Analysis of 866 postmenopausal women found that higher serum estradiol levels were associated with lower baseline tau protein concentrations in cerebrospinal fluid and slower tau accumulation over time. The protective effects were particularly pronounced in women carrying the APOE ε4 genetic risk variant for Alzheimer's disease. Notably, estradiol showed no relationship with amyloid-beta plaques, suggesting hormone therapy's neuroprotective mechanisms may target tau-related rather than amyloid pathology. This distinction matters because tau tangles correlate more closely with cognitive decline than amyloid plaques in Alzheimer's progression. The findings align with observational studies showing reduced dementia risk among women using hormone replacement therapy, potentially explaining why timing matters—estrogen's benefits may stem from preventing tau accumulation rather than clearing existing amyloid deposits. However, this preprint awaits peer review, and the observational design cannot establish causation. The research represents confirmatory evidence supporting estrogen's neuroprotective role, though questions remain about optimal timing, dosing, and whether synthetic hormones could replicate endogenous estradiol's benefits for brain health.