Psychometric data from a cohort of 445 individuals with DS indicate that a single-point assessment of acquired mild cognitive impairment, which is expected for the majority of adults with DS, reveals two peaks for age‐related prevalence of impairment, suggesting that the risk for AD onset conferred by DS is moderated by other factors than trisomy [36], which could include the APOE ε4 allele or overexpression of regulatory factors encoded by HSA21 genes. This evidence concerns the gene APOE and Cognitive impairment.