MRI and fluid biomarkers reveal determinants of myelin and axonal loss with aging

OBJECTIVE: White matter damage is a feature of Alzheimer's disease, yet little is known about how facets of the Alzheimer's disease process relate to key features of white matter structure. We examined the association of Alzheimer's disease (Aß(42/40) ratio; pTau181), neuronal injury (NfL), and reactive astrogliosis (GFAP) biomarkers with MRI measures of myelin content and axonal density. METHODS: Among cognitively normal participants in the BLSA and GESTALT studies who received MRI measures of myelin content (defined by myelin water fraction [MWF]) and axonal density (defined by neurite density index [NDI]), we quantified plasma levels of Aβ(42), Aβ(40), pTau181, NfL, and GFAP. Linear regression models adjusted for demographic variables were used to relate these plasma biomarker levels to the MRI measures. RESULTS: In total, 119 participants received MWF imaging (age: 56 [SD 21]), of which 43 received NDI imaging (age: 50 [SD 18]). We found no relationship between plasma biomarkers and total brain myelin content. However, secondary analysis found higher GFAP was associated with lower MWF in the temporal lobes (ß = −0.13; P = 0.049). Further, higher levels of NfL (ß = −0.22; P = 0.009) and GFAP (ß = −0.29; P = 0.002) were associated with lower total brain axonal density. Secondary analyses found lower Aβ(42/40) ratio and higher pTau181 were also associated with lower axonal density, but only in select brain regions. These results remained similar after additionally adjusting for cardiovascular risk factors. INTERPRETATION: Plasma biomarkers of neuronal injury and astrogliosis are associated with reduced axonal density and region‐specific myelin content. Axonal loss and demyelination may co‐occur with neurodegeneration and astrogliosis ahead of clinically meaningful cognitive decline.