Combating cognitive decline starts early

When a close family member suddenly started asking the same question over and over, could no longer recognize the family car, and forgot where we were going almost as soon as I told him, I realized how different Alzheimer’s disease is from everyday forgetfulness. Alzheimer’s disease is a progressive brain disease that affects learning, memory, and reasoning. Because there is currently no cure, researchers are interested in interventions that may delay its progression. Scientists from Spain recently investigated how cognitive enrichment affects the brain and whether beginning this enrichment early in life can help combat cognitive decline.

How can scientists use laboratory animals to model cognitive decline similar to what happens in people with Alzheimer’s disease? Genes provide instructions that help our bodies function correctly, but sometimes those genes do not work as expected. People with abnormal functioning of the amyloid precursor protein, presenilin 1, or presenilin 2 genes have a higher likelihood of developing Alzheimer’s disease (1). The research team used rats with abnormal functioning in these same genes. These rats show many of the same brain changes seen in people with Alzheimer’s disease, including cognitive impairment. The researchers compared these rats to genetically normal rats without cognitive impairment.

A subset of rats from each group completed a cognitive enrichment task. In this task, rats received a sugar pellet when they correctly remembered which of two levers had extended into the box. Sometimes they only had to remember for 1 second, but other times they had to remember for as long as 30 seconds. This cognitive enrichment began in young adulthood and continued throughout the rats’ lives. Although the control rats did not receive cognitive enrichment, they were still given popsicle sticks and nesting material to play with.

Cognitive enrichment improved brain communication and memory

Different brain regions have distinct roles, but an important part of brain function depends on communication among regions. Like a well-choreographed dance, the system works best when all the dancers are coordinated. The researchers wanted to know how well the hippocampus and entorhinal cortex were communicating with the rest of the brain. These areas are negatively affected by Alzheimer’s disease and are important for working memory, which allows us to temporarily hold and use information while solving a problem. The rats were placed in a magnetic resonance imaging (MRI) machine that measured blood flow in different areas of the brain. More blood flow generally indicates more brain activity. The researchers then used mathematical analyses of the brain scans to determine how effectively these and other brain regions were working together.

The hippocampus and entorhinal cortex were not communicating well with the rest of the brain in rats with cognitive impairment. However, prolonged cognitive enrichment improved that communication in both males and females. These two brain regions were not the only ones that benefited from the intervention. Cognitive enrichment also improved global efficiency, or how easily information travels across different brain regions. Surprisingly, this effect was found only in males.

This finding piqued the researchers’ interest. Would improved communication between brain regions also improve the rats’ performance on a recognition memory task? To investigate this idea, rats had to distinguish between an object they had seen before and a new object. Rats with cognitive impairment had difficulty remembering which object they had encountered before. However, prolonged cognitive enrichment improved their ability to recognize the familiar object—again, only in males.

How does cognitive enrichment help?

These exciting results raised an important question: how does repeated cognitive enrichment improve brain communication and memory? And why were the benefits stronger in males? The researchers conducted several additional experiments to explore these questions.

First, they focused on neuroplasticity—the brain’s ability to strengthen or weaken connections between brain areas to support learning and memory (2). Unfortunately, neuroplasticity is disrupted by Alzheimer’s disease (2). The researchers found that rats with cognitive impairment had lower markers of neuroplasticity in brain areas that were not communicating well with the hippocampus and entorhinal cortex. Interestingly, females appeared to be protected from some of these negative effects, meaning these neuroplasticity markers were especially reduced in males. Cognitive enrichment restored some neuroplasticity markers in females, others in males, and some in both sexes. This female resilience, along with sex differences in which neuroplasticity markers were affected, may help explain why males showed stronger improvements in memory.

This finding led the researchers to examine microglia, immune cells in the brain that are important for neuroplasticity but can also become harmful under certain conditions (3). To determine whether microglia were in a harmful or beneficial state, the researchers examined their number and structure in the brains of cognitively impaired rats. These rats had fewer microglia, and the microglia they did have were more circular and less branched—a pattern consistent with a harmful inflammatory state. In contrast, cognitive enrichment increased the number of microglia and shifted their structure toward a more protective, anti-inflammatory state. Together, these experiments suggest that neuroplasticity and brain immune cells may help explain why cognitive enrichment improved memory in this study.

How will this research help future work on Alzheimer’s disease?

Is early cognitive enrichment only beneficial for males? While this study suggests that males may benefit more than females, it is too early to know for sure. In fact, a separate research group found that exercise improved memory in female rats with cognitive impairment, but not in males (4). Perhaps a combination of cognitive enrichment and exercise could benefit both sexes.

Alzheimer’s disease affects other forms of memory, too. Although this study focused on working memory, cognitive enrichment may improve another type of memory in females that was not measured here, such as spatial memory (5) or long-term memory (6). This paper highlights the complexity of Alzheimer’s disease and shows why it is important to study its progression and treatment in both females and males. With a growing aging population (7) and an expected increase in the number of people living with Alzheimer’s disease (8), research like this provides valuable insight into how we might slow cognitive decline.

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Image Credits

1. Cover photo: Canva
2. Infographic: OpenAI’s GPT 5.5
   

Additional References

1. Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. (2001) Physiol Rev. 81(2):741-66. doi: 10.1152/physrev.2001.81.2.741. PMID: 11274343.
2. Jahan I, Harun-Ur-Rashid M, Islam MA, Sharmin F, Al Jaouni SK, Kaki AM, Selim S. Neuronal plasticity and its role in Alzheimer’s disease and Parkinson’s disease. (2026) Neural Regen Res. 1;21(1):107-125. doi: 10.4103/NRR.NRR-D-24-01019. Epub 2024 Dec 16. PMID: 39688547; PMCID: PMC12094540.
3. Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer’s disease. (2018) J Cell Biol. Feb 5;217(2):459-472. doi: 10.1083/jcb.201709069. PMID: 2919646.
4. Hall SE, White ZJ, Rohn TT, Sudasinghe KH, Young ME. (2025) Exercise Improves Alzheimer’s Disease Phenotype in the TgF344-AD Rat, a Behavioral Time Course Study of Males and Females. Brain Sci. 15(6):631. doi: 10.3390/brainsci15060631. PMID: 40563801.
5. Cohen RM, Rezai-Zadeh K, Weitz TM, Rentsendorj A, Gate D, Spivak I, Bholat Y, Vasilevko V, Glabe CG, Breunig JJ, Rakic P, Davtyan H, Agadjanyan MG, Kepe V, Barrio JR, Bannykh S, Szekely CA, Pechnick RN, Town T. (2013) A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss. J Neurosci. 10;33(15):6245-56. doi: 10.1523/JNEUROSCI.3672-12.2013. PMID: 23575824
6. Bernaud VE, Bulen HL, Peña VL, Koebele SV, Northup-Smith SN, Manzo AA, Valenzuela Sanchez M, Opachich Z, Ruhland AM, Bimonte-Nelson HA. (2022) Task-dependent learning and memory deficits in the TgF344-AD rat model of Alzheimer’s disease: three key timepoints through middle-age in females. Sci Rep. 26;12(1):14596. doi: 10.1038/s41598-022-18415-1. PMID: 36028737
7. U.S. Census Bureau. National Population Projections (2023). https://www.census.gov/data/tables/2023/demo/popproj/2023‐summary‐tables.html
8. 2025 Alzheimer’s disease facts and figures. (2025) Alzheimers Dement. 21(4):e70235. doi: 10.1002/alz.70235.