Alzheimer’s pathologic change indexed by CSF B‐amyloid42 associates with longitudinal alterations in myelin content

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AbstractBackgroundCSF Ab42 levels are associated with myelin content alterations in cognitively‐unimpaired adults (Dean et al, 2017), suggesting that myelin alterations may be an early feature of the Alzheimer’s disease (AD) pathophysiological cascade. We expand on these prior findings to examine longitudinal change in myelin content.Method98 cognitively‐unimpaired (Table 1) participants from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention underwent longitudinal multicomponent relaxometry (mcDESPOT) MRI, T2FLAIR MRI, and lumbar puncture (LP). All mcDESPOT MRI were normalized to MNI space using ANTs. White matter lesion volumes were extracted from T2FLAIR images using Lesion Segmentation Toolbox version 2.0.1 in SPM12. CSF was assayed for Ab42 using enzyme‐linked immunosorbent (INNOTEST) methods. 212 mcDESPOT‐derived myelin water fraction (MWF) maps, sensitive to myelin content, were generated for this analysis. MWF values were extracted from 6 white matter tracts affected in AD, and MWF values were averaged across regions to create a global index of myelin content at each timepoint. Linear mixed models were fit with longitudinal regional or global MWF as the outcome. All models included random intercepts and age‐related slopes with fixed effects of age (mean‐centered), sex, years between MRI and LP, white matter hyperintensity volume (log‐transformed) measured at first MRI, CSF Ab42 (mean‐centered) levels measured near first MRI, and Age*Ab42. All models were fitted in R (“lmer” package) version 3.6.0 and considered significant at unadjusted p < .05.ResultWe observed widespread age associations with myelin content such that older age associated with lower global myelin content (Figure 1) and lower CSF Ab42 was associated with lower global myelin content (Figure 2). There was no significant interaction of age and CSF Ab42 on global myelin content. However, an age*Ab42 effect in the cingulum and uncinate fasciculus indicated that older age and lower CSF Ab42 was associated with decreased myelin content (Figure 3).ConclusionWe previously found that lower CSF Ab42 was associated with lower myelin content among cognitively unimpaired adults. Here, we determined that for cognitively unimpaired middle‐aged adults, amyloid‐related longitudinal changes in myelin content also occur. Future studies will test if amyloid‐related myelin alterations may account for AD cognitive decline.