Apolipoprotein E (ApoE) mediates the regulation of lipid metabolism ¹ and is expressed throughout the brain ². Compared with ApoE2 and ApoE3 alleles, inheritance of ApoE4 allele is known to be associated with an increased risk of cognitive impairments, earlier age of onset of Alzheimer’s disease (AD) and reduced capacity for synaptic plasticity ^3-4. Since lipid and cholesterol are major components of myelin, it may affect myelination and white matter integrity ⁵. To understand the genetic influence of ApoE isoforms on the brain in the aging process, we conducted longitudinal diffusion tensor imaging (DTI) on transgenic mice expressing human ApoE3 (hApoE3) or hApoE4 gene to understand the microstructural changes in white matter.The study was approved by the IACUC of Biomedical Sciences Institutes, Singapore. Female mice carrying hApoE3 (n=6) and hApoE4 (n=11) were scanned at 12 and 18 months old. Wild-type (WT) mice (n=7 and n=5 at 12 and 18 months old, respectively) were also compared. Imaging was carried out on a 7T scanner (ClinScan, Bruker BioSpin, Germany) using 4 channel array coils. The DTI was acquired using a spin echo EPI sequence with 8 averages of 30 diffusion sensitizing directions, b=1500s/mm2, TR=10000ms, TE=40ms, voxel size=0.2x0.2x0.5mm3. After eddy current distortion and motion correction, fractional anisotropy (FA), radial diffusivity (Dr), parallel diffusivity (Dp) and mean diffusivity (MD) were obtained by weighted least squares tensor fitting ⁶. FA images were linearly registered to a mouse FA template ⁷ and averaged to create time-point specific templates. Individual FA maps were then nonlinearly registered to the corresponding time-point specific template using FSL ⁸. The transformation was applied to Dr, Dp, and MD maps. After Gaussian smoothing of 0.3 mm (FWHM), voxel-wise group comparison was conducted using SPM8 ⁹. T-tests were further conducted over regions of interest (ROI) defined based on the voxel-wise comparison, particularly in the anterior corpus callosum (cc). Compared to hApoE3, hApoE4 mice showed higher FA in part of the cc at 12m, which spread widely in almost the entire cc and external and internal capsules at 18m (Fig. 1a). WT consistently showed higher FA than hApoE3 mice at both time points (Fig. 1b). There was no FA difference between hApoE4 and WT in cc at 12m, but increased at 18m (Fig. 1c). ROI analysis of the anterior cc showed that FA decreased with age in all groups, with hApoE3 mice having significantly lower FA compared to WT and hApoE4 at both time points (Fig. 2). Dp and Dr of hApoE4 increased from 12 to 18m, while remained the same in hApoE3.The FA showed difference in major fiber bundles with a general trend of hApoE4 » WT > hApoE3. The age-dependent reduction of FA in all the animals was due to increased Dr which may be related to myelination change. The hApoE4 mice also show larger increase of Dp which may be associated with axonal structure. Many human studies reported lower FA in non-demented hApoE4 carriers. Similar to ours, another mouse study reported higher hApoE4 than WT though they didn’t have hApoE3 ¹⁰. We are in the process of analyzing data acquired at earlier time points to understand whether this is due to different ageing trajectory of the genotypes.