Alzheimer’s disease (AD) is a common neurodegenerative disorder, which is increasingly prevalent among the elderly. AD patients usually complain of memory impairment and serious decline of the daily living abilities. The aMCI is an intermediate state between normal cognitive aging and dementia, which is easily progressed to AD dementia. Thus, the effective therapy of AD is to be delivered once the diagnosis is made at the very early stages of AD, ideally in the phase of aMCI. The human apolipoprotein E (APOE) gene has three polymorphic alleles (E2, E3, and E4) [
1]. APOE-ε4 was confirmed to be related with sporadic AD risks by increasing the risk of developing AD and reducing the age of onset [
2]. Therefore, it is an urgent requirement in the field of cognitive neuroscience to reveal the underlying neurological mechanism of the conversion of aMCI to AD in the patients with APOE-ε4.
Although the cognition evaluation is simple, the accuracy of the diagnosis depends on the professional skills of the doctor and the collaboration of patients. On the other hand, MRI might be a promising strategy for early diagnosis of AD [
3]. MRI might be the best diagnosis method for AD by mapping both structures and functions of the human brain. Structurally, studies showed that brain atrophy in AD patients first appears in the medial temporal lobe (MTL), and then involves the parietal lobe, frontal lobe and occipital lobe, and finally the anterior cingulate cortex [
4,
5]. Consistent with these findings, evidence from our team has demonstrated the progressive alterations of brain structures during the progression to AD [
6]. Compared with APOE-ε4 non-carriers, the carriers exhibited greater medial temporal lobe atrophy [
7]. APOE-ε4 is an independent risk factor for the hypotrophy hippocampus in patients with AD and MCI [
8]. Decreased gray matter volume mainly restricts in the right brain area for aMCI-ε4 patients [
9]. Not the degree of atrophy, but the rate of atrophy in a certain region of brain demonstrate close relationship with the AD progression [
10]. The rate of hippocampal atrophy is suggested to be an early marker of incipient memory decline and dementia [
11]. The longitudinal study indicated that rate of volumetric loss was significantly greater among MCI-ε4 compared with non-carriers [
12]. Compared with structural MRI, diffusion tensor imaging (DTI) is a more sensitive method for detecting white matter damage [
13]. A short-term follow-up study showed that AD patients had lower fractional anisotropy (FA) than controls in the fornix and anterior portion of the cingulum bundle, and these FA values were positively correlated with cognitive score [
14]. The APOE-ɛ4 modulates white matter (WM) before clinical manifestations and cognitive impairment [
15]. The changes of white matter is accompanied with the cognitive function decline in APOE-ε4 carriers [
16]. Previous studies suggested that rs-fMRI is a potential functional biomarker for cognitive impairment. The aMCI subjects showed that posterior cingulate cortex/precuneus (PCC/PCu) hyper-functional connectivity was found at baseline, while a substantial decrease of these connections was observed at follow-up [
17]. Our team observed that the aMCI patients had decreased amplitude of low-frequency fluctuations (ALFF) values in the PCC/PCu, anterior medial prefrontal cortex (aMPFC), hippocampus/parahippocampal gyrus (PHG), basal ganglia, and prefrontal regions, and increased ALFF values mainly in several occipital and temporal regions [
18]. APOE-ε4 exerts an influence on brain function in patients with MCI. Using whole-brain pulsed arterial spin labeling (ASL) magnetic resonance imaging suggest that cognitive status and APOE genotype have interactive effects on cerebral blood flow (CBF) [
19]. MCI-ε4 patients demonstrated significantly increased CBF [
20]. However, deficits exist in these studies that using rs-fMRI to reveal the effect of APOE-ε4 on MCI patients.
For the purpose of early diagnosis, the researchers have been focusing on the aMCI window. Although previous studies provide important information for the conversion of aMCI to AD, they were based on the single modality neuroimaging analysis. Moreover, previous studies ignored one of the major factors that affects the course of the MCI converting to AD is the APOE-ε4. Thus, the purpose of the current trial is to longitudinally investigate the multi-modal (structural MRI, resting state-fMRI and diffusion tensor imaging) neuroimaging characteristics of aMCI-ε4 patients. We hope to provide scientific evidence for more effective prevention, diagnosis and treatment of AD.