Plasma phosphorylated tau‐217 exhibits sex‐specific prognostication of cognitive decline and brain atrophy in cognitively unimpaired adults

INTRODUCTION Accumulating evidence indicates disproportionate tau burden and tau‐related clinical progression in females. However, sex differences in plasma phosphorylated tau (p‐tau)217 prediction of subclinical cognitive and brain changes are unknown. METHODS We measured baseline plasma p‐tau217, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) in 163 participants (85 cognitively unimpaired [CU], 78 mild cognitive impairment [MCI]). In CU, linear mixed effects models examined sex differences in plasma biomarker prediction of longitudinal domain‐specific cognitive decline and brain atrophy. Cognitive models were repeated in MCI. RESULTS In CU females, baseline plasma p‐tau217 predicted verbal memory and medial temporal lobe trajectories such that trajectories significantly declined once p‐tau217 concentrations surpassed 0.053 pg/ml, a threshold that corresponded to early levels of cortical amyloid aggregation in secondary amyloid positron emission tomography analyses. CU males exhibited similar rates of cognitive decline and brain atrophy, but these trajectories were not dependent on plasma p‐tau217. Plasma GFAP and NfL exhibited similar female‐specific prediction of medial temporal lobe atrophy in CU. Plasma p‐tau217 exhibited comparable prediction of cognitive decline across sex in MCI. DISCUSSION Plasma p‐tau217 may capture earlier Alzheimer's disease (AD)‐related cognitive and brain atrophy hallmarks in females compared to males, possibly reflective of increased susceptibility to AD pathophysiology.