Background The high prevalence of Alzheimer’s dementia in females have long puzzled researchers in the field. Despite similar amyloid levels, females show higher load of neurofibrillary tangles (NFTs). Previous literature proposed that amyloid‐β (Aβ) and phosphorylated tau (p‐tau) synergism accelerates biomarker abnormalities. However, it remains to be answered whether this synergism is the driving force behind faster tau progression in females. The overarching goal of the study wa to investigate whether amyloid‐β aggregates differentially impose tau hyperphosphorylation and neurofibrillary tangles formation in a sex‐specific manner. Method In this longitudinal study, we assessed 287 participants from TRIAD cohort at McGill University Research Centre for Studies in Aging. Cerebral Aβ and tau deposition were assessed with positron emission tomography (PET) radiotracers 18FAZD4694 (18FNAV4694) and 18FMK6240, respectively. Cerebrospinal fluid (CSF) p‐tau181 and p‐tau217 were also measured (analysed at the Clinical Neurochemistry Laboratory at the University of Gothenburg, Sweden). Regression and voxel‐based models with interaction terms were used to evaluate baseline tau load and NFT accumulation rate as a function of sex and baseline biomarkers (Aβ and p‐tau). Result We identified sex difference in the relationships between CSF p‐tau, Aβ and NFT (Fig 1). Specifically, voxelwise analyses demonstrated that female presented stronger positive correlations between CSF p‐tau and AD core biomarkers (Aβ and NFT). Furthermore, we discovered that Aβ and CSF ptau181 interactively potentiated tau accumulation in females but not males (Fig 2, Table 1). Together, the present results support that Aβ load imposes higher tau aggregation in females. Conclusion Aβ‐dependent tau phosphorylation was the key driver for faster NFT accumulation observed in female.