Alzheimer’s disease is a leading cause of dementia and cognitive decline. Currently, there is no treatment for Alzheimer’s disease but there are treatment strategies and lifestyle factors that to some extent, slow the progression of the disease. In our previously funded research we used a mouse model of Alzheimer’s disease to investigate the impact of cognitive stimulation and environmental enrichment on changes in brain connectivity and the rate of cognitive decline. Our results indicated that daily cognitive stimulation, (in the form of daily learning episodes) can cause changes in the patterns of activity between different brain regions. Ultimately, the result is more efficient brain communication which corresponds to enhanced cognitive performance. When we examined underlying mechanisms, we found a particular region of the brain, the retrosplenial cortex, had a large change in patterns of connectivity that appear to relate to the activity of a population of inhibitory neurons. This is an intriguing finding because 1) there is known to be a decrease in the number of these neurons in Alzheimer’s disease that occurs to a greater degree in the female brain compared to the male brain. 2) Females tend to exhibit faster cognitive decline in Alzheimer’s disease. Given that disruption of this particular population of neurons appears to impair brain connectivity and cognitive ability, we predicted that this greater loss in females versus males might explain to some extent the sex differences in cognitive decline. Our current proposal is designed to directly test the impact of modulating the activity of this population of inhibitory neurons on cognitive decline in females versus males using transgenic mice that mimic the development of Alzheimer’s disease. Understanding sex differences in cognitive decline is a key step towards focused neuroprotective strategies to limit the impact of Alzheimer’s disease on cognitive function.