Association of biological sex with clinical outcomes and biomarkers of Alzheimer’s disease in adults with Down syndrome
Authors: Iulita M Florencia , Bejanin Alexandre , Vilaplana Eduard , Carmona-Iragui Maria , Benejam Bessy , Videla Laura , Barroeta Isabel , Fernández Susana , Altuna Miren , Pegueroles Jordi , Montal Victor , Valldeneu Silvia , Giménez Sandra , González-Ortiz Sofía , Torres Soraya , El Bounasri El Bennadi Shaimaa , Padilla Concepcion , Rozalem Aranha Mateus , Estellés Teresa , Illán-Gala Ignacio , Belbin Olivia , Valle-Tamayo Natalia , Camacho Valle , Blessing Esther , Osorio Ricardo S , Videla Sebastian , Lehmann Sylvain , Holland Anthony J , Zetterberg Henrik , Blennow Kaj , Alcolea Daniel , Clarimón Jordi , Zaman Shahid H , Blesa Rafael , Lleó Alberto , Fortea Juan 
Published: March 2023

Abstract
The study of sex differences in Alzheimer’s disease is increasingly recognized as a key priority in research and clinical development. People with Down syndrome represent the largest population with a genetic link to Alzheimer’s disease (&gt;90% in the 7th decade). Yet, sex differences in Alzheimer’s disease manifestations have not been fully investigated in these individuals, who are key candidates for preventive clinical trials. In this double-centre, cross-sectional study of 628 adults with Down syndrome [46% female, 44.4 (34.6; 50.7) years], we compared Alzheimer’s disease prevalence, as well as cognitive outcomes and AT(N) biomarkers across age and sex. Participants were recruited from a population-based health plan in Barcelona, Spain, and from a convenience sample recruited via services for people with intellectual disabilities in England and Scotland. They underwent assessment with the Cambridge Cognitive Examination for Older Adults with Down Syndrome, modified cued recall test and determinations of brain amyloidosis (CSF amyloid-β 42 / 40 and amyloid-PET), tau pathology (CSF and plasma phosphorylated-tau181) and neurodegeneration biomarkers (CSF and plasma neurofilament light, total-tau, fluorodeoxyglucose-PET and MRI). We used within-group locally estimated scatterplot smoothing models to compare the trajectory of biomarker changes with age in females versus males, as well as by apolipoprotein ɛ4 carriership. Our work revealed similar prevalence, age at diagnosis and Cambridge Cognitive Examination for Older Adults with Down Syndrome scores by sex, but males showed lower modified cued recall test scores from age 45 compared with females. AT(N) biomarkers were comparable in males and females. When considering apolipoprotein ɛ4, female ɛ4 carriers showed a 3-year earlier age at diagnosis compared with female non-carriers (50.5 versus 53.2 years, P = 0.01). This difference was not seen in males (52.2 versus 52.5 years, P = 0.76). Our exploratory analyses considering sex, apolipoprotein ɛ4 and biomarkers showed that female ɛ4 carriers tended to exhibit lower CSF amyloid-β 42/amyloid-β 40 ratios and lower hippocampal volume compared with females without this allele, in line with the clinical difference. This work showed that biological sex did not influence clinical and biomarker profiles of Alzheimer’s disease in adults with Down syndrome. Consideration of apolipoprotein ɛ4 haplotype, particularly in females, may be important for clinical research and clinical trials that consider this population. Accounting for, reporting and publishing sex-stratified data, even when no sex differences are found, is central to helping advance precision medicine.