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Despite a similar amyloid-\u03b2 (A\u03b2) load, a higher load of neurofibrillary tangles (NFTs) is seen in females than males. Previous literature has proposed that A\u03b2 and phosphorylated-tau (p-tau) synergism accelerates tau tangle formation, yet the effect of biological sex in this process has been overlooked.<\/jats:p>\n                  <jats:p>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\u03b2 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.<\/jats:p>\n                  <jats:p>The upstream pathological events contributing to faster tau progression in females were investigated\u2014specifically, whether the contribution of A\u03b2 and p-tau synergism to accelerated tau tangle formation is modulated by biological sex. We hypothesized that cortical A\u03b2 predisposes tau phosphorylation and tangle accumulation in a sex-specific manner.<\/jats:p>\n                  <jats:p>Findings revealed that A\u03b2-positive females presented higher CSF p-tau181 concentrations compared with A\u03b2-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\u03b2-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\u03b2 and CSF p-tau181 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).<\/jats:p>\n                  <jats:p>Overall, we report sex-specific modulation of cortical A\u03b2 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\u03b2 plaques and tau phosphorylation may be a promising therapeutic strategy in females to prevent the further accumulation and spread of tau aggregates.<\/jats:p>","DOI":"10.1093\/brain\/awad397","type":"journal-article","created":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T18:24:41Z","timestamp":1700591081000},"page":"1497-1510","source":"Crossref","is-referenced-by-count":50,"title":["Sex-specific modulation of amyloid-\u03b2 on tau phosphorylation underlies faster tangle accumulation in females"],"prefix":"10.1093","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9130-5461","authenticated-orcid":false,"given":"Yi-Ting","family":"Wang","sequence":"first","affiliation":[{"name":"Translational Neuroimaging Laboratory, McGill Research Centre for Studies in Aging , Montreal, QC H4H 1R3 ,","place":["Canada"]},{"name":"Department of Neurology and Neurosurgery, 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