🧬 The APOE4 Gene and Its Relationship to Alzheimer’s Disease

🧠 Brief Summary

New research reveals that the presence of the inherited gene APOE4, strongly linked to the risk of developing Alzheimer’s disease, may lead to changes in brain cell activity and shrinkage years before the disease’s behavioral symptoms appear. The study links these changes to increased production of the protein Nell2, which makes neurons smaller and abnormally more active. Most notably, reducing Nell2 levels restored neuron size and function to normal in mice, paving the way for future drugs that target this mechanism before symptoms appear.

🧬 The APOE4 Gene and Its Relationship to Alzheimer’s Disease

The APOE gene is considered one of the important genes that has three main forms, and the APOE4 form is the most influential in increasing the likelihood of developing Alzheimer’s disease.

About one in four people carries this gene, and it is believed to be present in 60 to 75% of people with the disease, making it a key target for understanding the causes of the disease and the mechanisms behind its progression.

🧠 How Does APOE4 Affect the Brain?

Overactivity of brain cells precedes symptoms

Previous studies have shown abnormal excessive activity in the brains of APOE4 carriers even before middle age, and this activity is associated with the emergence of cognitive decline later in life.

To clarify the reason behind these changes, the research team at the Gladstone Institutes studied brain activity in mouse models carrying the gene, recording neuron activity in hippocampus regions associated with memory.

Young mice carrying the APOE4 gene showed a noticeable increase in activity in these regions, and this excessive activity was later linked to greater difficulty in learning and memory tasks.

Neuron shrinkage and accelerated brain aging

The scientists observed that the size of neurons in mice carrying the APOE4 gene was smaller compared with mice carrying the APOE3 gene, which is associated with a lower risk of Alzheimer’s.

Smaller cells are more excitable, meaning they tend to fire nerve signals excessively, which explains the phenomenon of brain hyperactivity.

These changes begin in memory regions before the signs of normal brain aging appear, suggesting that APOE4 speeds up this process and therefore explains why Alzheimer’s disease appears at a younger age in carriers of this gene.

🩺 The Source of APOE4’s Effect: Inside Neurons

Contrary to previous assumptions that astrocytes were the main source of the APOE4 gene and its effect on Alzheimer’s risk, the research showed that the neural effect is mainly linked to the production of APOE4 inside neurons themselves.

When the APOE4 gene was removed from astrocytes, no noticeable changes occurred, but deleting the gene from inside neurons led to restoration of normal cell size and recovery of function to a healthy level.

What does this mean in practice?

This discovery suggests that targeting gene expression inside neurons may be more effective in modifying or even preventing the effects of APOE4 associated with Alzheimer’s disease.

🧪 The Nell2 Protein: A Key to Controlling APOE4 Damage

The scientific team sought to identify the molecules responsible for shrinking and stimulating neurons to excessive levels, and the Nell2 protein emerged as a primary candidate linked to increased neuron activity and small cell size.

The researchers observed elevated levels of Nell2 in cells from mice carrying APOE4, associated with increased neural excitability.

How did they prove Nell2’s role?

• The researchers used CRISPRi to suppress the activity of the Nell2 gene in adult mouse cells carrying APOE4.
• As a result, the neurons returned to a larger size and became more stable in their activity.
• This indicates that elevated Nell2 levels are primarily responsible for the APOE4-induced overactivity of neurons.

The findings also suggest that reducing Nell2 may be a promising therapeutic option, even after some pathological changes have begun to appear, providing a time window for early intervention.

🌱 Future Research and Therapeutic Prospects

This research is considered a turning point in understanding how Alzheimer’s disease occurs at the molecular and cellular levels, as it:

• Highlights the role of the APOE4 gene in early brain changes that precede clinical symptoms.
• Reveals a new biological mechanism associated with the Nell2 protein, a possible target for future treatments.
• Indicates the possibility of modifying the effects of the inherited gene even during adolescence or adulthood, rather than limiting treatment to advanced stages.

This study, led by experts from the Gladstone Institutes, provides a strong basis for further research into developing drugs that target Nell2 or the neural functions associated with APOE4, something that could change the course of Alzheimer’s disease management in the future.

In conclusion

The next challenge remains turning these discoveries into effective treatments based on modifying gene and protein activity in the brain. With ongoing research and advances in medical technology, we may one day see preventive interventions that protect millions from the risk of developing Alzheimer’s disease.

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