When most people think about Alzheimer’s disease, memory loss is usually the first thing that comes to mind. Forgetting a loved one’s name, missing appointments or repeatedly misplacing everyday items are often considered early warning signs.
But what if the disease begins affecting the brain long before memory problems become noticeable? New research from scientists at Texas A&M Health suggests that another change in brain function may appear even earlier: difficulty adapting when circumstances change.
In a recent study, researchers found that animal models with Alzheimer’s-related brain changes developed problems with cognitive flexibility months before they showed signs of memory impairment. Cognitive flexibility refers to the brain’s ability to adjust behavior, learn new rules and adapt when situations change.
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“We found that this function was impaired before we could detect deficits in spatial memory,” said neuroscientist Jun Wang, PhD, professor in the Texas A&M University Naresh K. Vashisht College of Medicine at Texas A&M Health.
The findings suggest memory loss is not always the earliest sign of Alzheimer’s disease. Instead, they suggest that by the time memory problems become noticeable, disease-related brain changes may already be underway. Paying attention to earlier changes in executive function — the mental processes that help people plan, adapt and make decisions — may provide additional clues about the earliest stages of the disease.
Testing the brain’s ability to adapt
To investigate these early changes, researchers used a widely studied animal model of Alzheimer’s disease known as 5xFAD. These models develop amyloid-beta plaques, one of the key features found in the brain of humans with Alzheimer’s disease.
The research team focused on measuring cognitive flexibility through a method called reversal learning. In this type of test, animal models first learn that a particular action leads to a reward. Once that association is established, researchers change the rules and reward a different action instead.
Healthy animal models quickly adjusted and learned the new rule. 5xFAD models struggled to adapt, continuing to follow the original rule even after it no longer led to a reward. What made the finding particularly significant was that although they struggled to adapt to change, the animal models still performed normally on tests of spatial memory, which is the ability to remember where things are and helps us navigate our surroundings.
A hyperactive brain circuit
The researchers then discovered abnormally high activity in the medial prefrontal cortex, the region involved in decision-making, behavioral flexibility and goal-directed actions. This hyperactivity extended through a network connecting the prefrontal cortex and the striatum, two brain regions that work together to help people adjust their behavior when circumstances change.
The team also found reduced activity in a specialized group of brain cells called cholinergic interneurons. These cells play an important role in learning and behavioral adaptation, and their decreased activity closely matched the cognitive flexibility deficits observed in the animal models.
Together, the findings suggest that Alzheimer’s disease may affect neural circuits involved in executive function and adaptability before causing noticeable memory problems.
Breaking a harmful cycle
Scientists have known that amyloid-beta production increases when neurons are highly active. At the same time, amyloid-beta can make neurons even more excitable. This creates a potentially harmful cycle in which increased brain activity promotes amyloid accumulation, which then drives even more activity.
Wang describes this cycle as a “chicken-and-egg” problem. To test whether breaking this cycle could help, the researchers used a targeted approach to quiet the overactive brain pathway. The method worked like a temporary “dimmer switch,” allowing the team to reduce the activity of selected brain cells in the front part of the brain that send signals to the striatum, a region involved in flexible behavior.
The intervention improved cognitive flexibility, restored more normal patterns of brain activity and reduced amyloid-beta accumulation. The benefits persisted after treatment ended, suggesting lasting changes within the affected neural circuits.
Implications for Alzheimer’s research
Although the study was conducted in animal models and further research is needed to determine whether the same pattern occurs in humans, the findings point to a promising new direction for Alzheimer’s research and potential future treatments.
Rather than focusing exclusively on memory loss, scientists may need to pay closer attention to early changes in cognitive flexibility and executive function that may provide clues that Alzheimer’s-related changes are already underway. The findings also suggest that abnormal brain activity may be more than just a consequence of the disease. Reducing activity in the overactive brain circuit improved cognitive flexibility and reduced amyloid-beta accumulation, suggesting that targeting these neural networks could help slow disease progression.
Wang is hopeful that if future research confirms these findings, cognitive flexibility tests could potentially complement existing diagnostic evaluations. That may help identify people at earlier stages of the disease, perhaps years before more obvious memory symptoms appear.
“One thing that most people in the field agree on is that early diagnosis is extremely important,” Wang said. “Alzheimer’s disease is progressive. Neurons continue to degenerate over time. If we can identify the disease earlier, then treatment has a much better chance of helping.”
This research was supported by the funding from the National Institute on Alcohol Abuse and Alcoholism and the Texas A&M University Division of Research Targeted Proposal Teams (TPT) funding program.
