Using a cross-sectional case-control study of amnestic-mild cognitive impairment (aMCI), we characterised the relationships among cognitive function, serum levels of angiotensin converting enzyme (ACE), brain activity, and ACE insertion or deletion (VD) polymorphism. Forty-eight patients with aMCI and 36 well-matched normal controls were assessed by a comprehensive battery of standardized neuropsychological tests. In addition, regional homogeneity (ReHo) approaches were used to analyze blood oxygen level-dependent functional magnetic resonance imaging data on the resting state in all subjects, and genotyping of the serum ACE was measured in aMCI patients. The D carriers with aMCI patients were found to have markedly higher serum ACE levels than I homozygote carriers. Importantly, compared with the carried I homozygote group of patients with aMCI, the D carriers of aMCI patients were significantly impaired in the AVLT-delayed recall and had decreased ReHo over the bilateral precuneus, left middle occipital gyrus, right inferior parietal lobe, and right angular gyrus, whilst increased ReHo was found mainly in the left medial frontal gyrus, right paracentral lobe, and right anterior cingulate cortex. The findings indicated that ACE genotype was associated with episodic memory, serum levels of ACE, and resting-state brain activity in aMCI patients, and the findings of cognitive function and brain activity further suggests that the ACED allele may have a specific role in semantic memory dysfunction and brain activity in aMCI. Published by Elsevier By.