Science Daily

by Netherlands Institute for Neuroscience - KNAW

    Some people have the brain changes associated with Alzheimer's disease but never develop dementia. While others experience worsening memory and thinking problems, these individuals remain mentally sharp despite signs of the disease in their brains. Scientists have long struggled to explain why.

    Now, researchers at the Netherlands Institute for Neuroscience have uncovered a promising clue. Their findings suggest that a rare group of brain cells, known as immature neurons, may behave differently in people who resist Alzheimer's symptoms. Rather than simply replacing damaged cells, these neurons could help protect the brain from the harmful effects of the disease.

    This remarkable ability is known as cognitive resilience. It describes how some people maintain their memory and thinking abilities even when their brains show signs of damage or disease.

"Around 30 percent of older adults who develop Alzheimer's disease never experience its symptoms," says Evgenia Salta, senior author of the research. "We really don't know why. That's a big mystery, and a very important one."

    Understanding this mystery could transform how scientists approach Alzheimer's, shifting attention from what causes brain cells to deteriorate toward what allows certain brains to remain healthy and functional.

Can the Aging Brain Repair Itself

    One possible explanation for cognitive resilience is that some brains have a greater ability to repair or protect themselves as Alzheimer's progresses.

    "Perhaps they can add new brain cells to a network that is degenerating," Salta says.

    This possibility involves a biological process called adult neurogenesis, which refers to the production of new nerve cells (neurons) in an adult brain. Neurons are specialized cells that transmit information throughout the nervous system, allowing us to think, learn, remember, and respond to our surroundings.

    Scientists have established that adult neurogenesis occurs in several animal species. Whether it continues to happen in the adult human brain, however, has been a subject of scientific debate for decades.

    If the human brain can produce new neurons later in life, those cells might help maintain important connections as aging and disease damage existing networks. However, finding immature neurons does not necessarily prove that they were recently formed.

    To investigate this possibility, Salta and her colleagues examined donated human brain tissue obtained through the Netherlands Brain Bank, a research resource that collects and preserves brain samples.

    The researchers compared three groups: people without detectable brain pathology, patients who developed Alzheimer's dementia, and individuals whose brains showed Alzheimer's pathology but who remained cognitively resilient.

    The team concentrated on a small region within the brain's memory center, an area believed to be among the few locations where new neurons might develop.

    Finding the relevant cells was far from straightforward.

"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 researchers also developed new approaches to analyzing their data, allowing them to identify the cells more precisely without relying heavily on assumptions drawn from animal studies.

Scientists Find Immature Neurons in Brains Over 80

    The search revealed something remarkable. Immature neurons were present across all three groups, including in the brains of older adults.

    These cells resemble neurons that have not yet fully matured, suggesting that the aging brain may retain cellular features associated with development and adaptability.

    "Even at an average age of over 80, we still found these immature neurons in all groups," Salta says.

    But the most intriguing discovery came when researchers compared the brains of people who had developed dementia with those who had remained mentally sharp despite Alzheimer's pathology.

    Initially, the scientists expected resilient individuals to have substantially more immature neurons. If these cells help replace damaged neurons, having greater numbers might explain why some brains withstand the disease.

    Instead, the difference in cell numbers was much smaller than anticipated.

    That unexpected result pointed toward another explanation. The important distinction might not be how many immature neurons a brain contains, but how those cells respond when the brain comes under attack.

A Hidden Defense Against Alzheimer's Damage

    When the team examined the activity of immature neurons more closely, they identified striking differences between the groups.

    In cognitively resilient individuals, the cells showed signs of activating biological processes associated with survival and protection against damage.

"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."

    Inflammation is part of the body's normal defense system, but when it becomes persistent in the brain, it can contribute to damage and interfere with communication between neurons. Cell death, meanwhile, gradually disrupts the networks responsible for memory and thinking.

    The findings suggest that immature neurons in resilient brains may be better equipped to withstand these harmful conditions.

    More surprisingly, their role might extend beyond protecting themselves.

"It might not be (only) about replacing lost neurons," Salta 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."

    In other words, rather than serving only as replacements for dying neurons, immature cells could potentially help maintain the environment surrounding existing brain cells.

    Such support might allow neural networks to continue functioning even as Alzheimer's related damage accumulates.

Why Scientists Are Cautious About the Discovery

    Although the results offer an intriguing explanation for cognitive resilience, Salta emphasizes that the researchers have not established exactly what these immature neurons do.

    Their conclusions about the cells' possible protective roles are based on patterns observed in brain tissue, not direct experiments demonstrating those functions.

    "We assume the cells' function based on the data, but we cannot confirm it in this type of study," she explains.

    That distinction is particularly important because research on adult neurogenesis has attracted considerable public attention, sometimes leading to claims that go beyond what scientists have demonstrated.

    The presence of immature neurons does not establish that new neurons are continuously being produced in older humans, nor does it prove that these cells are responsible for preventing dementia.

    Other biological mechanisms almost certainly contribute to cognitive resilience as well.

"This is one piece of a very large puzzle," Salta concludes. "There will never be just one factor that explains resilience."

Could Alzheimer's Research Shift Toward Protecting the Brain

The findings raise a broader question about aging: Why do some people's brains remain relatively stable while others experience progressive cognitive decline

"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."

    To explore this further, the researchers plan to investigate how immature neurons communicate and interact with neighboring brain cells. Understanding those relationships may reveal whether the cells actively contribute to resilience and how their protective responses might work.

    The research also reflects a growing change in how scientists think about Alzheimer's disease.

    Traditionally, much of the field has focused on understanding the processes that damage the brain, including the accumulation of abnormal proteins and the loss of neurons. Increasingly, researchers are also asking why some brains remain functional despite those changes.

    By identifying the mechanisms behind this natural resistance, scientists hope to uncover new ways to preserve memory and cognitive abilities as people age.

"Cognitive resilience is extremely exciting," Salta says. "If we understand what protects these brains, it could eventually lead to new therapeutic strategies."

    Although practical treatments remain a distant possibility, the discovery suggests that even in old age, the human brain may possess protective abilities that scientists are only beginning to understand.