Relationship between APOE risk score and myelin in Alzheimer’s disease

Abstract

AbstractBackgroundPostmortem brain tissue analysis suggests that apolipoprotein E (APOE) ε4 is associated with lower brain myelination (Blanchard et al. 2022). However, in vivo evidence for this association is lacking. Here, we examined the relationship between APOE genotype and myelin content in the brain using multicomponent relaxometry (mcDESPOT) imaging and an APOE neuropathologic risk score (Deming et al, 2023).Methods121 cognitively unimpaired participants from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention completed at least one mcDESPOT MRI scan and were APOE genotyped. Myelin content was quantified using mcDESPOT‐derived myelin water fraction (MWF) maps. Amyloid positivity was determined using CSF Aβ42/Aβ40 or a [C‐11]PiB PET scan. Cutoffs for amyloid positivity was a CSF Aβ42/Aβ40 ratio of <0.046 (Van Hulle et al, 2020) or a global PiB DVR threshold >1.19 (Betthauser et al, 2020). MWF maps were registered to MNI space and smoothed with an 8mm FWHM kernel. We conducted a voxel‐wise regression analysis to determine the relationship between APOE risk and myelin content. Covariates included age, age difference between MRI and amyloid acquisition, gender, race, amyloid status, APOE by amyloid status interaction, and APOE by gender interaction. We followed up these analyses examining specific brain regions implicated in AD. All analyses were corrected for multiple comparisons.ResultsParticipant characteristics are shown in Table 1. Voxel‐wise analysis indicated that MWF was negatively associated with age in the superior longitudinal fasciculus and small regions of the brainstem (Figure 1). MWF was not associated with APOE risk, gender, or race. ROI analysis showed a significant APOE by amyloid status interaction in the left (β = 0.006, p‐value = 0.035) and right cingulum (β = ‐0.013, p‐value = 0.037; Table 2). However, these interactions did not survive FDR correction.ConclusionThese findings suggest that myelin content decreases with age. Although APOE ε4 increases risk for developing AD dementia, it was not associated with brain myelin content in this cohort. In preclinical participants harboring amyloid pathology, APOE risk may impact myelin content although our findings did not survive FDR correction. More research is needed to fully elucidate this relationship.