APOE4 genotype associations with longitudinal change in hippocampal microstructure

Abstract Background Apolipoprotein E4 (APOE4) is a major risk factor for late‐onset Alzheimer’s disease (AD). Associations between APOE4 genotype and hippocampal atrophy have been reported, but few longitudinal studies have evaluated microstructural changes. There is evidence that risk conferred by APOE4 may be partially driven by factors such as cerebral iron burden, neuronal injury, and inflammation. Brain iron concentration and other microstructural properties may be detected in vivo using quantitative susceptibility mapping (QSM) and diffusion‐weighted MRI (dMRI). Here, we characterized the effects of APOE4 genotype on longitudinal changes in hippocampal QSM and dMRI microstructural measures in a population‐based sample of adults from the UK Biobank (UKB). Method 598 UKB participants of European ancestry (baseline age: 48‐78 years) with baseline and ∼2 year follow‐up brain MRI data were analyzed ( Figure 1A ). Four dMRI measures were derived from diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI; Figure 1B ). Median dMRI and QSM hippocampal measures were extracted and averaged across hemispheres. For comparison with microstructure, bilateral hippocampal volume was also estimated. Linear regressions were used to test associations between change in six hippocampal measures (FollowUp‐Baseline) and number of E4 alleles (e3e3/e3e4/e4e4) adjusting for the time‐interval between scans, baseline MRI measure, age, sex, age‐by‐sex, age2, age2‐by‐sex, education, and the first 4 genetic ancestry principal components. Age‐dependent effects were explored in post‐hoc analyses including a sensitivity analysis stratifying associations by age (< 65 or ≥ 65 yrs) and evaluation of APOE4‐by‐age interactions. Result Compared to e3e3 homozygotes, E4 carriers had significantly greater increases in MD and ISOVF and greater decreases in ND ( p 更多