Scientists Discover How the APOE4 Gene May Set the Stage for Alzheimer’s Long Before Symptoms

A common genetic variant linked to Alzheimer’s disease may begin reshaping the brain long before memory problems appear, according to new research. Scientists report that APOE4, the strongest known genetic risk factor for Alzheimer’s, can make neurons smaller and hyperactive years before cognitive decline becomes apparent.

The study, conducted at Gladstone Institutes and published in Nature Aging, traces a chain of events linking APOE4 to altered brain circuits and later memory loss. The research also identifies a protein called Nell2 as a key mediator of these changes and a potential target for future therapies.

APOE4’s role in Alzheimer’s risk

APOE is a gene involved in cholesterol transport and brain repair and exists in three common forms: APOE2, APOE3 and APOE4. About one in four people carries at least one copy of APOE4, and the variant is found in an estimated 60% to 75% of people with Alzheimer’s disease.

People with one APOE4 copy have a substantially higher lifetime risk of developing Alzheimer’s, while those with two copies face an even greater risk and often earlier onset. Until now, however, scientists have struggled to pinpoint how APOE4 alters brain function long before symptoms emerge.

The new findings suggest that APOE4 accelerates processes resembling normal aging within memory circuits, pushing vulnerable neurons toward disease-related changes earlier in life. This could help explain why carriers of the variant are more likely to develop dementia sooner than non-carriers.

Early hyperactivity in memory circuits

Previous human imaging studies have detected unusually high activity in the hippocampus, a key memory center, among young and middle-aged APOE4 carriers. This hyperactivity has been associated with faster cognitive decline, although the underlying cellular mechanisms have remained poorly understood.

To investigate, the Gladstone team examined brain activity in young mice engineered to carry human APOE4. Recordings from the hippocampus revealed excessive firing in two regions important for spatial learning and memory, mirroring patterns previously observed in human carriers.

Researchers then followed the mice as they aged and tested their performance on memory tasks. Animals with the greatest hippocampal hyperactivity early in life later performed worst on spatial learning and memory tests, linking early circuit changes to subsequent cognitive deficits.

By contrast, mice carrying APOE3, a neutral or lower-risk version of the gene, did not show the same early hyperactivity. Their hippocampal neurons became more excitable only at older ages, suggesting that APOE4 accelerates an age-related trajectory rather than creating an entirely different pathway.

Neurons shrink and become overexcitable

When researchers examined individual hippocampal neurons in APOE4 mice, they found that affected cells were notably smaller than those in APOE3 mice. Neuron size matters because smaller cells generally require less input to fire, making them easier to overstimulate.

This combination of reduced size and increased excitability appears to create chronic hyperactivity within important memory circuits. Over time, such excessive activity may stress neurons, interfere with information processing and contribute to the synaptic and cognitive decline associated with Alzheimer’s disease.

Importantly, these changes appeared while young mice were still performing normally on memory tests. This suggests that brain circuits may compensate for early dysfunction for a period, concealing underlying vulnerability until the system can no longer adapt.

APOE4 inside neurons, not support cells

Most APOE protein in a healthy brain is produced by astrocytes, support cells that help nourish and protect neurons. For years, researchers believed APOE4’s harmful effects were primarily driven by astrocytes and their interactions with plaques and inflammation.

However, the new research points toward a different source: APOE4 produced within neurons themselves. When researchers removed APOE4 only from astrocytes in mice, hippocampal hyperactivity remained unchanged, suggesting that astrocyte-derived APOE4 was not the main driver.

In contrast, deleting APOE4 specifically from neurons caused hippocampal cells to grow larger and behave more like normal neurons. Their firing patterns became less extreme and circuit hyperactivity was significantly reduced, directly linking neuronal APOE4 to functional disruption.

Nell2 emerges as a key molecular link

To determine how APOE4 inside neurons produces these structural and functional changes, researchers analyzed gene expression patterns across different hippocampal cell types. One molecule, Nell2, stood out because its levels were unusually high in APOE4-expressing neurons.

Nell2 is a neuronal protein involved in axon growth and synaptic development, but its role in Alzheimer’s disease and APOE4 biology has not been extensively studied. Previous research had reported elevated Nell2 in the brains of people with Alzheimer’s, with higher levels associated with worse cognitive function.

Using a gene-silencing technique called CRISPR interference, researchers reduced Nell2 production in hippocampal neurons from adult APOE4 mice. After Nell2 levels declined, the neurons became larger and less excitable, while hyperactivity within the affected circuits decreased.

These experiments suggest that elevated Nell2 is a critical step connecting APOE4 with neuronal shrinkage and hyperexcitability. Targeting Nell2 or its downstream signaling pathways could therefore represent a potential therapeutic strategy for people at increased genetic risk.

Therapeutic window and future directions

One of the study’s notable findings was that reducing Nell2 in adult mice could still reverse key aspects of neuronal dysfunction. This suggests that APOE4-induced changes may not be fixed and that there could be an opportunity for intervention even after these risk pathways have become active.

Any future treatment targeting Nell2 would require careful safety testing because the protein plays a role in normal brain development and plasticity. Researchers will also need to establish whether the same mechanisms operate in human neurons and across diverse populations of APOE4 carriers.

The findings come amid a broader shift in Alzheimer’s research toward earlier detection and prevention. As blood tests and imaging methods improve at identifying risk years before dementia develops, molecular targets such as Nell2 could potentially provide ways to move beyond monitoring risk toward modifying underlying disease-related processes.

Although APOE4 represents only one part of the complex biology behind Alzheimer’s disease, understanding its effects on neurons could help inform more tailored strategies for millions of people who carry the variant. The Gladstone team plans to investigate whether approaches targeting Nell2 can be translated into drug candidates and combined with other emerging treatments.

The research was supported by multiple grants from the U.S. National Institute on Aging, the National Institute of Neurological Disorders and Stroke, and the National Center for Research Resources. Together, these efforts reflect continued investment in understanding and potentially intercepting Alzheimer’s disease at its earliest stages.