Associations Among miR-33, APOE ε4, and Metabolic Markers in Down Syndrome Youth

Abstract Background Down syndrome (DS), caused by trisomy 21, is associated with intellectual disability and early metabolic and neurodegenerative alterations. Cholesterol homeostasis, regulated by microRNAs (miRNAs), miR-33 through ABCA1 and HDL cholesterol (HDL-c) biogenesis, influences cognitive decline linked to the APOE ε 4 isoform. Methods A cross-sectional study was conducted in 50 children and adolescents with Down syndrome (3–18 years) and matched controls, measuring miR-33a/b expression, lipid profiles, thyroid function, and APOE genotypes Statistical analyses included correlation and multivariate regression tests (p < 0.05). Results We found significantly reduced miR-33a/b levels and lower HDL-c in DS participants, alongside frequent thyroid and glycemic abnormalities. The presence of the APOE ε 4 allele correlated with decreased HDL-c in DS, suggesting a genetic-metabolic interaction contributing to neurological vulnerability. Conclusions These findings suggest that dysregulation of miR-33 cknand thyroid hormones, combined with APOE ε4 status, may underlie early metabolic disturbances and increased neurodegenerative risk in DS, highlighting potential targets for personalized preventive and therapeutic strategies. Registration : The study protocol was reviewed and approved by the Ethics Committee of the Faculty of Medicine, Autonomous University of Sinaloa, with registration number CEI-FM-PI-2023-009, in accordance with current ethical standards and regulations.