Abstract Females are disproportionately affected by dementia due to Alzheimer’s disease. Despite a similar Aβ load, females showed a higher load of neurofibrillary tangle as compared to males. Previous literature has proposed that Aβ and p-tau synergism accelerates tau tangle formation, yet the effect of biological sex in this process was overlooked. In this observational study, we examined longitudinal neuroimaging data from two cohorts, the TRIAD cohort in Canada, and the ADNI cohort in the United States. We assessed a total number of 457 participants across the clinical spectrum of AD. All participants underwent a baseline multimodal imaging assessment, including MRIs and PET scans with radioligands targeting Aβ plaques and tau tangles respectively. CSF data was also collected. Follow-up imaging assessments were conducted at the 1-year and 2-year intervals for the TRIAD cohort, and at the 1-year, 2-year and 4-year intervals for the ADNI cohort. The goal of the present study was to investigate the upstream pathological events contributing to the faster tau progression observed in females. Specifically, we assessed if the contribution of Aβ and p-tau synergism on accelerated tau tangle formation was modulated by the biological sex. We hypothesized that the cortical Aβ predisposes tau phosphorylation and tangle accumulation in a sex-specific manner. Findings from this study revealed that Aβ-positive females presented higher CSF p-tau181 concentrations as compared to Aβ-positive males in both TRIAD (P = 0.04, Cohen's d = 0.51) and ADNI cohort (P = 0.027, Cohen's d = 0.41). In addition, Aβ-positive females also presented faster NFT accumulation compared to their male counterparts (TRIAD: P = 0.026, Cohen's d = 0.52; ADNI: P = 0.049, Cohen's d = 1.14). Finally, findings from this present study unveiled that the triple interaction between female sex, Aβ and CSF p-tau181 is a significant predictor of accelerated tau accumulation at the 2-year follow-up visit (Braak I: P = 0.0067, t = 2.81; Braak III: P = 0.017, t = 2.45; Braak IV: P = 0.002, t = 3.17; Braak V: P = 0.006, t = 2.88; Braak VI: P = 0.0049, t = 2.93). Overall, this study reported a sex-specific modulation of cortical Aβ on tau phosphorylation, and this consequently facilitates faster NFT progression seen in female individuals over time. This presents important clinical implications suggesting the early intervention targeting Aβ plaques and tau phosphorylation may be promising therapeutic strategies for females to prevent further accumulation and spread of tau aggregates.