Summary: Approximately 30% of older adults whose brains are riddled with Alzheimer’s pathology never actually experience dementia symptoms. This phenomenon, known as cognitive resilience, is the focus of a new study.
Using samples from the Netherlands Brain Bank, the research found that even in donors over age 80, the brain continues to produce “immature” neurons. The key to resilience isn’t just the number of these new cells, but their behavior: in resilient brains, these cells activate survival programs that reduce inflammation and “fertilize” the surrounding degenerating tissue.
Key Facts
- The 80-Year-Old Nursery: The study confirmed that adult neurogenesis (the birth of new neurons) occurs in the human brain even at advanced ages, regardless of whether the person has Alzheimer’s or not.
- Survival Programs: In resilient individuals, immature neurons show lower signals of cell death and inflammation. Instead, they activate genetic programs that help them cope with damage.
- The Fertilizer Hypothesis: Rather than simply replacing dead cells (a one-for-one swap), these young neurons may act as a “support system,” helping to maintain the health and youthfulness of the surrounding brain network.
- A Strategic Pivot: This research marks a shift in neuroscience from studying how the brain fails to studying how some brains succeed in the face of pathology.
Source: KNAW
Why do some people experience memory loss and cognitive decline as Alzheimer’s builds up in their brain, while others stay mentally sharp?
This question lies at the heart of new research into “cognitive resilience”, a phenomenon that is gaining attention in neuroscience.
“Around 30 percent of older adults who develop Alzheimer’s disease never experience its symptoms”, Evgenia Salta, last author begins. “We really don’t know why. That’s a big mystery, and a very important one.”
Can the brain repair itself?
One possible explanation is that resilient brains are better at repairing themselves during Alzheimer’s. “Perhaps they can add new brain cells to a network that is degenerating”, Salta says.
This idea is linked to a process called adult neurogenesis, which refers to the birth of new brain cells (neurons) in the adult brain. It has been well-established in other animals, but its existence in humans has been debated for years.
To study this, Salta’s team used human brain tissue from the Netherlands Brain Bank, which collects and stores donated brain samples for research. They included brains from control donors with no brain pathology, Alzheimer’s patients, and individuals with Alzheimer’s pathology who remained resilient to developing dementia.
The team focused on a small part of the brain’s memory centre, likely one of the few areas where these new brain cells could form. “These cells are extremely rare, so we had to develop new ways to find them,” Salta says. “We really zoomed in on the exact spot where we expected them to be.”
The team also used new data analysis methods to make sure they could identify these cells as accurately as possible, without relying too much on assumptions from research on animals.
Finding immature neurons
Salta’s team found what they were looking for: so-called “immature” neurons. These cells resemble young, not fully developed neurons. “Even at an average age of over 80, we still found these immature neurons in all groups,” Salta says.
But the biggest surprise came next. While the team had expected to find much more of these cells in the resilient group than in the Alzheimer’s patients, the difference was not as big as expected.
It’s not the number, it’s the behaviour
Surprisingly, the team found that the key difference lies in how the immature neurons behave. “In resilient individuals, these cells seem to activate programs that help them survive and cope with damage,” Salta says. “We also see lower signals related to inflammation and cell death.”
This points to a more complex story than they thought. “It might not be (only) about replacing lost neurons,” she explains. “It could be that these cells support the surrounding tissue and help the brain stay functional and ‘youthful’. They may act as a sort of fertilizer in a garden that has started falling apart.”
Salta is careful not to jump to any conclusions, especially in light of recent media hype surrounding the topic. While the data suggest how cells might function, this can’t be tested directly yet. “We assume the cells’ function based on the data, but we cannot confirm it in this type of study,” she explains.
“This is one piece of a very large puzzle,” she concludes. “There will never be just one factor that explains resilience.”
Towards new perspectives on Alzheimer’s
Ultimately, Salta’s research points to a broader question: what determines how the brain ages? “Somewhere along this trajectory, there’s a kind of decision point,” Salta explains. “Some people remain stable, others develop dementia. We want to understand what drives that difference.”
Future work will focus on how these immature neurons interact with other brain cells, and how this interaction might influence resilience.
Although the findings do not provide immediate answers on why some cells behave different in Alzheimer’s patients and resilient individuals, they contribute to a growing shift in Alzheimer’s research: from focusing solely on disease progress to understanding resilience to it.
“Cognitive resilience is extremely exciting,” Salta says. “If we understand what protects these brains, it could eventually lead to new therapeutic strategies.” For now, the message is clear: the aging brain may be more adaptable, and more complex, than we once thought.
Key Questions Answered:
A: It’s a matter of “quality over quantity.” While most brains continue to make these cells, the cells in resilient brains appear to be better “trained” or equipped to survive the toxic Alzheimer’s environment. They don’t just exist; they actively fight back against inflammation.
A: It suggests the brain has an intrinsic capacity for repair. However, in people with symptomatic Alzheimer’s, that repair mechanism seems to be stalled or overwhelmed. The goal of future therapy would be to “wake up” these immature neurons in everyone.
A: These immature neurons are incredibly rare and fragile. The team had to use high-resolution “zooming” techniques and new data analysis methods to identify them without relying on old assumptions from animal studies, which often don’t translate perfectly to 80-year-old human brains.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Alzheimer’s disease and neurology research news
Author: Eline Feenstra
Source: KNAW
Contact: Eline Feenstra – KNAW
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Transcriptional profiles of immature neurons in aged human hippocampus track Alzheimer’s pathology and cognitive resilience” by Giorgia Tosoni, Dilara Ayyildiz, Sarah Snoeck, Elena P. Moreno-Jiménez, Amber Penning, Estibaliz Santiago-Mujika, Olmo Ruiz Ormaechea, Hyunah Lee, Suresh Poovathingal, Kristofer Davie, Julien Bryois, Will Macnair, Jasper Anink, Luuk E. De Vries, Sahand Farmand, Erik Nutma, Dick F. Swaab, Eleonora Aronica, Jinte Middeldorp, Sandrine Thuret, Laurent Roybon, Onur Basak, Carlos P. Fitzsimons, Paul J. Lucassen, and Evgenia Salta. Cell Stem Cell
DOI:10.1016/j.stem.2026.04.002
Abstract
Transcriptional profiles of immature neurons in aged human hippocampus track Alzheimer’s pathology and cognitive resilience
The existence and functional significance of immature neurons in the adult human brain, particularly in the context of neurodegenerative disorders, remain an open question.
Although rodent studies have highlighted active roles for adult-born immature neurons in the hippocampus both under healthy conditions and in Alzheimer’s disease (AD), evidence from the human brain is limited and lacks detailed molecular characterization.
To address this gap, we performed single-nucleus RNA sequencing in aged healthy, AD, and dementia-resilient human hippocampus samples to probe immature neuronal signatures and gene expression alterations associated with AD pathology and resilience.
By applying an integrated experimental and computational pipeline, we identified persistent populations of immature neurons across all donor groups, with transcriptional profiles reflecting “juvenile” cellular functions, which are compromised in AD.
Our findings suggest that the presence of these immature neuronal populations per se may actively contribute to maintaining homeostasis within the aged human hippocampus and to cognitive resilience in AD.
