SAT-149 Sex Steroids And Cognition In Patients With Down Syndrome

Abstract Disclosure: A. Jacobs: None. L. Del Hoyo: None. T. Todisco: None. O. Salamin: None. J. Fortea: None. N. Pitteloud: None. Introduction: Down syndrome (DS), the most common genetic cause of intellectual disability (ID), confers a high risk of early-onset Alzheimer’s disease (AD). Emerging evidence suggests that pulsatile GnRH therapy may improve neurocognition in DS, yet the role of sex steroid hormones in ID level and AD progression remains unclear. The objective of the study is to analyze whether lower sex steroid concentrations correlate with ID level and AD diagnosis. Methods: In this cross-sectional study, 150 adults with DS (95 males, 55 females) were included, with mild to profound ID levels as assessed with DSM-5 criteria, at different AD stages. The Cambridge Cognitive Examination modified for use in people with Down syndrome (CAMCOG-DS) was used to measure cognitive performance in participants with mild to moderate ID, able to complete the test in a meaningful way. Serum sex steroids were measured using liquid chromatography-mass spectrometry. Results: Median age and BMI were similar across sexes (48.6 years; ∼28 kg/m²). Most participants had moderate ID (61% of men, 54% of women), followed by mild (23% of men, 33% of women), severe ID (16% of men, 9% of women) and profound ID (0% of men, 4% in women). AD dementia was diagnosed in 28% of men and 27% of women; an additional 24% of men and 31% of women had prodromal AD, while 38% of men and 31% of women were asymptomatic. CAMCOG-DS scores and serum DHEA, cortisol, androstenedione levels did not differ significantly between sexes. Testosterone levels were significantly higher in men (p<0.0001) but remained below typical reference values for adult men (median 11.1 nmol/L, IQR 7.4-16.0). In multivariable analyses, low testosterone levels in men were independently associated with moderate/severe ID (p=0.03), but not with AD diagnosis (p=0.22), after adjustment for age and BMI. Discussion and Conclusion: In adults with DS, testosterone levels in men were lower than population norms and independently associated with greater ID level, but not AD. These findings align with prior reports suggesting a neurocognitive role for GnRH therapy to improve neurocognition in DS men and support further investigation into the gonadal axis as a therapeutic target in DS. Presentation: Saturday, July 12, 2025