Alzheimer's may start with too many brain connections, not too few

The standard narrative of Alzheimer's disease goes like this: amyloid-beta protein accumulates, synapses die, connections are lost, and cognition declines. But what if the disease does not begin with losing connections? What if it begins with gaining too many?

A study from King's College London, published in Translational Psychiatry, provides evidence for this alternative sequence. Working with rat brain cells, researchers showed that low concentrations of amyloid-beta -- the protein that forms the hallmark plaques of Alzheimer's -- can trigger an increase in neural connections. This hyperconnectivity closely resembles the pattern seen in human patients with mild cognitive impairment (MCI), the clinical stage that often precedes full Alzheimer's disease.

More connections, worse function

The idea that early Alzheimer's involves increased connectivity is not entirely new. Previous brain imaging studies have detected hyperconnectivity in patients with MCI, and the finding has correlated with the earliest clinical symptoms. But the mechanism driving this increase has been poorly understood.

The King's College team, led by senior author Professor Karl Peter Giese, found that exposing rat neurons to low doses of amyloid-beta for five days was sufficient to induce the hyperconnectivity pattern. The key word is "low" -- not the massive amyloid accumulations associated with late-stage disease, but the modest levels that might be present years before diagnosis.

The researchers also identified changes in 49 proteins associated with this hyperconnectivity, including amyloid-beta's own precursor protein. This finding suggests a self-reinforcing loop: amyloid-beta at low levels triggers protein changes that promote conditions for producing even more amyloid-beta.

"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," said first author Kaiyu Wu. "Over time, this unstable state could make brain circuits more vulnerable, eventually leading to the synaptic failure and cognitive decline seen in later stages."

A cancer drug enters the picture

The Giese lab had previously identified a drug target called MAP kinase interacting kinase (MNK), which regulates the protein production changes associated with synapse increases. That target happens to be the same one hit by eFT508, a drug currently in cancer clinical trials. No one had tested it against Alzheimer's-related hyperconnectivity before.

In the rat cell experiments, eFT508 prevented the increase in connectivity caused by amyloid-beta exposure. It also restored 70% of the altered protein production back to normal levels. The drug essentially interrupted the feedback loop.

"Our research suggests a promising drug treatment for memory loss in mild cognitive impairment and early Alzheimer's disease," Giese said. "Next, our findings need to be validated first in suitable animal models, before clinical trials can commence."

What this does not mean -- yet

The study was conducted entirely in rat brain cells in culture, not in living animals or humans. Cell culture experiments can reveal mechanisms and test drug effects, but they cannot replicate the complexity of an intact brain -- the blood-brain barrier, the immune system's involvement, the interactions between brain regions, or the years-long timescale of human disease progression.

eFT508 has not been tested for safety or efficacy in Alzheimer's patients. Moving from cell culture to animal models to human trials is a process that typically takes many years and has a high failure rate, particularly in neurodegenerative disease. Many compounds that show promise in early-stage experiments do not survive this journey.

The self-reinforcing loop hypothesis, while supported by the protein expression data, would need confirmation in animal models that develop Alzheimer's-like pathology over time. The five-day exposure window in cell culture is a compressed model of what might take years in human disease.

Michelle Dyson, CEO of Alzheimer's Society, which funded the research, was cautious but optimistic. "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."

The finding does, however, contribute to a shift in how the field conceptualizes early Alzheimer's disease. If the initial problem is not synapse loss but rather the formation of excessive, poorly organized connections, then the therapeutic window -- and the therapeutic target -- may be different from what most current drug development programs assume.