Long Before Memory Fails, The Brain May Already Be Showing Signs of Alzheimer's

What if the first signs of Alzheimer's disease weren't forgetfulness? A new study shows that the brain may first lose its ability to adapt to change, long before memory fails. This discovery could transform how we identify the disease and pave the way for increasingly early treatments.

When we think of Alzheimer's disease, we almost always imagine a person forgetting names, faces, or important events. In fact, memory loss is the most well-known characteristic of the disease. However, scientists have been discovering that the brain can begin to show changes many years before forgetfulness appears.

A new study reveals that one of the first signs may be much more subtle: difficulty in changing strategies or adapting behavior in the face of new situations, a process known as cognitive flexibility.

Cognitive flexibility is one of the brain's most important functions. It allows us to change plans when something stops working, learn new rules, adapt to unexpected changes, and abandon old habits to adopt better solutions.

This ability is used daily, from finding an alternative route when there's a traffic jam to learning a new computer program or modifying a routine. When this skill begins to fail, the person may repeatedly insist on the same behaviors, even when they no longer produce the desired results.

To investigate when these changes arise, the researchers used a genetically modified mouse model that develops alterations very similar to those observed in human Alzheimer's disease. The interesting aspect is that the animals were still young and did not present evident memory problems. The scientists subjected these mice to learning tests in which they needed to discover which action generated a reward.

After they correctly learned the task, the rules were reversed. The reward ceased to appear in the old behavior and became dependent on a new response. This type of experiment allows for the evaluation of cognitive flexibility, that is, the ability to abandon a learned behavior and quickly replace it with a more appropriate one.

At the same time, the researchers analyzed in detail the functioning of the brains of these animals. They recorded the electrical activity of individual neurons, measured the communication between different brain regions, and evaluated the quantity of important neurotransmitters involved in learning and decision-making.

The main focus was a connection between two fundamental areas: the prefrontal cortex, responsible for planning, self-control, and decision-making, and the striatum, a region involved in habit formation, action selection, and reward-based learning. Scientists also examined the behavior of acetylcholine, a neurotransmitter essential for attention, learning, and memory, whose reduction is one of the main characteristics of Alzheimer's disease.

The results showed that, even before any significant memory impairment, the animals already had great difficulty adapting their behavior to the new rules. This alteration was accompanied by hyperactivity of neurons in the prefrontal cortex, which began sending excessive signals to the striatum.

This excess of communication ended up reducing the activity of neurons that release acetylcholine, harming a brain system fundamental for flexible learning. In other words, the brain remained "stuck" in the old pattern of functioning, making it much more difficult to abandon strategies that were no longer useful.

To confirm that this circuit was indeed responsible for the behavioral changes, the researchers used a modern technique capable of selectively reducing the activity of this brain pathway.

After artificially decreasing this hyperactivity, something surprising occurred: acetylcholine levels increased again, excessive communication between brain regions was normalized, the accumulation of beta-amyloid protein in the brain decreased, and the mice recovered virtually all of their ability to learn new rules and modify their behavior.

This suggests that these brain changes are not only a consequence of the disease, but may directly participate in its initial development.

Although the study was conducted on animals and further studies in humans are still needed, the results point to an important shift in how we understand the onset of Alzheimer's disease. Instead of starting only with memory loss, the disease may first affect the circuits responsible for adaptation, decision-making, and mental flexibility.

If future research confirms this hypothesis, tests that assess these abilities could help identify the disease many years before the appearance of classic symptoms, opening a valuable window for early interventions and treatments capable of slowing its progression.

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Early-Stage Corticostriatal Hyperactivity Impairs Cognitive Flexibility Alongside Striatal Cholinergic Dysfunction in an Alzheimer’s Disease Model

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

Nature Communications. 26 June 2026DOI: 10.1038/s41467-026-74817-z

Abstract: 

Cognitive flexibility declines early in Alzheimer’s disease, yet the underlying circuit mechanisms remain unknown. Here, we report that young 5xFAD mice exhibit deficits in instrumental reversal learning prior to spatial memory impairment. This behavioral inflexibility is associated with abnormal neuronal reactivation in the medial prefrontal cortex and dorsomedial striatum. Electrophysiological recordings reveal that medial prefrontal cortex neurons are hyperexcitable and receive increased excitatory input. Furthermore, glutamatergic transmission from the medial prefrontal cortex to striatal direct-pathway medium spiny neurons is enhanced and coincides with strengthened inhibitory transmission onto striatal cholinergic interneurons, reduced spontaneous firing, and diminished striatal acetylcholine release. Critically, sustained chemogenetic inhibition of this corticostriatal circuit attenuates cortical amyloid accumulation, reduces glutamatergic transmission, and increases acetylcholine levels. This also rescues reversal learning deficits in 5xFAD mice. Here, we show that pathological corticostriatal hyperactivity contributes to early cognitive inflexibility in a mouse model of Alzheimer’s disease.