New research suggests the brain may lose its ability to adjust to change before the first obvious memory symptoms appear.
What if Alzheimer’s disease first reveals itself not through memory loss, but through an inability to adapt? New research from Texas A&M Health suggests the brain’s capacity to change course, learn new rules, and adjust to unexpected situations may begin to decline before the memory problems most people associate with the disease.
In the study, young 5xFAD mice, a widely used model of Alzheimer’s disease, struggled with this kind of cognitive flexibility months before they showed spatial memory deficits. Because these mice also develop amyloid-beta plaques similar to those seen in humans, the findings point to executive function as a potential early target for detecting and treating Alzheimer’s disease.
Executive Function Changes Appear First
“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.
To test adaptability, researchers used a reversal learning task. The animals first learned that one action led to a reward. Then the rule changed, and a different action became the right choice. Healthy animals adjusted. The Alzheimer’s models kept choosing the old option, even when it no longer paid off.
Despite this, they performed normally on spatial memory tests, indicating that their memory remained intact even as their ability to adapt declined.
This pattern suggests the earliest effects of Alzheimer’s disease may involve executive function rather than memory. Executive function helps people plan, make decisions, control their behavior, and adapt to new information. When it begins to falter, people may become stuck in routines, struggle when plans change, or have difficulty shifting away from familiar behaviors.
Overactive Brain Circuits Drive Early Changes
The researchers traced the problem to an overactive brain circuit linking the medial prefrontal cortex and the striatum. These regions help guide flexible, goal-directed behavior. In the Alzheimer’s models, the pathway appeared unusually active, while a group of cells called cholinergic interneurons showed reduced activity. These cells help regulate learning and behavioral adjustment.
The finding points to a possible chain reaction. Highly active neurons can increase amyloid-beta production. Amyloid-beta can then make neurons more excitable, creating a feedback loop that may push the brain further out of balance.
Wang described the problem as a “chicken-and-egg” cycle. To test whether interrupting it could help, the team used a targeted method to quiet the overactive pathway, like temporarily turning down a “dimmer switch” in the circuit connecting the front of the brain to the striatum.
The result was striking. Reducing activity in that circuit improved cognitive flexibility, helped restore more normal brain activity, and lowered amyloid-beta accumulation. The benefits also lasted after the intervention ended, suggesting the circuit may have been partly reset.
What the Findings Could Mean for Early Diagnosis
The work was done in animal models, so it cannot yet show that the same pattern happens in people. Still, it adds to a growing idea in Alzheimer’s research: memory loss may be only one part of the early disease story. Changes in adaptability, judgment, and flexible thinking may also deserve closer attention.
If future studies confirm the findings in humans, cognitive flexibility tests could one day help support earlier Alzheimer’s detection. They would not replace existing diagnostic tools, but they might add another way to spot brain changes before more obvious memory decline begins.
“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.”
Reference: “Early-Stage Corticostriatal Hyperactivity Impairs Cognitive Flexibility Alongside Striatal Cholinergic Dysfunction in an Alzheimer’s Disease Model” by Yufei Huang, Xueyi Xie, Zhenbo Huang, Ruifeng Chen, Himanshu Gangal, Xuehua Wang, Karienn Souza, Julia Hunter, Xin Wu, Doodipala Samba Reddy, Jeannie Chin and Jun Wang, 26 June 2026, Nature Communications.
DOI: 10.1038/s41467-026-74817-z
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.
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