Destination Health

Does hyperactivity 'burn out' the brain? New lead behind Alzheimer's gene

The idea behind a new study is that the disease is not rooted in a deficit but in an excess of activity at the level of the hippocampus

by Maria Rita Montebelli

21 April 2026

Alzheimer's disease concept, Elderly woman holding brain symbol of missing jigsaw puzzle, World Alzheimer's, World mental health, Memory loss, Dementia, Parkinson disease. ipopba - stock.adobe.com

4' min read

Translated by AI

Versione italiana

Key points

Too much activity is not good news
The culprits are not 'support' cells but neurons
A new idea of Alzheimer's and new therapeutic targets

4' min read

Translated by AI

Versione italiana

Perhaps the most disturbing feature of Alzheimer's disease is that by the time it is diagnosed, it is already too late. Memory falters, names fade, the faces of loved ones blur into a thousand. But this is only the epilogue of the disease. The onset, we now know, lies much further back in time. And it unfortunately goes unnoticed.

But new research conducted by Dennis R. Tabuena and colleagues at the Gladstone Institute of Neurological Disease (San Francisco, USA) and published in Nature Aging sheds new light on this silent beginning. And it does so by following in the footsteps of a well-known player in Alzheimer's disease: the ε4 'variant' of the ApoE4 gene, the most important genetic risk factor for Alzheimer's (60-75% of people with the disease carry this gene).

For one in four people, ApoE4 is part of their DNA and while it is not a sentence, it significantly increases the risk of developing Alzheimer's. Complicating the picture is that it does not act suddenly, like a time bomb, in old age. This study shows that the 'fuse' is very long: that is, ApoE4 starts to do damage many years earlier, when the brain is still young and apparently fully functional.

In experimental animals carrying ApoE4, American researchers have observed that the hippocampus, the memory centre, is hyperactive. When there are as yet no symptoms and no memory loss, beneath this appearance of normality, the brain has already changed the way it functions. And it is these changes that predict what will happen many years later, according to the study authors.

Too much activity is not good news

And it seems a paradox, because we are used to thinking that an 'active' brain is a healthy brain. In this case, however, the opposite is true. The hyperactivity observed at the level of the hippocampus resembles more an electrical apparatus under stress, a voltage overload: everything works, but it consumes too much too quickly. And over time, this excess can wear down brain circuits, making them more vulnerable to decline. The idea behind this new theory, in short, is that Alzheimer's is not rooted in a deficit, but in an excess of activity.

Looking in even more detail, the authors of the study discovered another important clue. In the brains of Apoe4 carriers, some neurons are smaller than normal.

An almost invisible detail that makes a huge difference. Because a smaller neuron is also more 'nervous', more excitable. It activates more easily, responds more quickly to stimuli. And this generates a network that never switches off, that always stays switched on. Too much so.

The culprits are not the 'support' cells but the neurons

For years, scientists thought that the problem came from the brain's support cells, the astrocytes. But this research disproves this. Alzheimer's seems to originate from the neurons themselves. In fact, the researchers observed that by removing the ApoE4 gene from the neurons, everything normalised. By removing it from the other cells, practically nothing changed. And this is a real paradigm shift: the neurons do not suffer the damage. They cause it themselves, slowly, over years.

The possible 'culprit' in the story, the hand wielded by the ApoE4 gene is called Nell2 and is a protein that is more abundant in neurons with ApoE4. Nell2 seems to orchestrate the whole process, causing the formation of smaller, more excitable neurons and generating an imbalance in the electrical circuits.

At this point, the researchers tried to reduce Nell2 levels (by means of CRISPR, a targeted gene editing technique) in experimental animals (adult mice) and this resulted in the complete reversal of this Alzheimer's process. The 'defects' underlying the disease were not slowed down or limited. They have even been reversed. And this opens up a huge hope, almost too good to be true: the damage observed in the brain of a subject with Alzheimer's may not be a one-way, definitive and irrevocable journey.

A new idea of Alzheimer's and new therapeutic targets

Alzheimer's disease has always been portrayed as a disease of loss: neurons dying, memories fading. But this research suggests something different. The disease does not start with loss, but with overactivity, an overworked network. And the news is that this process could be stopped or even reversed by acting in time.

Admittedly, this is a study on animal models, so caution in drawing conclusions to apply to humans is in order. But these results are consistent with what has been observed so far in humans. The next step will therefore be to understand whether intervening in Nell2 or related mechanisms can also be successful in humans. A deeper understanding of these mechanisms could pave the way for targeted therapies capable of counteracting the damage linked to the ApoE4 variant in Alzheimer's disease. If so, it would be a revolution and would make it possible to rewrite the ending of the story, long before we reach the last page.