Objectives In 2012, Kamboh and colleagues published a genome‐wide association study that identified the DCHS2 gene (rs1466662 T/A) influencing the age at onset of Alzheimer's disease (AD). We aimed to investigate if there is association between the DCHS2 gene and amnestic mild cognitive impairment (aMCI) and AD in a sample of the Brazilian population. Methods 143 controls, 79 aMCI and 299 AD patients were selected and submitted to the same protocol of tests. Genotyping was performed using the Real Time PCR Results Amnestic MCI patients showed a higher prevalence of AA than controls and a lower frequency of TT when compared with controls. We also stratified the sample according to the APOE ε4 status. No difference in DCHS2 genotype or allelic frequency occurred in the APOE ε4 allele carrier subgroup. Amnestic MCI patients showed a higher frequency of AA genotype and a lower frequency of TA and TT when compared with controls in APOE ε4 allele non‐carrier subgroup. The allelic distribution followed the same pattern. In AD group, we observed a significant difference with a higher A allelic frequency in AD in this subgroup. A multiple logistic regression demonstrated that in APOE ε4 non‐carriers, allele rs1466662 was associated to aMCI group. Different variables were associated with aMCI and AD according to APOE ε4 status in our sample. Low level of education was associated with AD, while diabetes mellitus type 2 was associated with aMCI. Copyright © 2016 John Wiley & Sons, Ltd. Conclusions Our findings suggest a possible role for DCHS2 gene in aMCI and AD.