Abstract Alzheimer's disease and Down syndrome often exhibit close association and predictively share common genetic risk-factors. Presenilin-1 (PSEN-1) and Apolipoprotein E (APOE) genes are associated with early and late onset of Alzheimer's disease, respectively. Presenilin −1 is involved in faithful chromosomal segregation. A higher frequency of the APOE ε4 allele has been reported among young mothers giving birth to Down syndrome children. In this study, 170 Down syndrome patients, grouped according to maternal meiotic stage of nondisjunction and maternal age at conception, and their parents were genotyped for PSEN-1 intron-8 and APOE polymorphisms. The control group consisted of 186 mothers of karyotypically normal children. The frequencies of the PSEN-1 T allele and TT genotype, in the presence of the APOE ε4 allele, were significantly higher among young mothers (< 35 years) with meiosis II nondisjunction than in young control mothers (96.43% vs. 65.91% P = 0.0002 and 92.86% vs. 45.45% P < 0.0001 respectively) but not among mothers with meiosis I nondisjunction. We infer that the co-occurrence of the PSEN-1 T allele and the APOE ε4 allele associatively increases the risk of meiotic segregation error II among young women.