Background: Sex-related differences significantly impact biomedical research outcomes, yet female subjects are often excluded due to concerns about variability from the estrous cycle. This study aimed to investigate the sex-dependent differences in behavioral phenotypes and amyloid-beta plaque accumulation in the APPswe/PS1dE9/Blg transgenic mouse model of Alzheimer’s disease. Methods: Male and female APPswe/PS1dE9/Blg transgenic mice and wild-type (WT) controls were assessed at 7.5 and 10 months of age. A comprehensive behavioral test battery was employed, including the Open Field, Novel Object Recognition, Y-Maze, and Barnes Maze tests. Histological analysis of amyloid plaque was carried out. Results: Female transgenic mice displayed delayed accumulation of Aβ plaques and milder cognitive decline compared with males. At 10 months, plaque load in females corresponded to that of 7.5-month-old males, demonstrating a temporal lag in pathology. Behavioral impairments correlated negatively with cortical plaque burden (r = −0.4964, p = 0.0181), supporting its role as a structural biomarker of disease progression. Conclusions: This study identifies distinct sex-dependent trajectories of behavioral and histomorphometric biomarkers in APPswe/PS1dE9/Blg mice. Females exhibit delayed amyloid pathology and cognitive decline, suggesting intrinsic neuroprotective mechanisms that modulate biomarker expression over time. These findings emphasize the necessity of integrating both sexes in preclinical biomarker research and support the use of morphometric endpoints as translationally relevant indicators of Alzheimer’s disease progression.