Summary: For the one in four people carrying the APOE4 gene, the brain’s “wiring” begins to change decades before memory loss sets in. A landmark study has identified the exact molecular chain reaction behind this.
Researchers discovered that APOE4 produced within neurons triggers an overproduction of a protein called Nell2. This protein causes neurons in the hippocampus to physically shrink and become “hyperexcitable”—firing too easily and too often. This early-life hyperactivity acts as a direct predictor: the more “noisy” the brain is in youth, the more severe the memory deficits become in old age.
Key Facts
- The Nell2 Mechanism: High levels of Nell2 make neurons smaller. Because smaller cells are easier to stimulate, they become hyperactive, eventually exhausting the brain’s memory circuits.
- Reversibility: Using CRISPRi to lower Nell2 levels in adult mice, researchers successfully restored neurons to their normal size and stopped the hyperactivity, proving the damage isn’t permanent.
- Neuronal APOE4 vs. Astrocytes: While APOE4 is mostly made in support cells (astrocytes), this study proved that only the APOE4 made inside neurons causes the shrinking and hyperactivity.
- Early Predictor: The study found that hyperactivity in young mice (with otherwise normal memory) accurately predicted who would develop cognitive decline later in life.
- Human Connection: The specific regions of the hippocampus affected in mice are the exact same areas that show hyperactivity in human APOE4 carriers.
Source: Gladstone Institute
For the millions of people who carry the gene APOE4, the strongest known genetic risk factor for Alzheimer’s disease, their brain activity may begin changing long before any memory problems appear.
Now, researchers at Gladstone Institutes have uncovered a precise chain of molecular events behind those early changes and identified a potential way to reverse them.
Published in the journal Nature Aging, their new study in mouse models reveals how APOE4 triggers increased production of the protein Nell2, which makes neurons shrink and become hyperactive. The more hyperactive the neurons were in early life, the more severe were the memory problems the mice developed later in life.
When the researchers reduced the production of Nell2, neurons recovered their normal size and firing patterns—even in adult mice with the APOE4 gene. This points toward the possibility of developing drugs that block Nell2 for human APOE4 carriers at high risk for Alzheimer’s disease.
“To the best of our knowledge, this is the first study that has directly examined what APOE4 does to the function of neurons at different ages,” says Misha Zilberter, PhD, principal staff research scientist at Gladstone and a senior author of the study.
“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.”
APOE4 is one of three common variants of the APOE gene, and is by far the most consequential for Alzheimer’s risk: it can be found in roughly one in four people, and in an estimated 60 to 75 percent of all patients with Alzheimer’s.
“This study is a big breakthrough for the field of Alzheimer’s research,” says Yadong Huang, MD, PhD, associate director of the Gladstone Institute of Neurological Disease and a senior author of the study.
“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.”
Smaller Brain Cells, Bigger Problems
Previous studies had shown that human carriers of the APOE4 gene can develop brain hyperactivity even before middle age, and that this early hyperactivity predicts future cognitive decline. But exactly how APOE4 causes those changes at the cellular level—and how the early changes contribute to the risk of cognitive decline later in life—had remained a mystery.
To address these questions, the team analyzed recordings of brain activity in young mice and then examined individual neurons from their brains. In young mice with the APOE4 gene, the scientists found neuronal hyperactivity in two regions of the hippocampus, an important memory center of the brain. Strikingly, these are the same regions shown to be hyperactive in human carriers of the APOE4 gene.
“We found that the extent of hyperactivity in young mice predicted how poorly they performed on spatial learning and memory tests later in life,” says Dennis Tabuena, PhD, a scientist co-mentored by Zilberter and Huang, and first author of the new paper.
The researchers also examined the neurons of mice with APOE3—the variant of the APOE gene that is associated with a lower risk of developing Alzheimer’s disease in humans. At the cellular level, the team found that neurons in the affected regions of the brain were smaller in mice carrying the APOE4 gene than in those with the APOE3 gene. Smaller neurons are known to fire more readily in response to stimulation, which can result in hyperactivity.
In mice carrying the APOE3 gene, neurons in the hippocampus also became more excitable, but not until old age.
“This suggests APOE4 accelerates a process that resembles normal aging, and could explain why people with the gene variant are more likely to develop Alzheimer’s disease earlier in life,” Huang says.
Zooming In on Mechanism
In a healthy brain, the vast majority of APOE4 is produced by astrocytes, a type of brain cell that supports neurons. That’s why scientists have long assumed that APOE4’s effect on Alzheimer’s risk was likely due to its effect in astrocytes. But the new work shows that the link between APOE4 and hyperactivity in the hippocampus is entirely mediated by APOE4 made in neurons.
“When we deleted the APOE4 gene from astrocytes, nothing changed,” Zilberter says. “But when we deleted it from neurons, the cells became larger and started functioning normally again.”
To find the molecular mechanism causing neurons to become smaller and hyperexcitable, the team profiled gene expression in individual cells, across a variety of cell types in the hippocampus. This analysis pointed toward an important role of a molecule called Nell2, which was found at abnormally high levels in APOE4 neurons.
Using CRISPRi—a technique that reduces a gene’s expression without permanently altering DNA—the team lowered Nell2 levels in hippocampal neurons of adult mice with the APOE4 gene. Treated neurons grew larger and became less excitable, showing that Nell2 causes neuron hyperexcitability in brains with APOE4.
Nell2 had not previously been studied in the context of APOE4, although previous studies had reported elevated levels of the protein in the brains of Alzheimer’s patients, in whom those levels were associated with poorer cognitive function.
“What’s exciting about Nell2 is that we were able to reverse the disease manifestations in adult mice by lowering its level,” Huang says. “That tells us the damage is not irreversible, and that there may be a window for intervention even after disease processes have been triggered.”
About the Study
Funding: The work was supported by the National Institute on Aging (R01AG061150, R01AG087323, R01AG092390, R01AG085468, R01AG055682, R01AG071697, P01AG073082, F32AG0859612), the National Institute of Neurological Disorders and Stroke (K99NS134734), and the National Center for Research Resources (C06 RR018928).
Key Questions Answered:
A: Research in humans has shown that APOE4 carriers often show increased brain activity in their 20s and 30s. This study explains why: your neurons are likely smaller and “trigger-happy.” While you might feel fine now, this constant “over-firing” may be wearing down your memory circuits prematurely.
A: Think of a neuron like a bucket being filled with electricity. A smaller bucket overflows (fires) much faster than a large one. When millions of “small” neurons fire too easily, it creates a “noisy” brain environment that makes it harder to store and retrieve clear memories.
A: Not yet, but that is the goal! This study identifies Nell2 as a clear drug target. Because the researchers were able to fix the problem in adult mice, it suggests we might be able to treat human APOE4 carriers even after the “shrinking” process has started.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this genetics and Alzheimer’s disease research news
Author: Kelly Quigley
Source: Gladstone Institutes
Contact: Kelly Quigley – Gladstone Institutes
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Neuronal APOE4-induced Early Hippocampal Network Hyperexcitability in Alzheimer’s Disease Pathogenesis” by Dennis R. Tabuena, Sung-Soo Jang, Brian Grone, Oscar Yip, Emily A. Aery Jones, Jessica Blumenfeld, Zherui Liang, Rajkamalpreet S. Mann, Yaqiao Li, Deanna Necula, Nicole Koutsodendris, Antara Rao, Leonardo Ding, Alex R. Zhang, Yanxia Hao, Qin Xu, Seo Yeon Yoon, Samuel De Leon, Yadong Huang & Misha Zilberter. Nature Aging
DOI:10.1038/s43587-026-01096-0
Abstract
Neuronal APOE4-induced Early Hippocampal Network Hyperexcitability in Alzheimer’s Disease Pathogenesis
The full impact of APOE4 (apolipoprotein E4), the strongest genetic risk factor for Alzheimer’s disease (AD), on neuronal and network function remains unclear, particularly during early preclinical stages of disease.
Here we show that young APOE4 knockin (E4-KI) mice exhibit hippocampal region-specific network hyperexcitability that predicts later cognitive deficits. This early phenotype arises from cell-type-specific subpopulations of smaller, hyperexcitable neurons and is eliminated by selective removal of neuronal APOE4.
With aging, E4-KI mice develop granule cell hyperexcitability, progressive inhibitory dysfunction and excitation–inhibition imbalance in the dentate gyrus. Single-nucleus RNA sequencing with multilevel gene filtering reveals age-dependent and cell-type-specific transcriptional changes and identifies candidate mediators of early neuronal hyperexcitability, including Nell2.
Targeted CRISPR interference knockdown of Nell2 rescues abnormal excitability, implicating Nell2 as a contributor to APOE4-driven dysfunction.
Together, these findings define molecular and circuit mechanisms linking neuronal APOE4-induced early network impairment to AD pathogenesis with aging.
