Memory loss is by far the most notorious symptom of Alzheimer’s disease, but it might not be the initial sign of the illness. According to a new study published in Nature Communications, there’s an even earlier tell—impaired cognitive flexibility.
Cognitive flexibility is one of the brain’s executive functions governing our ability to switch between different tasks, adapt to novel situations, learn new rules, and so on. To study changes in this vital function, neuroscientists at Texas A&M University used mice genetically engineered to produce the amyloid-beta plaques associated with Alzheimer’s disease (5xFAD mice).
The team conditioned the mice to learn that a particular action (pulling a lever) led to a reward (a delicious food pellet). They then changed the rules to find out how they reacted. Healthy mice had no trouble adapting to the new regime, but the 5xFAD mice struggled, often repeatedly pulling the original lever without receiving a reward.
Read more: “Alzheimer’s Early Tell”
Importantly, these cognitive flexibility problems surfaced earlier than the kinds of memory problems typically associated with Alzheimer’s. “We found that this function was impaired before we could detect deficits in spatial memory,” study author Jun Wang said in a statement.
Taking a closer look into the 5xFAD mice brains, the researchers discovered abnormally high levels of neuroactivity in the medial prefrontal cortex, a region involved in decision-making and behavioral flexibility. Previous research has shown this kind of hyperactivity can lead to amyloid-beta plaques piling up, which in turn makes neurons even more excitable. It basically leads to a positive feedback loop.
To find out what happens when the feedback loop is interrupted, the researchers chemically quieted the overactive neurons in 5xFAD mice. They showed reduced amyloid-beta accumulation, more normalized neural activity, and improved cognitive flexibility. Remarkably, the treatment demonstrated lasting benefits, indicating persistent changes in their neural circuitry.
Of course, these findings will have to be confirmed and further researched in humans, but the team is optimistic that incorporating cognitive flexibility into the mix could help lead to earlier Alzheimer’s diagnoses.
“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.” 
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