Historically, sex differences in biology were underexplored due to the exclusion of females as research subjects, creating a gap in women’s health knowledge only recently addressed. Sex differences are now recognized in prevalence, risk, and treatment response across many diseases. The McGill-R-Thy1-hAPP transgenic (Tg) rat, carrying two familial Alzheimer’s disease (AD) mutations (Swe/Ind), is a valuable model to study sex differences. Wt and hemizygous (Tg+/-) rats of both sexes were evaluated at 4 and 12 months (mo). All groups showed open-field (OF) habituation. In inhibitory avoidance (IA), wt and Tg+/- females formed Long-Term Memory (LTM), but only wt females retained it; Tg+/- males did not form memory. In novel object recognition (NOR), only wt animals consolidated LTM. In novel object location (NOL), at 4 mo, wt and Tg+/- females discriminated the new location, whereas at 12 mo only wt females did so. Deficits in Tg+/- animals were more pronounced in males and worsened with age. Brain amyloid-β measurements showed higher load in males at 4 mo and greater sex heterogeneity at 12 mo. Our results show sexual dimorphism in learning and associative memory in middle-aged rats, especially hippocampus-dependent tasks. In the Tg model, it is most evident in aversive and spatial memory. Thus, incorporating sex as a biological factor will be essential to advance toward precision medicine in AD, as well as to achieve a more personalized and sustainable approach to patient care.