CSF Proteomic Profiles Associated With White Matter Integrity in Cognitively Normal Older Adults With and Without Amyloid Pathology

BACKGROUND AND OBJECTIVES: Increasing evidence indicates a potential role of white matter (WM) damage in the onset and progression of Alzheimer disease (AD). However, the biological processes underlying in vivo WM imaging biomarkers remain unclear. We sought to determine the molecular signatures associated with WM integrity in cognitively normal individuals with and without amyloid pathology. METHODS: We selected older individuals without dementia (Clinical Dementia Rating <1) from the Alzheimer Centrum Amsterdam when they had diffusion tensor imaging (DTI) and CSF proteomic (untargeted tandem mass-mass spec) data available. Fractional anisotropy (FA) and mean diffusivity (MD) values were computed for the total WM and for 12 tracts of interest. We tested associations between protein levels (predictors) and both global and regional FA and MD values (outcomes) with linear models. Models further included an interaction between protein levels and amyloid status to evaluate specificity to disease. Gene-set and cell-type enrichment analyses were performed on proteins showing significant associations to characterize the underlying biological and cellular processes. RESULTS: A total of 96 participants were included in this study (mean age 67.82 ± 6.93 years; 45% male participants). A total of 234 protein levels (17.1%) were significantly associated with global DTI measures. Of these, 29.9% was unique for FA, and 29.9% for MD, while levels of the remaining proteins were associated with both measures (WM-generic proteins). WM-generic proteins were mostly enriched for pathways related to lipid metabolism and in endothelial cells, whereas proteins specific to FA were mostly related to blood coagulation and enriched in astrocytes and those specific to MD were mainly associated with processes related to actin filaments and enriched in oligodendrocytes. When looking at the interaction with amyloid status, both global FA and MD alterations in A+ participants were associated with biological processes of axonogenesis and synaptic plasticity. Regional analysis revealed distinct proteomic profiles associated with variations in regional FA and MD, with processes linked to synaptic plasticity specifically related to integrity of limbic fibers. DISCUSSION: Loss of WM integrity in the very early stages of AD seems to be related to alterations in biological processes associated with neuronal plasticity and oligodendrocyte integrity. Our findings provide new insights into the distinct biological mechanisms regulating WM integrity and its relationship with AD pathology.