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Background: Women exhibit higher tau pathology than men on central nervous system biomarkers of tau (e.g., PET imaging, CSF), particularly among APOE4 carriers and those with symptomatic Alzheimer's disease (AD). The purpose of this study was to determine if these sex differences were detectible using a novel plasma biomarker of tau pathology in non‐demented adults. Method: Plasma phosphorylated‐tau181 (P‐tau181)was assayed (Quanterix Simoa) in 132 cognitively unimpaired individuals (CU; 61 men, 71 women) and 43 individuals with mild cognitive impairment (MCI; 28 men, 15 women)who underwent florbetapir PET imaging. Controlling for age, linear regression examined plasma P‐tau181 as a function of sex, diagnosis, and their interaction. To determine whether sex‐differences in plasma P‐tau181 were influenced by amyloid pathology, results were compared before and after accounting for APOE4 genotype and Aβ‐PET positivity. Result: The sex by diagnosis interaction on plasma P‐tau181 was statistically significant (β = 0.19; p =.044), and this effect strengthened after covarying for APOE4 and Aβ‐PET (β = 0.23; p =.006). In MCI, women exhibited higher mean plasma P‐tau181 concentrations than men (3.59 pg/ml vs. 3.06 pg/ml; Cohen's d = 0.70; p = 0.032). In CU, women trended towards lower mean pTau concentrations than men (1.90 pg/ml vs. 2.28 pg/ml; Cohen's d = ‐0.33; p = 0.064). Conclusion: Results demonstrate greater tau burden, as measured with plasma P‐tau181, in women than men with MCI, consistent with prior studies using CSF P‐tau181 and tau‐PET imaging. In contrast, women without cognitive symptoms had the lowest levels of plasma P‐tau181, suggesting elevated plasma P‐tau181 may be particularly sensitive to cognitive impairment in women. Statistical adjustment for APOE4 and Aβ‐PET did not account for, but instead magnified, the sex by diagnosis interaction on plasma P‐tau181, suggesting factors beyond amyloid (e.g., sex hormones) may mediate diagnostic‐dependent patterns of sex‐differences in plasma P‐tau181 and could help clarify mechanisms that predispose women to tau pathology. [ABSTRACT FROM AUTHOR]