Our results demonstrated that compared to female Tg mice, male P301S mice exhibited greater changes in weight loss, survival rate, grip strength test, stride length test, clasping, kyphosis, composite phenotype assessment, nest-building performance, tau phosphorylation at S202/T205, and astrocyte activation, which can be served as a more sensitive platform to assess tau-targeting therapeutic strategies for AD and related tauopathies. The gene discussed is MAPT; the disease is tauopathy.