Background: Dementia with Lewy bodies (DLB) is more prevalent in men than in women. In addition, postmortem studies found sex differences in underlying pathology. It remains unclear whether these differences are also present antemortem in in vivo biomarkers, and whether sex differences translate to variability in clinical manifestation. The objective of this study was to evaluate sex differences in cerebrospinal fluid (CSF) biomarker concentrations (i.e., alpha-synuclein (α-syn), amyloid β1-42 (Aβ42), total tau (Tau), phosphorylated tau at threonine 181 (pTau)) and clinical characteristics in DLB. Methods: We included 223 DLB patients from the Amsterdam Dementia Cohort, of which 39 were women (17%, age 70 ± 6, MMSE 21 ± 6) and 184 men (83%, age 68 ± 7, MMSE 23 ± 4). Sex differences in CSF biomarker concentrations (i.e., α-syn, Aβ42, Tau, and pTau) were evaluated using age-corrected general linear models (GLM). In addition, we analyzed sex differences in core clinical features (i.e., visual hallucinations, parkinsonism, cognitive fluctuations, and REM sleep behavior disorder (RBD) and cognitive test scores using age-and education-adjusted GLM. Results: Women had lower CSF α-syn levels (F 1429 ± 164 vs M 1831 ± 60, p = 0.02) and CSF Aβ42 levels (F 712 ± 39 vs M 821 ± 18, p = 0.01) compared to men. There were no sex differences for (p) Tau concentrations (p > 0.05). Clinically, women were older, had a shorter duration of complaints (F 2 ± 1 vs M 4 ± 3, p < 0.001), more frequent hallucinations (58% vs 38%, p = 0.02), and scored lower on MMSE and a fluency task (MMSE, p = 0.02; animal fluency, p = 0.006). Men and women did not differ on fluctuations, RBD, parkinsonism, or other cognitive tests.

Objective:To evaluate sex-differences in cerebrospinal fluid (CSF) biomarkers, taking the potential modifying role of clinical disease stage and APOE-e4 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 (t-Tau) and tau phosphorylated at threonine 181 (p-Tau) levels. Age corrected three-way interactions between sex, disease stage (i.e. syndrome diagnosis at baseline) and APOE-e4 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-e4 genotype including age as a covariate.Results:Three-way interactions were significant for total Tau (p<0.001) and p-Tau (p<0.01), but not Aβ42. In APOE-e4 carriers, women showed higher (p)Tau concentrations than men in SCD (Cohens d (95%CI): t-Tau= 0.52 (0.19-0.84), p<.001; p-Tau=0.44 (0.11-0.77) p=.004 ) and MCI (Cohens d (95%CI): t-Tau= 0.54 (0.28-0.80), p<.001; p-Tau=0.52 (0.26-0.77),p<.001), but not in AD dementia. In APOE-e4 non-carriers, women showed higher (p)Tau concentrations in MCI (Cohens d (95%CI): t-Tau= 0.49 (0.17-0.80), p=.002; p-Tau=0.47 (0.16-0.78), p=.003) and AD dementia (Cohens d (95%CI): t-Tau= 0.42 (0.19-0.65), p<.001; p-Tau=0.38 (0.15-0.61) p=.002), but not in SCD.Conclusions:Within APOE-e4 carriers, sex-differences in CSF (p)Tau are more evident in early disease stages, whereas for APOE-e4 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.