APOE-E4 is associated with altered myelin content in preclinical AD

Background: TheAPOE ε4 allele is the major late-onset Alzheimer's disease (AD) susceptibility gene and is found inmore than half of patients with AD dementia. It has been hypothesized that risk factors associated with AD, including the APOE ε4 allele, may impact the myelinated white matter of the aging brain. In this work, we used a novel multi-component relaxometry technique to compare T1, T2, and myelin water fraction (MWF) measures in late-middle aged ε4 carriers and non-carriers. Methods: Participants from the Wisconsin Registry for Alzheimer's Prevention study were imaged on a GE MR750 3T scanner (N=73, 45-74 years, mean age = 62.22 ± 6.81 years). Multi-flip angle SPGR and bSSFP images were acquired and B1 inhomogeneities were corrected using an actual flip-angle imaging strategy. APOE allele status was characterized for each subject (45 non-carriers). Three-pool mcDESPOT processing was used to calculate T1, T2, andMWF maps. These parameter maps were transformed to a study specific template that was created using the Advanced Normalization Tools software package. A whole-brain GLM (FSL's randomize) to compare T1, T2, and MWF values between ε4 carriers and non-carriers, while correcting for age. Results: Overall, T2 times were found to increase and MWF was found to decrease with age in our subject sample (p<0.05, corrected). APOE ε4 carriers were observed to have lower (p<0.05, uncorrected) MWF in the right insular cortex and lateral temporal regions compared to non-carriers. APOE ε4 carriers were also found to have lower (p<0.05, uncorrected) T2values across widespread brain regions. Conclusions: Myelin alterations in AD are suspected, but understudied in the preclinical stage, and therefore we sought to compare T1, T2, and MWF between preclinical APOE ε4 carriers and non-carriers. Extensive differences in T2, and lower MWF in ε4 carriers compared to non-carriers in the insular cortex and lateral temporal lobe were found. These regions are known to show significant atrophy in AD, and our results suggest this atrophy may be due to myelin loss. Understanding the role of APOE on white matter microstructure is essential given that white matter abnormalities may precede amyloid-b plaques and neurofibrillary tangles. (Figure Presented).