Objective:  To evaluate sex-differences in cerebrospinal fluid (CSF) biomarkers, taking the potential modifying role of clinical disease stage and APOEe4 genotype into account.

Method: We included participants (n=1801) with probable AD dementia (n=937), Mild Cognitive Impairment (MCI; n=437) and Subjective Cognitive Decline (SCD; n=427). Main outcomes were CSF amyloid β1-42 (Aβ42), total tau (Tau) and tau phosphorylated at threonine 181 (pTau) levels. Age corrected three-way interactions between sex, disease stage (i.e. syndrome diagnosis at baseline) and APOEe4 were tested with linear regression analyses for each outcome measure. In case of significant interactions (p<0.05), sex-differences were further evaluated by stratifying analyses for clinical disease stage and APOEe4 genotype including age as a covariate.

Results: Three-way interactions were significant for Tau (p<0.001) and pTau (p<0.01), but not Aβ42. In APOE carriers, women showed higher (p)Tau concentrations than men in SCD (Cohens d (95%CI): Tau= 0.52 (0.19-0.84), p<.001; pTau=0.44 (0.11-0.77),p=.004 ) and MCI (Cohens d (95%CI): Tau= 0.54 (0.28-0.80), p<.001; pTau=0.52 (0.26-0.77), p<.001), but not in AD dementia. In APOE non-carriers, women showed higher (p)Tau concentrations in MCI (Cohens d (95%CI): Tau= 0.49 (0.17-0.80), p=.002; pTau=0.47 (0.16-0.78), p=.003) and AD dementia (Cohens d (95%CI): Tau= 0.42 (0.19-0.65), p<.001; pTau=0.38 (0.15-0.61), p=.002), but not in SCD.

Conclusions: Within APOEe4 carriers, sex-differences in CSF (p)Tau are more evident in early disease stages, whereas for APOEe4 non carriers sex-differences are more evident in advanced disease stages. These findings suggest that the effect of APOE e4 on sex-differences in CSF biomarkers depends on disease stage in AD.