Sex differences in CSF biomarkers vary by Alzheimer disease stage and <i>APOE</i> ε4 genotype.

Abstract

To evaluate sex differences in CSF biomarkers, taking the potential modifying role of clinical disease stage and <i>APOE</i> ε4 genotype into account. 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 <i>APOE</i> ε4 were tested with linear regression analyses for each outcome measure. In case of significant interactions (<i>p</i> < 0.05), sex differences were further evaluated by stratifying analyses for clinical disease stage and <i>APOE</i> ε4 genotype, including age as a covariate. Three-way interactions were significant for t-Tau (<i>p</i> < 0.001) and p-Tau (<i>p</i> < 0.01) but not Aβ₄₂. In <i>APOE</i> 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], <i>p</i> < 0.001; p-Tau = 0.44 [0.11-0.77] <i>p</i> = 0.004) and MCI (Cohen d [95% CI]: t-Tau = 0.54 [0.28-0.80], <i>p</i> < 0.001; p-Tau = 0.52 [0.26-0.77], <i>p</i> < 0.001) but not in AD dementia. In <i>APOE</i> ε4 noncarriers, women showed higher p-Tau concentrations in MCI (Cohen d [95% CI]: t-Tau = 0.49 [0.17-0.80], <i>p</i> = 0.002; p-Tau = 0.47 [0.16-0.78], <i>p</i> = 0.003) and AD dementia (Cohen d [95% CI]: t-Tau = 0.42 [0.19-0.65], <i>p</i> < 0.001; p-Tau = 0.38 [0.15-0.61] <i>p</i> = 0.002) but not in SCD. Within <i>APOE</i> ε4 carriers, sex differences in CSF p-Tau are more evident in early disease stages, whereas for <i>APOE</i> ε4 noncarriers, sex differences are more evident in advanced disease stages. These findings suggest that the effect of <i>APOE</i> ε4 on sex differences in CSF biomarkers depends on disease stage in AD.