Women have about a two-thirds more likely to develop Alzheimer’s Disease (AD) than men. However, recent longitudinal findings suggest sex-dependent differences in brain resilience: a study on “SuperAgers”—individuals aged 80 or older who maintain exceptional memory performance—reported that 74% of such individuals are women. Interestingly, some SuperAgers exhibit traditional pathological hallmarks of AD such as amyloid-β and tau accumulation yet remain cognitively unimpaired. These findings indicate that factors beyond traditional biomarkers may contribute to sex-dependent resilience against cognitive decline in AD.

My aim is to determine whether the variation of neuronal response to repetitive stimuli (defined here as neuronal volatility) plays a role in sex-dependent brain resilience to cognitive impairment in AD. Although a large population of neurons is available to encode each stimulus, only a dynamic subset is recruited on any given trial, and the composition of this active subset varies considerably across stimulus repetitions. This volatility in neuron’s responsiveness is thought to arise from ongoing, activity-independent synaptic remodeling and may serve as a hallmark of healthy, adaptive network function. My guiding hypothesis is that sex-dependent attenuation in neuronal functional volatility represents an early indicator of network dysfunction in a transgenic Fischer 344 rat model of AD. Understanding sex-dependent patterns in neuronal volatility could offer critical insights into mechanisms of cognitive resilience and identify a novel, pre-symptomatic biomarker for AD. This might lead to sex-specific early stratification of AD patients based on their susceptibility to dementia, resulting in more personalized and effective treatments to prevent the progression of dementia.