lee, Raquel Martinez-Serra, Lanyue Zhang, Steven Lynham, and Karl Peter Giese
Source/Credit: King’s College London
Reference Number: ns030926_03