Background: The epsilon 4 allele of the Apolipoprotein E gene (APOE-epsilon 4) is a potent genetic risk factor for sporadic Alzheimer's disease (AD). Amnestic mild cognitive impairment (aMCI) is an intermediate state between normal cognitive aging and dementia, which is easy to convert to AD dementia. It is an urgent problem in the field of cognitive neuroscience to reveal the conversion of aMCI-epsilon 4 to AD. Based on our preliminary work, we will study the neuroimaging features in the special group of aMCI-epsilon 4 with multi-modality magnetic resonance imaging (structural MRI, resting state-fMRI and diffusion tensor imaging) longitudinally. Methods/Design: In this study, 200 right-handed subjects who are diagnosed as aMCI with APOE-epsilon 4 will be recruited at the memory clinic of the Neurology Department, XuanWu Hospital, Capital Medical University, Beijing, China. All subjects will undergo the neuroimaging and neuropsychological evaluation at a 1 year-interval for 3 years. The primary outcome measures are 1) Microstructural alterations revealed with multimodal MRI scans including structure MRI (sMRI), resting state functional MRI (rs-fMRI), diffusion tensor imaging (DTI); 2) neuropsychological evaluation, including the World Health Organization-University of California-LosAngeles Auditory Verbal Learning Test (WHO-UCLA AVLT), Addenbrook's cognitive examination-revised (ACE-R), mini-mental state examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating scale (CDR). Discussion: This study is to find out the neuroimaging biomarker and the changing laws of the marker during the progress of aMCI-epsilon 4 to AD, and the final purpose is to provide scientific evidence for new prevention, diagnosis and treatment of AD.