Biomarkers.

Background: Virtually all adults with Down Syndrome(DS) show Alzheimer's disease(AD)-related pathologic change by the age of 40 years. While sex differences in Aβ-dependent tauopathy are apparent during early sporadic AD, sex differences in the DS population remain under-investigated. Moreover, menopause onset occurs earlier in the DS population (45 years), and it remains unknown whether menopause status and hormone therapy(HT) exposure influences Aβ-dependent tauopathy in women with DS. In a cognitively unimpaired DS population, we investigated cross-sectional associations between Aβ and regional tau as a function of sex, menopause-status, and HT-exposure.

Method: 115 cognitively unimpaired individuals from the Alzheimer Biomarkers Consortium-Down Syndrome (Mean Age 37.9; 56 women [48%]; 13 APOEε4 carriers [11%];Table 1) underwent Pittsburgh Compound-B/Florbetapir(Aβ-PET) and Flortaucipir(tau-PET). Global Aβ was transformed to centiloid scale. 10 (20.6%) women self-reported as being menopausal. 11 (20.4%) women reported HT exposure. Four a priori tau regions previously demonstrating sex differences in sporadic AD were selected (entorhinal cortex, inferior temporal gyrus, fusiform gyrus, lateral occipital cortex). Linear regressions (covarying age) examined the sex*Aβ interaction for each tau-PET outcome. Similar models were examined in the subset of women, investigating menopause-status[not menopausal/menopausal]*Aβ and HT*Aβ interactions. Exploratory whole-brain vertex-wise tau-PET analyses were conducted with sex*Aβ and menopause*Aβ (modelled-separately) and a FDR threshold p=0.05.

Result: The sex*Aβ interaction showed a trend level association with tau-PET, suggesting men exhibit elevated posterior-temporal and lateral-occipital tau with higher Aβ, relative to women (Figure 1). The menopause status*Aβ analyses indicated that menopausal women with higher Aβ exhibit significantly elevated temporal, lateral occipital and parietal tau (Figure 2). Sensitivity analyses covarying an age*Aβ interaction suggested that the menopause-tau association was not driven solely by advancing age. Finally, higher temporal fusiform(p=0.020) and lateral occipital(p=0.004) tau-PET signal was observed in women with HT-exposure at higher levels of Aβ, relative to women without exposure.

Conclusion: Sex differences in the Aβ-tau association were marginal and require additional investigation. Menopause-status and HT-exposure influenced the association between Aβ and regional tau. While our results lack statistical power and should be replicated in larger DS populations, the findings suggest that sex-specific biomarker profiles in DS may help determine sex-specific pathways and hormonal mechanisms underlying increased risk of dementia.