Women have a two-fold increased risk of developing Alzheimer's disease (AD) than men, yet the underlying mechanisms of this sex-specific vulnerability remain unknown. Here, we aimed at determining in the 5XFAD mouse model whether deficits in prefrontal-dependent cognitive functions, which are impacted in the preclinical stages of AD, appear earlier in females, and whether these cognitive deficits are associated with alterations in the activity of prefrontal parvalbumin (PV)-neurons that regulate prefrontal circuits activity. We observed that 3.5-month-old 5XFAD females, but not males, display impairments in spatial short-term recognition memory, a function that relies on the integrity of the prefrontal cortex. Hippocampal-dependent cognitive functions were intact in both sexes. We then observed that 5XFAD females have more prefrontal PV neurons expressing the marker of chronic activity FosB; this was inversely correlated with prefrontal-dependent cognitive performances. Our findings show for the first time sex-specific, early deregulation of prefrontal PV neurons activity, which is associated with early appearance of prefrontal-dependent cognitive functions in 5XFAD females providing a potential novel mechanism to the increased risk to AD in females., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)