Sex differences in CSF biomarkers vary by Alzheimer disease stage and APOE ε4 genotype

Objective To evaluate sex differences in CSF biomarkers, taking the potential modifying role of clinical disease stage and APOE ε4 genotype into account.

Method We included participants (n = 1,801) with probable Alzheimer disease (AD) dementia (n = 937), mild cognitive impairment (MCI; n = 437), and subjective cognitive decline (SCD; n = 427). Main outcomes were CSF β-amyloid_1–42 (Aβ₄₂), total tau (t-Tau), and tau phosphorylated at threonine 181 (p-Tau) levels. Age-corrected 3-way interactions between sex, disease stage (i.e., syndrome diagnosis at baseline), and APOE ε4 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 APOE ε4 genotype, including age as a covariate.

Results Three-way interactions were significant for t-Tau (p < 0.001) and p-Tau (p < 0.01) but not Aβ₄₂. In APOE ε4 carriers, women showed higher p-Tau concentrations than men in SCD (Cohen d [95% confidence interval]: t-Tau = 0.52 [0.19–0.84], p < 0.001; p-Tau = 0.44 [0.11–0.77] p = 0.004) and MCI (Cohen d [95% CI]: t-Tau = 0.54 [0.28–0.80], p < 0.001; p-Tau = 0.52 [0.26–0.77], p < 0.001) but not in AD dementia. In APOE ε4 noncarriers, women showed higher p-Tau concentrations in MCI (Cohen d [95% CI]: t-Tau = 0.49 [0.17–0.80], p = 0.002; p-Tau = 0.47 [0.16–0.78], p = 0.003) and AD dementia (Cohen d [95% CI]: t-Tau = 0.42 [0.19–0.65], p < 0.001; p-Tau = 0.38 [0.15–0.61] p = 0.002) but not in SCD.

Conclusions Within APOE ε4 carriers, sex differences in CSF p-Tau are more evident in early disease stages, whereas for APOE ε4 noncarriers, sex differences are more evident in advanced disease stages. These findings suggest that the effect of APOE ε4 on sex differences in CSF biomarkers depends on disease stage in AD.