For the millions of people who carry the gene APOE4, the strongest known genetic risk factor for Alzheimer’s disease, brain activity can begin to change long before memory problems appear. Now, researchers at the Gladstone Institute have uncovered the exact chain of molecular events behind the initial changes and identified potential ways to reverse them.
Published in a magazine natural aging, Their new research using a mouse model reveals how APOE4 triggers increased production of the protein Nell2, causing neurons to shrink and become hyperactive. The more hyperactive the neurons are during early childhood, the more severe the memory deficits the mice develop later in life.
When the researchers reduced Nell2 production, neurons regained normal size and firing patterns even in adult mice carrying the APOE4 gene. This suggests the possibility of developing drugs that block Nell2 in human APOE4 carriers who are at high risk for Alzheimer’s disease.
To our knowledge, this is the first study to directly examine how APOE4 influences the function of neurons at different ages. We found that fundamental changes in brain circuitry occur in young mice that still have normal learning and memory, and importantly, that these changes predict the development of cognitive impairment at older ages. ”
Dr. Mischa Gilberter, Gladstone Principal Researcher, Lead Study Author
APOE4 is one of the three common variants of the APOE gene and is the one that most influences Alzheimer’s disease risk. APOE4 is found in approximately 1 in 4 people and an estimated 60 to 75 percent of all Alzheimer’s patients.
“This study is a major advance for the field of Alzheimer’s disease research,” says Yadong Huang, MD, PhD, associate director of the Gladstone Institute for Neurological Diseases and senior author of the study. “This opens the door to a deeper understanding of how APOE4 alters neuronal function at a young age and increases the risk of cognitive decline, and to the development of treatments that can block APOE4’s harmful effects early.”
The smaller the brain cells, the bigger the problem.
Previous research has shown that people with the APOE4 gene can develop brain hyperactivity even before middle age, and that this early hyperactivity predicts future cognitive decline. But exactly how APOE4 drives these changes at the cellular level, and how these early changes contribute to the risk of later cognitive decline, remained a mystery.
To address these questions, the research team analyzed recordings of brain activity in young mice and examined individual neurons in the brain. Scientists found increased neuron activity in two areas of the hippocampus, an important memory center in the brain, in young mice carrying the APOE4 gene. Surprisingly, these are the same regions that have been shown to be hyperactive in human carriers of the APOE4 gene. “We found that the level of hyperactivity in young mice predicted how poorly they would perform on tests of spatial learning and memory later in life,” said Dr. Dennis Tabuena, co-supervisor of Gilberter and Huang and lead author of the paper.
The researchers also examined neurons in mice that carry APOE3, a variant of the APOE gene that is associated with a reduced risk of developing Alzheimer’s disease in humans. At a cellular level, the researchers found that neurons in the affected areas of the brain were smaller in mice with the APOE4 gene than in mice with the APOE3 gene. Smaller neurons are known to fire more easily in response to stimulation, which can result in hyperactivity.
In mice carrying the APOE3 gene, neurons in the hippocampus also became more excitable, but this did not occur until old age.
“This suggests that APOE4 promotes a process similar to normal aging and may explain why people with the genetic mutation are more likely to develop Alzheimer’s disease early in life,” Huang says.
Let’s zoom in on the mechanism
In a healthy brain, the majority of APOE4 is produced by astrocytes, a type of brain cell that supports neurons. This is why scientists have long speculated that APOE4’s effect on Alzheimer’s disease risk is due to effects in astrocytes. However, new research shows that the relationship between APOE4 and hippocampal hyperactivity is mediated entirely by APOE4, which is made in neurons.
“When we deleted the APOE4 gene from astrocytes, nothing changed,” Gilberter says. “But when we removed it from the neurons, the cells grew larger and started functioning normally again.”
To uncover the molecular mechanisms that cause neurons to become smaller and hyperexcitable, the researchers profiled gene expression in individual cells across different cell types in the hippocampus. This analysis pointed to an important role for a molecule called Nell2, which was detected at abnormally high levels in APOE4 neurons.
Using CRISPRi, a technology that reduces gene expression without permanently altering DNA, the researchers reduced Nell2 levels in hippocampal neurons in adult mice carrying the APOE4 gene. Treated neurons became larger and less excitable, indicating that Nell2 causes hyperexcitability of neurons in APOE4-bearing brains.
Although Nell2 had not previously been studied in relation to APOE4, previous studies reported that levels of this protein are elevated in the brains of Alzheimer’s patients and that its levels are associated with cognitive decline.
“What’s interesting about Nell2 is that by reducing its levels, we were able to reverse disease symptoms in adult mice,” Huang says. “This shows that the damage is not irreversible and that there may be room for intervention even after the disease process has been triggered.”
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Reference magazines:
Tabuena, DR; others. (2026). APOE4-induced early hippocampal network hyperexcitability of neurons in the pathogenesis of Alzheimer’s disease. natural aging. DOI: 10.1038/s43587-026-01096-0. https://www.nature.com/articles/s43587-026-01096-0
