For millions of people worldwide, carrying the APOE4 gene variant means a significantly higher risk of developing Alzheimer’s disease. Yet one of the biggest unanswered questions has been when, and how, that risk begins to take hold in the brain.
New research from the Gladstone Institutes, published in Nature Aging, suggests that the effects of APOE4 emerge far earlier than previously understood. The study shows that subtle but important changes in brain activity occur long before memory loss begins, offering a potential window for early intervention.
Early changes in a seemingly healthy brain
Alzheimer’s disease is typically diagnosed after cognitive symptoms appear, but growing evidence suggests that the disease process begins decades earlier. The new study adds to this picture by demonstrating that brain circuits in young individuals carrying APOE4 are already functioning differently.
We found fundamental changes in brain circuits occurring in young mice that still had normal learning and memory, and importantly, that those changes predicted the development of cognitive deficits at older ages, ” said Misha Zilberter, PhD, principal staff research scientist at Gladstone and senior author of the study.
The researchers observed increased neuronal activity in the hippocampus, a brain region essential for learning and memory. Similar patterns of hyperactivity have been reported in human APOE4 carriers, even before clinical symptoms arise.
According to the scientists, this suggests that Alzheimer’s risk is not simply a matter of late-stage degeneration, but may instead involve long-term changes in how brain circuits are wired and function.
Smaller neurons, stronger signals
To understand what drives this early hyperactivity, the team examined individual brain cells. They found that neurons in key regions of the hippocampus were physically smaller in APOE4 carriers compared to those with the more common, lower-risk APOE3 variant.
While this might seem like a minor structural difference, it has functional consequences. Smaller neurons are more easily activated, meaning they fire more readily in response to stimuli. This heightened sensitivity can lead to persistent hyperactivity within neural circuits.
Over time, this imbalance may place stress on the brain and contribute to the gradual decline seen in Alzheimer’s disease.
A surprising source of dysfunction
For years, researchers believed that APOE4’s effects were primarily driven by astrocytes, support cells in the brain that produce most of the APOE protein. However, the new findings challenge this assumption.
The team discovered that the disruptive effects on brain activity were instead linked to APOE4 produced directly by neurons themselves. When APOE4 was removed from neurons, their size and activity returned to normal. Removing it from astrocytes, by contrast, had little effect.
This shift in understanding refocuses attention on neurons as key drivers of early disease processes, rather than passive victims of surrounding dysfunction.
A reversible pathway—and a new target
Perhaps the most striking finding of the study is that these early changes may not be permanent.
The researchers identified a protein called Nell2 as a central player in the process. Levels of Nell2 were elevated in APOE4 neurons and appeared to drive both the reduction in cell size and the increase in neuronal activity.
By reducing Nell2 levels in adult mice, the team was able to restore normal neuron structure and function—even after the changes had already occurred.
“What’s exciting about Nell2 is that we were able to reverse the disease manifestations in adult mice by lowering its level,” said Yadong Huang, co-senior author of the study. “That tells us the damage is not irreversible […].”
This raises the possibility of developing therapies that target Nell2, potentially slowing or preventing disease progression in individuals at high genetic risk.
Implications for early intervention
APOE4 is present in roughly one in four people and in the majority of Alzheimer’s patients. Despite this, current treatments largely focus on late-stage symptoms rather than early prevention.
The new findings suggest that intervening earlier, before cognitive decline begins, could be key. If brain circuit changes can be detected and corrected at an early stage, it may be possible to delay or even prevent the onset of Alzheimer’s disease.
The study also highlights the importance of understanding how genetic risk translates into functional changes in the brain. Rather than acting as a simple risk marker, APOE4 appears to actively reshape neural activity over time.
A shift in perspective
More broadly, the work reflects a growing shift in Alzheimer’s research, from focusing solely on hallmark features such as amyloid plaques and tau tangles to examining earlier, subtler changes in brain function.
By identifying a concrete pathway linking genetic risk to altered brain activity, the study provides a clearer framework for understanding how the disease develops.
“This study is a big breakthrough for the field of Alzheimer’s research,” Huang said. “It opens the door to a better understanding of how APOE4 alters the function of neurons at a young age to increase risk of cognitive decline, and to the development of therapies that could block the detrimental effects of APOE4 early on.”
While the findings are based on mouse models, they align closely with observations in humans and offer a strong foundation for future research. The next steps will involve determining whether targeting Nell2 or similar pathways can produce similar benefits in human patients.
If successful, such approaches could transform how Alzheimer’s disease is treated, not as an inevitable consequence of aging, but as a process that can be detected early and potentially reversed.
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