Amnestic mild cognitive impairment (aMCI) is a transitional stage between normal aging and Alzheimer disease (AD), and is associated with an increased risk of AD. Many studies have shown that apolipoprotein E epsilon 4 (APOE ε4) genotype is a major genetic predictor of AD progression, especially in patients with aMCI. However, the application of APOE genotyping in the diagnosis of MCI progressing to AD is limited by its low sensitivity and specificity, which often leads to high false-positive rate. The aim of this study was to evaluate serum brain-derived neurotrophic factor (BDNF) and hippocampal volume as predictors of aMCI to AD transition in APOE ε4 genotype patients.A total of 178 subjects were diagnosed with aMCI. The patients with aMCI that progressed to AD within 2 years were included in the MCI-AD group (n = 86), those maintaining an aMCI diagnosis after 2 years were placed in the MCI-MCI group (n = 92), and neurologically healthy age-matched individuals were set as controls (n = 90). APOE genotypes were determined. Blood samples from all subjects were drawn at baseline, 12 months, and 24 months for serum BNDF assessments. Hippocampal delineations were monitored by magnetic resonance imaging.Compared to control group, aMCI-AD patients (the patients with aMCI that progressed to AD within 2 years) exhibited worse performance on cognitive and neuropsychological batteries. Meanwhile, we found that aMCI-AD patients were associated with abnormally low serum BDNF level and greater hippocampal volume loss than MCI-MCI patients (patients maintaining an aMCI diagnosis after 2 years). Moreover, patients with aMCI who were carriers of APOE ε4 showed a notable decrease in serum BDNF and a significant reduction in hippocampal volume, especially in those who progressed to AD.The present study demonstrates that aMCI that evolves into AD in patients with the APOE ε4 genotype may be predicted by hippocampal volume and serum BDNF.