Sex-specific modulation of amyloid- on tau phosphorylation underlies faster tangle accumulation in females

Females are disproportionately affected by dementia due to Alzheimer's disease. Despite a similar amyloid-beta (A beta) load, a higher load of neurofibrillary tangles (NFTs) is seen in females than males. Previous literature has proposed that A beta and phosphorylated-tau (p-tau) synergism accelerates tau tangle formation, yet the effect of biological sex in this process has been overlooked. In this observational study, we examined longitudinal neuroimaging data from the TRIAD and ADNI cohorts from Canada and USA, respectively. We assessed 457 participants across the clinical spectrum of Alzheimer's disease. All participants underwent baseline multimodal imaging assessment, including MRI and PET, with radioligands targeting A beta plaques and tau tangles, respectively. CSF data were also collected. Follow-up imaging assessments were conducted at 1- and 2-year intervals for the TRIAD cohort and 1-, 2- and 4-year intervals for the ADNI cohort. The upstream pathological events contributing to faster tau progression in females were investigated-specifically, whether the contribution of A beta and p-tau synergism to accelerated tau tangle formation is modulated by biological sex. We hypothesized that cortical A beta predisposes tau phosphorylation and tangle accumulation in a sex-specific manner. Findings revealed that A beta -positive females presented higher CSF p-tau(181) concentrations compared with A beta -positive males in both the TRIAD (P = 0.04, Cohen's d = 0.51) and ADNI (P = 0.027, Cohen's d = 0.41) cohorts. In addition, A beta -positive females presented faster NFT accumulation compared with their male counterparts (TRIAD: P = 0.026, Cohen's d = 0.52; ADNI: P = 0.049, Cohen's d = 1.14). Finally, the triple interaction between female sex, A beta and CSF p-tau(181) was revealed as 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, we report sex-specific modulation of cortical A beta in tau phosphorylation, consequently facilitating faster NFT progression in female individuals over time. This presents important clinical implications and suggests that early intervention that targets A beta plaques and tau phosphorylation may be a promising therapeutic strategy in females to prevent the further accumulation and spread of tau aggregates. Why do female patients with Alzheimer's disease have more pronounced tau pathology compared to males? Wang et al. present evidence showing that amyloid modulates phosphorylation of tau in a sex-specific manner, contributing to faster neurofibrillary tau accumulation in females.