We investigated the effect of baseline Aβ, sex, and APOE on longitudinal tau accumulation in cerebrospinal fluid (CSF) in clinically normal older adults. Two hundred thirty-nine participants (aged 56–89 years, clinical dementia rating = 0) underwent serial CSF collection for Aβ1–42, total-tau (t-tau) and phospho-tau181P (p-tau). We used preprocessed data from fully automated Roche Elecsys immunoassays. A series of linear regressions were used to examine cross-sectional effects of Aβ1–42, sex, and APOEε4 on baseline CSF tau and linear mixed models for longitudinal changes in CSF tau. Cross-sectionally, CSF t-tau and p-tau were associated with abnormal Aβ1–42 and APOEε4 but not with sex. Longitudinally, low baseline CSF Aβ1–42 levels, but not APOEε4 or sex, predicted faster p-tau accumulation. The relationship between baseline CSF Aβ1–42 and tau accumulation was strongest in APOEε4 carriers, and particularly female carriers, relative to other groups. The current findings support an association between baseline CSF Aβ1–42 and changes in CSF tau. Elevated risk in females, apparent only in carriers, reinforces findings of sex-related vulnerability in those with genetic predisposition for Alzheimer's disease. •No sex, sex-APOE, or sex-Aβ1–42 effects on baseline CSF tau in healthy older adults.•Accelerated CSF t-tau and p-tau change in older adults with lower CSF Aβ1–42.•Female APOEɛ4 carriers with low Aβ1–42 show trends of greater CSF tau change.