Sex differences in preclinical tauopathy models remain undercharacterized, yet they carry important implications for study design and translational validity. Presented at AD/PD 2026 in Copenhagen, this poster describes a longitudinal phenotyping study of male and female Tau[P301S] mice from 2 to 5.25 months of age. 

Our data reveal meaningful sex-specific differences: female Tau[P301S] mice display pronounced hyperactivity in automated home-cages and significant cognitive deficits at 4 months — including impaired spatial memory in the Morris Water Maze and selective discrimination learning deficits in the CognitionWall™ — while motor coordination impairments on the balance beam are comparable between sexes. These findings support inclusion of both sexes in preclinical cohorts when evaluating therapeutic candidates targeting tau pathology in Alzheimer’s disease and frontotemporal dementia (FTD). 

The homozygous Tau[P301S] (Thy1-TauP301S) mouse is one of the most widely used preclinical models for evaluating therapeutics targeting tauopathies. This model overexpresses human tau carrying the disease-associated P301S mutation, with tau pathology emerging from approximately 3 months and associated behavioral phenotypes developing around 4 months of age. 

Although previous studies suggest that male and female Tau[P301S] mice exhibit a similar onset of tau pathology, their phenotypic differences remain largely undercharacterized. In this study, we systematically evaluated both male and female Tau[P301S] mice from 2 to 5.25 months of age to capture potential sex-specific differences and improve the translational relevance of preclinical study design. 

Motor function was assessed using spontaneous behavior monitoring in automated PhenoTyper home-cages, rotarod, balance beam, grip strength, open field, and CatWalk gait analysis. Cognitive testing at 4 months included novel object recognition (NOR), PhenoTyper CognitionWall™, and Morris Water Maze. Blood was collected longitudinally for plasma neurofilament light chain (NfL) analysis, and organs collected for histopathology at termination. 

Female Tau[P301S] mice displayed stronger hyperactivity than males at younger ages. Both sexes developed comparable motor coordination impairments on the balance beam. Only female Tau[P301S] mice exhibited cognitive deficits at 4 months, including impaired spatial memory in the Morris Water Maze probe trial and selective discrimination learning deficits in the CognitionWall™. No significant sex differences were observed in the NOR test. 

These findings highlight the importance of including both sexes in preclinical tauopathy studies and support more representative cohort design for Alzheimer’s disease and frontotemporal dementia therapeutic evaluation.