The Impact Of Apolipoprotein E Gene Polymorphism On The Cerebral Blood Flow In Patients With Mild Cognitive Impairment

Background:Alzheimer’s disease (AD) is a kind of neurodegenerative disorder which may be affected by a multi-gene and multiple factors, and the genetic factor accounts for 58% -79%. Apolipoprotein E (APOE) gene including APOEε2, APOEε3 and APOEε4 alleles is a AD risk gene, and APOEs4 is an important risk allele, whereas APOEε2 allele prevents people from AD. The pathogenesis and pathophysiological mechanisms of AD are not yet clear, and it’s difficult to reverse its course once been diagnosed.Obtaining cerebrospinal fluid is too difficult and PET application is limited in clinical,thus early diagnosis of AD is beyond achievement. A lot of studies have showed the impacts that mild cognitive impairment (MCI) and APOE have on the integrity of white matter fiber structure, skin thickness,the default network functional connectivity and AP deposition respectively from the points of structural and functional imaging using magnetic resonance.But brain metabolism and brain atrophy have been excluded from the AD diagnostic system in the second edition of IWG criteria in 2014. So the neuroimaging of AD is been argued again. In recent years, studies have found that cerebral blood flow of medial temporal lobe in MCI patients decreases comparing with those in healthy control group;The perfusion in the medial temporal lobe and the medial prefrontal increases in elder APOE ε4 carriers, But the effect that aMCI and APOE genotype have on cerebral perfusion is inconsistent, and less study is implemented to research their possible interactional effects. Arterial spin labeling (ASL) is a kind of magnetic resonance imaging which is easy to operate, non-invasive, non-ionizing radiation, repetitive nature, and it will help to explore the effects of APOE genotypes,aMCI and their interaction on the cerebral blood flow of the whole brain and its the correlation with cognitive function scores from another level. It may lay a foundation for the perfusion index of AD early diagnosis, disease severity, the following-up of AD and drug efficacy determination.Objective:We sought to investigate whether the apolipoprotein E (APOE) genotype specifically modulates cerebral blood flow in patients with amnesic mild cognitive impairment (aMCI) by using the pulsed arterial spin labeling (ASL) data.Methods:83 aMCI and 130 healthy controls (HC) underwent neuropsychological battery assessments, genetic screening and MRI scanning. ASL data preprocessing was carried out using the ASLtbx toolbox. A voxel-wise two-way ANOVA was performed to examine the main effects of diagnosis (aMCI vs. HC) and APOE genotype (s2 vs. ε3ε3 vs. ε4), and the diagnosis-by-genotype interactions on CBF maps. Then, we performed multiple linear regression analyses to examine the relationships between the neuropsychological test scores and CBF values in brain areas showing significant diagnosis-by-genotype interactions.Results:(1) Significant diagnosis-by-genotype interactions on CBF were observed in the left superior frontal gyrus, right anterior cingulate/medial prefrontal cortex and bilateral superior temporal gyrus. Post-hoc pairwise analysis revealed that compared with the ε2 carriers and ε3ε3 carriers, the ε4 carriers had significant higher CBF values in the above areas in the aMCI group, but there were no significant genotype differences in the HC group. (2) APOE ε4 carriers showed significant higher CBF values in the right anterior and posterior cingulate cortex than the ε2 carriers and ε3ε3 carriers respectively; (3) Compared with HC group, the aMCI group exhibited higher CBF values primarily in the left medial frontal gyrus. (4) We found that the CBF values in the right anterior cingulate/medial preforntal gyrus and superior temporal gyrus were negatively correlated with the similarity test scores (r=-0.453, P= 0.014; r=-0.497, P= 0.006).Conclusion:The APOE genotype has diaease-specific effects on cerebral perfusion; the increased CBF within the lateral prefrontal and temperal cortex in the aMCI ε4 carriers may be interpreted as reflecting greater cognitive "effect" by aMCI ε4 carriers to achieve the same level of performance as aMCI ε4 non-carriers (e.g., ε2 carriers and ε3ε3 carriers).